# AMR release; corpus: bio; section: dev; number of AMRs: 500 (generated on Mon Mar 14, 2016 at 21:45:05) # ::id a_pmid_2488_5690.10 ::date 2015-06-08T05:01:37 ::annotator SDL-AMR-09 ::preferred # ::snt Genetic targeting of mutant BRAF resulted in restoration of sensitivity to serum starvation-induced apoptosis and efficiently inhibited cell proliferation in the absence of growth factors. # ::save-date Wed Feb 24, 2016 ::file a_pmid_2488_5690_10.txt (a / and :op1 (r2 / result-01 :ARG1 (t / target-01 :ARG1 (g2 / gene :wiki "BRAF_(gene)" :name (n / name :op1 "BRAF") :ARG1-of (m / mutate-01)) :mod (g / gene)) :ARG2 (r / restore-01 :ARG1 (s / sensitive-03 :ARG1 (a2 / apoptosis :ARG2-of (i / induce-01 :ARG0 (s2 / starve-01 :ARG2 (s3 / serum))))))) :op2 (i2 / inhibit-01 :ARG0 t :ARG1 (p / proliferate-01 :ARG0 (c / cell) :condition (a3 / absent-01 :ARG1 (g3 / growth-factor))) :ARG2-of (e / efficient-01) :condition a3)) # ::id a_pmid_2488_5690.11 ::date 2015-06-08T23:25:37 ::annotator SDL-AMR-09 ::preferred # ::snt Among tested agents, the B-Raf inhibitor dabrafenib was found to induce a strong V600E-dependent shift in cell viability. # ::save-date Sun Dec 20, 2015 ::file a_pmid_2488_5690_11.txt (f / find-01 :ARG1 (i2 / induce-01 :ARG0 (s / small-molecule :name (n3 / name :op1 "dabrafenib") :ARG0-of (i3 / inhibit-01 :ARG1 (e2 / enzyme :name (n2 / name :op1 "B-Raf"))) :ARG1-of (i4 / include-01 :ARG2 (a / agent :ARG1-of (t2 / test-01)))) :ARG2 (s2 / shift-01 :ARG1 (v / viability :mod (c / cell)) :ARG0-of (d / depend-01 :ARG1 (m / mutate-01 :value "V600E")) :mod (s3 / strong)))) # ::id a_pmid_2488_5690.12 ::date 2015-06-08T23:42:39 ::annotator SDL-AMR-09 ::preferred # ::snt In contrast, no differential sensitizing effect was observed for conventional chemotherapeutic agents (mitomycin C, oxaliplatin, paclitaxel, etoposide, 5-fluorouracil), nor for the targeted agents cetuximab, sorafenib, vemurafenib, RAF265, or for inhibition of PI3 kinase. # ::save-date Sun Jun 14, 2015 ::file a_pmid_2488_5690_12.txt (c / contrast-01 :ARG2 (o / observe-01 :ARG1 (a / affect-01 :polarity - :ARG0 (a2 / and :op1 (a3 / agent :mod (c2 / conventional) :mod (c3 / chemotherapy) :ARG1-of (m / mean-01 :ARG2 (a5 / and :op1 (s2 / small-molecule :name (n / name :op1 "mitomycin" :op2 "C")) :op2 (s3 / small-molecule :name (n2 / name :op1 "oxaliplatin")) :op3 (s4 / small-molecule :name (n3 / name :op1 "paclitaxel")) :op4 (s5 / small-molecule :name (n4 / name :op1 "etoposide")) :op5 (s6 / small-molecule :name (n5 / name :op1 "5-fluorouracil"))))) :op2 (a4 / agent :ARG1-of (t / target-01) :ARG1-of (m2 / mean-01 :ARG2 (a6 / and :op1 (s7 / small-molecule :name (n6 / name :op1 "cetuximab")) :op2 (s8 / small-molecule :name (n7 / name :op1 "sorafenib")) :op3 (s9 / small-molecule :name (n8 / name :op1 "vemurafenib")) :op4 (s10 / small-molecule :name (n9 / name :op1 "RAF265"))))) :op3 (i / inhibit-01 :ARG1 (k / kinase :name (n10 / name :op1 "PI3")))) :ARG2 (s / sensitize-01) :ARG1-of (d / differ-02)))) # ::id a_pmid_2488_5690.13 ::date 2015-06-08T23:54:05 ::annotator SDL-AMR-09 ::preferred # ::snt Treatment with dabrafenib efficiently inhibited phosphorylation of the B-Raf downstream targets Mek 1/2 and Erk 1/2. # ::save-date Sun Jan 3, 2016 ::file a_pmid_2488_5690_13.txt (i / inhibit-01 :ARG0 (t / treat-04 :ARG2 (s / small-molecule :name (n5 / name :op1 "dabrafenib"))) :ARG1 (p2 / phosphorylate-01 :ARG1 (a / and :op1 (e3 / enzyme :name (n3 / name :op1 "Mek1/2")) :op2 (e4 / enzyme :name (n4 / name :op1 "Erk1/2")) :ARG1-of (t2 / target-01 :ARG0 (e2 / enzyme :name (n2 / name :op1 "B-Raf"))) :direction (d / downstream))) :ARG2-of (e / efficient-01 :ARG1 t)) # ::id a_pmid_2488_5690.33 ::date 2015-06-09T00:01:34 ::annotator SDL-AMR-09 ::preferred # ::snt BRAF targeting in RKO # ::save-date Tue Jun 9, 2015 ::file a_pmid_2488_5690_33.txt (t / target-01 :ARG1 (g / gene :name (n / name :op1 "BRAF")) :location (c / cell-line :name (n2 / name :op1 "RKO"))) # ::id a_pmid_2488_5690.34 ::date 2015-06-09T00:10:23 ::annotator SDL-AMR-09 ::preferred # ::snt It has been shown that B-RafV600E is sufficient to promote proliferation via Erk 1/2 signaling independently of exogenous growth factors and confers mechanisms to evade apoptosis [14-16]. # ::save-date Wed Feb 24, 2016 ::file a_pmid_2488_5690_34.txt (s / show-01 :ARG0 (p3 / publication :ARG1-of (c2 / cite-01 :ARG2 (v / value-interval :op1 14 :op2 16))) :ARG1 (a / and :op1 (s2 / suffice-01 :ARG0 (e2 / enzyme :name (n2 / name :op1 "B-Raf") :ARG1-of (m / mutate-01 :value "V600E")) :ARG1 (p / promote-01 :ARG0 e2 :ARG1 (p2 / proliferate-01 :instrument (s3 / signal-07 :ARG0 (e3 / enzyme :name (n3 / name :op1 "Erk1/2"))) :ARG0-of (d / depend-01 :polarity - :ARG1 (g / growth-factor :mod (e4 / exogenous)))))) :op2 (c / confer-02 :ARG0 e2 :ARG1 (m2 / mechanism :purpose (e5 / evade-01 :ARG1 (a2 / apoptosis)))))) # ::id a_pmid_2488_5690.35 ::date 2015-06-09T00:20:02 ::annotator SDL-AMR-09 ::preferred # ::snt However, these results are primarily based on non-quantitative RNA interference (RNAi) methods which are prone to artifacts in mammalian cells due to nonspecific defense mechanisms [17]. # ::save-date Mon Dec 21, 2015 ::file a_pmid_2488_5690_35.txt (c / contrast-01 :ARG2 (b / base-02 :ARG1 (t2 / thing :ARG2-of (r / result-01) :mod (t / this)) :ARG2 (m / method :ARG1-of (p / prone-01 :ARG2 (a / artifact) :location (c2 / cell :part-of (a2 / animal :name (n2 / name :op1 "Mammalia"))) :ARG1-of (c3 / cause-01 :ARG0 (m2 / mechanism :purpose (d / defend-01) :ARG1-of (s / specific-02 :polarity -)))) :mod (q / quantitative :polarity -) :manner-of (i / interfere-01 :ARG1 (n / nucleic-acid :name (n3 / name :op1 "RNA")))) :manner (p3 / primary)) :ARG1-of (d2 / describe-01 :ARG0 (p2 / publication :ARG1-of (c4 / cite-01 :ARG2 17)))) # ::id a_pmid_2488_5690.36 ::date 2015-06-09T00:25:38 ::annotator SDL-AMR-09 ::preferred # ::snt In contrast, somatic cell gene targeting enables quantitative knockouts of single alleles (Figure 1A) and the generation of endogenous models featuring well-defined genetic backgrounds [18]. # ::save-date Mon Dec 21, 2015 ::file a_pmid_2488_5690_36.txt (c / contrast-01 :ARG2 (e / enable-01 :ARG0 (t / target-01 :ARG1 (g / gene :part-of (c2 / cell :mod (s / somatic)))) :ARG1 (a / and :op1 (k / knock-out-03 :ARG1 (a2 / allele :ARG1-of (s2 / single-02)) :mod (q / quantity) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "1A"))) :op2 (g2 / generate-01 :ARG1 (m / model :mod (e2 / endogenous) :ARG0-of (f2 / feature-01 :ARG1 (b / background :mod (g3 / gene) :ARG1-of (d2 / define-01 :manner (w / well)))))))) :ARG1-of (d3 / describe-01 :ARG0 (p / publication :ARG1-of (c3 / cite-01 :ARG2 18)))) # ::id a_pmid_2488_5690.37 ::date 2015-06-09T00:31:02 ::annotator SDL-AMR-09 ::preferred # ::snt Utilizing this method, we have disrupted BRAF alleles in the colorectal cancer cell line RKO and established syngeneic clones which harbor a single BRAF allele of either wild-type or mutant genotype. # ::save-date Sun Jan 3, 2016 ::file a_pmid_2488_5690_37.txt (a / and :op1 (d2 / disrupt-01 :ARG0 (w2 / we) :ARG1 (a2 / allele :name (n2 / name :op1 "BRAF")) :location (c / cell-line :name (n3 / name :op1 "RKO") :mod (d3 / disease :wiki "Colorectal_cancer" :name (n6 / name :op1 "colorectal" :op2 "cancer")))) :op2 (e / establish-01 :ARG0 w2 :ARG1 (c2 / clone :mod (s / syngeneic) :ARG0-of (h2 / harbor-01 :ARG1 (o / or :op1 (a3 / allele :name (n4 / name :op1 "BRAF") :mod (w3 / wild-type) :ARG1-of (s2 / single-02)) :op2 (a4 / allele :name (n5 / name :op1 "BRAF") :ARG1-of (m / mutate-01) :ARG1-of s2))))) :manner (u / utilize-01 :ARG0 w2 :ARG1 (m2 / method :mod (t / this)))) # ::id a_pmid_2488_5690.38 ::date 2015-06-09T00:36:59 ::annotator SDL-AMR-09 ::preferred # ::snt Despite its near-diploid karyotype and MSI phenotype, the colorectal cancer cell line RKO carries a stable triplication of the BRAF gene locus (dup (7) (q21q36)) with one wild-type and two mutant alleles present in parental cells [13]. # ::save-date Sun Jan 3, 2016 ::file a_pmid_2488_5690_38.txt (c / carry-01 :ARG0 (c2 / cell-line :name (n2 / name :op1 "RKO") :mod (d / disease :wiki "Colorectal_cancer" :name (n / name :op1 "colorectal" :op2 "cancer"))) :ARG1 (t / triplicate-00 :ARG1 (l / locus :mod (g / gene :name (n3 / name :op1 "BRAF")) :ARG1-of (l2 / label-01 :ARG2 (s2 / string-entity :value "dup(7)(q21q36)"))) :ARG1-of (s / stable-03) :ARG1-of (m / mean-01 :ARG2 (b / be-located-at-91 :ARG1 (a / and :op1 (a2 / allele :quant 1 :mod (w / wild-type)) :op2 (a3 / allele :quant 2 :ARG1-of (m2 / mutate-01))) :ARG2 (c3 / cell :mod (p / parent))))) :concession (h2 / have-03 :ARG0 c2 :ARG1 (a4 / and :op1 (k / karyotype :ARG1-of (n4 / near-01 :ARG2 (d3 / diploid))) :op2 (p2 / phenotype :name (n5 / name :op1 "microsattelite" :op2 "instability")))) :ARG1-of (d2 / describe-01 :ARG0 (p3 / publication :ARG1-of (c4 / cite-01 :ARG2 13)))) # ::id a_pmid_2488_5690.39 ::date 2015-06-09T00:45:57 ::annotator SDL-AMR-09 ::preferred # ::snt This genotype was verified by DNA sequencing in RKO-E1, a subclone obtained from RKO that was found to be comparable to the parental cell line in terms of morphology and proliferation (Figure 1B and data not shown). # ::save-date Tue Feb 2, 2016 ::file a_pmid_2488_5690_39.txt (v / verify-01 :ARG1 (g / genotype :mod (t / this)) :location (c / cell-line :name (n2 / name :op1 "RKO-E1") :ARG3-of (s2 / subclone-01 :ARG1-of (o / obtain-01 :ARG2 (c2 / cell-line :name (n3 / name :op1 "RKO"))) :ARG1-of (c3 / compare-01 :ARG2 (c4 / cell-line :mod (p2 / parent)) :ARG1-of (p / possible-01) :topic (a / and :op1 (m / morphology) :op2 (p3 / proliferate-01)) :ARG1-of (f / find-01)))) :ARG1-of (d / describe-01 :ARG0 (a2 / and :op1 (f2 / figure :mod "1B") :op2 (d2 / data :ARG1-of (s / show-01 :polarity -)))) :manner (s3 / sequence-01 :ARG1 (n / nucleic-acid :wiki "DNA" :name (n4 / name :op1 "DNA")))) # ::id a_pmid_2488_5690.40 ::date 2015-06-09T04:41:16 ::annotator SDL-AMR-09 ::preferred # ::snt In the first targeting round, an oncogenic allele of BRAF exon 15 was recombined and deleted by somatic cell gene targeting to generate the cell clone RBOW (RKO-derived BRAFonc/wt/-). # ::save-date Mon Jan 4, 2016 ::file a_pmid_2488_5690_40.txt (a / and :op1 (r / recombine-01 :ARG1 (a2 / allele :mod (o2 / oncogenic) :mod (e / exon :mod 15 :part-of (g / gene :name (n / name :op1 "BRAF"))))) :op2 (d / delete-01 :ARG1 a2) :time (r2 / round-05 :ARG1 (t / target-01) :ord (o / ordinal-entity :value 1)) :instrument (t2 / target-01 :ARG1 (g4 / gene :part-of (c / cell :mod (s / somatic)))) :purpose (g2 / generate-01 :ARG1 (c2 / cell :name (n2 / name :op1 "RBOW") :ARG1-of (m / mean-01 :ARG2 (c4 / cell-line :location-of (g3 / gene :name (n3 / name :op1 "BRAF") :ARG1-of (d2 / derive-01 :ARG2 (c3 / cell-line :name (n4 / name :op1 "RKO"))) :ARG1-of (l / label-01 :ARG2 (s2 / string-entity :value "onc/wt/-"))))) :ARG1-of (c5 / clone-01)))) # ::id a_pmid_2488_5690.41 ::date 2015-06-09T04:51:08 ::annotator SDL-AMR-09 ::preferred # ::snt Subsequently, either wild-type or V600E-mutant B-Raf was disrupted by targeting a second allele in RBOW, yielding six BRAF-mutant and one wild-type clone from approximately 104 screened colonies. # ::save-date Wed Jan 13, 2016 ::file a_pmid_2488_5690_41.txt (d / disrupt-01 :ARG1 (o2 / or :op1 (e2 / enzyme :name (n2 / name :op1 "B-Raf") :mod (w / wild-type)) :op2 (e / enzyme :name (n / name :op1 "B-Raf") :ARG2-of (m / mutate-01 :value "V600E"))) :manner (t2 / target-01 :ARG1 (a2 / allele :part-of (c / cell :name (n3 / name :op1 "RBOW")) :mod (o / ordinal-entity :value 2))) :ARG0-of (y / yield-01 :ARG1 (a3 / and :op1 (c2 / clone :quant 6 :mod (m2 / mutate-01 :ARG1 (g / gene :name (n4 / name :op1 "BRAF")))) :op2 (c3 / clone :quant 1 :mod w)) :source (c4 / colony :ARG1-of (s2 / screen-01) :quant (a / approximately :op1 10000))) :time (s3 / subsequent)) # ::id a_pmid_2488_5690.42 ::date 2015-06-09T05:02:53 ::annotator SDL-AMR-09 ::preferred # ::snt Out of these double positive clones, BRAF knockout cell lines RBO-1 and RBO-2 (RKO-derived BRAFonc/-/- 1 and 2) as well as RBW-1 (RKO-derived BRAFwt/-/-) were established (Figure 1B). # ::save-date Sat Jan 16, 2016 ::file a_pmid_2488_5690_42.txt (e / establish-01 :ARG1 (a / and :op1 (c / cell-line :name (n / name :op1 "RBO-1") :ARG1-of (m / mean-01 :ARG2 (c3 / cell-line :mod 1 :location-of (g2 / gene :name (n4 / name :op1 "BRAF") :ARG1-of (d / derive-01 :ARG2 (c4 / cell-line :name (n5 / name :op1 "RKO"))) :ARG2-of (m2 / mutate-01 :mod "−/−") :ARG0-of (c9 / cause-01 :ARG1 (d4 / disease :wiki "Cancer" :name (n8 / name :op1 "cancer")))))) :location-of (k / knock-out-03 :ARG1 (g / gene :name (n3 / name :op1 "BRAF")))) :op2 (c2 / cell-line :name (n2 / name :op1 "RBO-2") :ARG1-of (m3 / mean-01 :ARG2 (c5 / cell-line :mod 2 :location-of g2)) :location-of k) :op3 (c6 / cell-line :name (n6 / name :op1 "RBW-1") :ARG1-of (m4 / mean-01 :ARG2 (c7 / cell-line :location-of (g3 / gene :name (n7 / name :op1 "BRAF") :ARG2-of (m5 / mutate-01 :mod "−/−") :ARG1-of d :mod (w / wild-type))))) :source (c8 / clone :mod (p / positive :mod (d2 / double)) :mod (t / this))) :ARG1-of (d3 / describe-01 :ARG0 (f / figure :mod "1B"))) # ::id a_pmid_2488_5690.43 ::date 2015-06-09T05:16:43 ::annotator SDL-AMR-09 ::preferred # ::snt The apparent counterselection against inactivation of B RafV600E might indicate the presence of an oncogene addiction for B-RafV600E as a cancer cell trait in RKO [19]. # ::save-date Wed Dec 9, 2015 ::file a_pmid_2488_5690_43.txt (p2 / possible-01 :ARG1 (i / indicate-01 :ARG0 (c / counterselect-00 :mod (a / apparent) :ARG0-of (c6 / counter-01 :ARG1 (a3 / activate-01 :polarity - :ARG1 (e3 / enzyme :name (n3 / name :op1 "B-Raf") :ARG2-of (m / mutate-01 :value "V600E"))))) :ARG1 (t / trait :domain (a2 / addict-01 :ARG1 e3 :ARG2 (o / oncogene)) :mod (c2 / cell :mod (d / disease :wiki "Cancer" :name (n / name :op1 "cancer"))) :location (c4 / cell-line :name (n5 / name :op1 "RKO")))) :ARG1-of (d2 / describe-01 :ARG0 (p3 / publication :ARG1-of (c5 / cite-01 :ARG2 19)))) # ::id a_pmid_2488_5690.44 ::date 2015-06-09T05:24:19 ::annotator SDL-AMR-09 ::preferred # ::snt For structural confirmation of the deleted alleles, DNA sequencing was performed and all genotypes were verified (Figure 1B). # ::save-date Tue Jan 19, 2016 ::file a_pmid_2488_5690_44.txt (a / and :op1 (p / perform-01 :ARG1 (s / sequence-01 :ARG1 (n / nucleic-acid :wiki "DNA" :name (n2 / name :op1 "DNA")))) :op2 (v / verify-01 :ARG1 (g / genotype :mod (a2 / all))) :purpose (c / confirm-01 :ARG1 (a3 / allele :ARG1-of (d / delete-01)) :mod (s2 / structure)) :ARG1-of (d3 / describe-01 :ARG0 (f / figure :mod "1B"))) # ::id a_pmid_2488_5690.45 ::date 2015-06-09T05:27:35 ::annotator SDL-AMR-09 ::preferred # ::snt Furthermore, all cells expressed BRAF protein at comparable levels (Figure 1C). # ::save-date Tue Jan 12, 2016 ::file a_pmid_2488_5690_45.txt (a / and :op2 (p2 / possible-01 :ARG1 (c2 / compare-01 :ARG1 (l / level :quant-of (e / express-03 :ARG2 (e2 / enzyme :wiki - :name (n / name :op1 "BRAF")) :ARG3 (c / cell :mod (a2 / all)))))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "1C"))) # ::id a_pmid_2488_5690.46 ::date 2015-06-09T05:31:04 ::annotator SDL-AMR-09 ::preferred # ::snt While the expression of Mek 1/2 and Erk 1/2 was independent of serum concentration and BRAF status, the phosphorylation of these effector kinases was constantly active in the BRAF-mutant clones but low in BRAF-wild-type cells (Figure 1C). # ::save-date Sun Jan 3, 2016 ::file a_pmid_2488_5690_46.txt (c / contrast-01 :ARG1 (c3 / contrast-01 :ARG1 (a3 / active :domain (p / phosphorylate-01 :ARG1 a) :manner (c4 / constant) :location (c5 / clone :location-of (g2 / gene :name (n4 / name :op1 "BRAF") :ARG2-of (m / mutate-01)))) :ARG2 (l / low-04 :ARG1 (c6 / cell :location-of (g3 / gene :name (n5 / name :op1 "BRAF") :mod (w / wild-type))) :ARG2 p)) :ARG2 (d / depend-01 :polarity - :ARG0 (e3 / express-03 :ARG2 (a / and :op1 (k / kinase :name (n / name :op1 "Mek1/2")) :op2 (k2 / kinase :name (n2 / name :op1 "Erk1/2")) :ARG0-of (e / effect-03))) :ARG1 (a2 / and :op1 (c2 / concentrate-02 :ARG1 (s / serum)) :op2 (s2 / status :mod (g / gene :name (n3 / name :op1 "BRAF"))))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "1C"))) # ::id a_pmid_2488_5690.47 ::date 2015-06-09T05:39:53 ::annotator SDL-AMR-09 ::preferred # ::snt This was found to be independent of the serum concentration, indicating that the phosphorylation status of Mek and Erk is dependent on mutant BRAF in RKO. # ::save-date Sat Jan 16, 2016 ::file a_pmid_2488_5690_47.txt (f / find-01 :ARG1 (d / depend-01 :polarity - :ARG0 (t / this) :ARG1 (c / concentrate-02 :ARG1 (s / serum)) :ARG0-of (i / indicate-01 :ARG1 (d2 / depend-01 :ARG0 (s2 / status :mod (p / phosphorylate-01 :ARG1 (a / and :op1 (e / enzyme :name (n / name :op1 "Mek")) :op2 (e2 / enzyme :name (n2 / name :op1 "Erk"))))) :ARG1 (g / gene :name (n3 / name :op1 "BRAF") :ARG2-of (m / mutate-01)) :location (c2 / cell-line :name (n4 / name :op1 "RKO")))))) # ::id a_pmid_2488_5690.48 ::date 2015-06-09T09:55:59 ::annotator SDL-AMR-09 ::preferred # ::snt Cell-biological phenotypes related to mutant BRAF # ::save-date Sun Jun 14, 2015 ::file a_pmid_2488_5690_48.txt (p / phenotype :mod (b / biology :mod (c / cell)) :ARG1-of (r / relate-01 :ARG2 (g / gene :name (n / name :op1 "BRAF") :ARG2-of (m / mutate-01)))) # ::id a_pmid_2488_5690.49 ::date 2015-06-09T09:59:07 ::annotator SDL-AMR-09 ::preferred # ::snt Under standard long-term cell culture conditions no differences in morphology or growth were observed between the cell clones (Figures 1B and 2A). # ::save-date Mon Dec 21, 2015 ::file a_pmid_2488_5690_49.txt (o / observe-01 :ARG1 (d / differ-02 :polarity - :ARG1 (c2 / cell :ARG1-of (c / clone-01)) :ARG3 (o2 / or :op1 (m / morphology) :op2 (g / grow-01))) :condition (c3 / condition :ARG1-of (s / standard-02) :mod (c4 / culture-01 :ARG1 (c5 / cell) :ARG1-of (l2 / long-03))) :ARG1-of (d2 / describe-01 :ARG0 (a / and :op1 (f / figure :mod "1B") :op2 (f2 / figure :mod "2A")))) # ::id a_pmid_2488_5690.50 ::date 2015-06-09T10:02:11 ::annotator SDL-AMR-09 ::preferred # ::snt Expectedly, decreased serum concentrations led to lower proliferation rates in these cells, but exponential growth was sustained under all applied conditions. # ::save-date Sun Jun 14, 2015 ::file a_pmid_2488_5690_50.txt (c3 / contrast-01 :ARG1 (l2 / lead-03 :ARG0 (c / concentrate-02 :ARG1 (s / serum) :ARG1-of (d / decrease-01)) :ARG2 (p / proliferate-01 :ARG2-of (l / low-04 :ARG1 (c2 / cell :mod (t / this)) :degree (m / more))) :ARG1-of (e2 / expect-01)) :ARG2 (s2 / sustain-01 :ARG1 (g / grow-01 :ARG2 (e / exponential)) :condition (c4 / condition :ARG1-of (a / apply-02) :mod (a2 / all)))) # ::id a_pmid_2488_5690.51 ::date 2015-06-09T10:05:20 ::annotator SDL-AMR-09 ::preferred # ::snt However, the withdrawal of serum resulted in the inhibition of cell growth of the wild-type cells RBW-1 (Figure 2B and C). # ::save-date Wed Jun 10, 2015 ::file a_pmid_2488_5690_51.txt (c / contrast-01 :ARG2 (r / result-01 :ARG1 (w / withdraw-01 :ARG1 (s / serum)) :ARG2 (i / inhibit-01 :ARG1 (g / grow-01 :ARG0 (c2 / cell-line :name (n / name :op1 "RBW-1") :mod (w2 / wild-type))))) :ARG1-of (d / describe-01 :ARG0 (a / and :op1 (f / figure :mod "2B") :op2 (f2 / figure :mod "2C")))) # ::id a_pmid_2488_5690.52 ::date 2015-06-09T10:07:28 ::annotator SDL-AMR-09 ::preferred # ::snt It has been shown previously that BRAF wild-type cells require glucose supply for survival whereas BRAF-mutant cell clones maintain proliferation in low-glucose environments [20]. # ::save-date Sun Jan 17, 2016 ::file a_pmid_2488_5690_52.txt (c / contrast-01 :ARG1 (r / require-01 :ARG0 (c2 / cell :location-of (g / gene :name (n / name :op1 "BRAF") :mod (w / wild-type))) :ARG1 (s2 / supply-01 :ARG1 (s3 / small-molecule :name (n2 / name :op1 "glucose"))) :purpose (s4 / survive-01 :ARG0 c2)) :ARG2 (m / maintain-01 :ARG0 (c4 / cell :ARG1-of (c3 / clone-01 :location-of (g2 / gene :name (n3 / name :op1 "BRAF") :ARG1-of (m2 / mutate-01)))) :ARG1 (p2 / proliferate-01) :location (e / environment :ARG1-of (l / low-04 :ARG2 s3))) :ARG1-of (s / show-01 :ARG0 (p3 / publication :ARG1-of (c5 / cite-01 :ARG2 20)) :time (p / previous))) # ::id a_pmid_2488_5690.53 ::date 2015-06-09T10:21:30 ::annotator SDL-AMR-09 ::preferred # ::snt Here we show that the V600E mutation of B-Raf also provides independency of serum-derived growth signals in RKO and that targeting of oncogenically mutant BRAF is sufficient to deprive this vital feature of malignancy from the cells, thereby corroborating previous reports [6]. # ::save-date Wed Dec 9, 2015 ::file a_pmid_2488_5690_53.txt (a / and :op1 (p / provide-01 :ARG0 (e2 / enzyme :name (n2 / name :op1 "B-Raf") :ARG2-of (m / mutate-01 :value "V600E")) :ARG1 (d / depend-01 :polarity - :ARG1 (s / signal-07 :ARG1 (g / grow-01) :ARG1-of (d2 / derive-01 :ARG2 (s2 / serum)))) :mod (a2 / also) :location (c / cell-line :name (n3 / name :op1 "RKO"))) :op2 (s3 / suffice-01 :ARG0 (t / target-01 :ARG1 (g2 / gene :name (n4 / name :op1 "BRAF") :ARG1-of (m2 / mutate-01 :ARG0-of (c6 / cause-01 :ARG1 (d5 / disease :wiki "Cancer" :name (n / name :op1 "cancer")))))) :ARG1 (d3 / deprive-01 :ARG0 t :ARG1 (f / feature-01 :ARG0 c2 :ARG1 (m3 / malignancy) :mod (t2 / this) :mod (v / vital)) :ARG2 (c2 / cell))) :ARG1-of (s4 / show-01 :ARG0 (w / we) :location (h / here) :ARG0-of (c3 / cause-01 :ARG1 (c4 / corroborate-01 :ARG1 (r / report :time (p2 / previous) :ARG1-of (d4 / describe-01 :ARG0 (p3 / publication :ARG1-of (c5 / cite-01 :ARG2 6)))))))) # ::id a_pmid_2488_5690.54 ::date 2015-06-09T10:31:52 ::annotator SDL-AMR-09 ::preferred # ::snt Sustained proliferative signaling is considered one of the major traits of cancer cells and is therefore used as a target mechanism of individualized therapy approaches including anti EGFR therapy strategies in colorectal cancer [21,22]. # ::save-date Thu Jan 28, 2016 ::file a_pmid_2488_5690_54.txt (c / consider-01 :ARG1 (i / include-01 :ARG1 (s / signal-07 :ARG0-of (p / proliferate-01) :ARG1-of (s2 / sustain-01)) :ARG2 (t / trait :poss (c2 / cell :mod (d2 / disease :wiki "Cancer" :name (n3 / name :op1 "cancer"))) :ARG1-of (m / major-02))) :ARG0-of (c4 / cause-01 :ARG1 (u / use-01 :ARG1 s :ARG2 (m2 / mechanism :ARG1-of (t2 / target-01) :poss (a / approach-02 :mod (t3 / therapy :ARG1-of (i2 / individualize-02)) :ARG2-of (i3 / include-91 :ARG1 (s3 / strategy :mod (t4 / therapy :ARG0-of (c7 / counter-01 :ARG1 (e / enzyme :name (n2 / name :op1 "EGFR")))) :prep-in (d / disease :wiki "Colorectal_cancer" :name (n / name :op1 "colorectal" :op2 "cancer"))) :ARG1-of (d4 / describe-01 :ARG0 (p3 / publication :ARG1-of (c6 / cite-01 :ARG2 22)))))))) :ARG1-of (d3 / describe-01 :ARG0 (p2 / publication :ARG1-of (c5 / cite-01 :ARG2 21)))) # ::id a_pmid_2488_5690.55 ::date 2015-06-09T23:18:51 ::annotator SDL-AMR-09 ::preferred # ::snt In another context, mutant B-Raf induced cellular senescence rather than proliferation [23,24]. # ::save-date Sun Dec 20, 2015 ::file a_pmid_2488_5690_55.txt (i / induce-01 :ARG0 (e2 / enzyme :name (n2 / name :op1 "B-Raf") :ARG2-of (m / mutate-01)) :ARG2 (s / senescence :mod (c / cell) :ARG1-of (i2 / instead-of-91 :ARG2 (p / proliferate-01 :ARG0 c))) :condition (c2 / context :mod (a / another)) :ARG1-of (d / describe-01 :ARG0 (p2 / publication :ARG1-of (c3 / cite-01 :ARG2 (a2 / and :op1 23 :op2 24))))) # ::id a_pmid_2488_5690.56 ::date 2015-06-09T23:22:38 ::annotator SDL-AMR-09 ::preferred # ::snt However, senescence can be overcome by phosphoinositide 3-kinase (PI3K)/AKT signaling [24] which is hyperactivated in RKO due to a PIK3CA mutation. # ::save-date Sun Jun 14, 2015 ::file a_pmid_2488_5690_56.txt (c / contrast-01 :ARG2 (p / possible-01 :ARG1 (o / overcome-01 :ARG0 (s2 / signal-07 :ARG0 (p2 / pathway :name (n2 / name :op1 "phosphoinositide" :op2 "3-kinase" :op3 "AKT")) :ARG1-of (a / activate-01 :degree (h / hyper) :location (c3 / cell-line :name (n3 / name :op1 "RKO")) :ARG1-of (c4 / cause-01 :ARG0 (m / mutate-01 :ARG1 (g / gene :name (n / name :op1 "PIK3CA")))))) :ARG1 (s / senescence)) :ARG1-of (d / describe-01 :ARG0 (p3 / publication :ARG1-of (c2 / cite-01 :ARG2 24))))) # ::id a_pmid_2488_5690.57 ::date 2015-06-09T23:29:10 ::annotator SDL-AMR-09 ::preferred # ::snt By staining of senescence-associated β-galactosidase activity [25] we examined whether the differential proliferation rates observed upon serum deprivation were attributable to cellular senescence. # ::save-date Mon Dec 21, 2015 ::file a_pmid_2488_5690_57.txt (e / examine-01 :ARG0 (w / we) :ARG1 (p / possible-01 :mode interrogative :ARG1 (a / attribute-01 :ARG1 (r / rate :mod (p2 / proliferate-01) :ARG1-of (d / differ-02) :ARG1-of (o / observe-01 :condition (d3 / deprive-01 :ARG1 (s3 / serum)))) :ARG2 (s / senescence :mod (c / cell)))) :manner (s2 / stain-01 :ARG1 (a2 / activity-06 :ARG0 (e2 / enzyme :name (n / name :op1 "senescence-associated" :op2 "β-galactosidase"))) :ARG1-of (d2 / describe-01 :ARG0 (p3 / publication :ARG1-of (c2 / cite-01 :ARG2 25))))) # ::id a_pmid_2488_5690.58 ::date 2015-06-09T23:32:53 ::annotator SDL-AMR-09 ::preferred # ::snt Cellular senescence was detected at very low levels in less than 5% of cells (Figure 2D-E), indicating that senescence alone cannot explain the strong reduction in cell growth observed upon withdrawal of serum. # ::save-date Thu Jun 18, 2015 ::file a_pmid_2488_5690_58.txt (d / detect-01 :ARG1 (l2 / level :quant-of (s / senescence :mod (c / cell)) :ARG1-of (l3 / low-04 :degree (v / very))) :location (c2 / cell :quant (l / less-than :op1 (p / percentage-entity :value 5))) :ARG1-of (d2 / describe-01 :ARG0 (a / and :op1 (f / figure :name (n / name :op1 "2D")) :op2 (f2 / figure :name (n2 / name :op1 "2E")))) :ARG0-of (i / indicate-01 :ARG1 (p2 / possible-01 :polarity - :ARG1 (e / explain-01 :ARG0 (s2 / senescence :mod (a2 / alone)) :ARG1 (r / reduce-01 :ARG1 (g / grow-01 :ARG1 (c3 / cell)) :ARG2 (s4 / strong) :ARG1-of (o / observe-01 :condition (w / withdraw-01 :ARG1 (s3 / serum)))))))) # ::id a_pmid_2488_5690.59 ::date 2015-06-09T23:38:16 ::annotator SDL-AMR-09 ::preferred # ::snt Flow cytometry revealed a significant increase of apoptotic cells in wild-type compared to mutant clones upon withdrawal of serum (Figure 2F and G). # ::save-date Fri Dec 18, 2015 ::file a_pmid_2488_5690_59.txt (r / reveal-01 :ARG0 (t / thing :name (n / name :op1 "flow" :op2 "cytometry")) :ARG1 (i / increase-01 :ARG1 (c / cell :mod (a / apoptosis)) :ARG2 (s / significant-02) :location (c2 / cell :mod (w / wild-type) :compared-to (c3 / clone :ARG2-of (m / mutate-01))) :condition (w2 / withdraw-01 :ARG1 (s2 / serum))) :ARG1-of (d / describe-01 :ARG0 (a2 / and :op1 (f / figure :mod "2F") :op2 (f2 / figure :mod "2G")))) # ::id a_pmid_2488_5690.60 ::date 2015-06-09T23:42:19 ::annotator SDL-AMR-09 ::preferred # ::snt Apoptosis was confirmed by the detection of cleaved caspase 3 at considerable levels in serum-starved RBW-1, while all other samples showed full-length protein only (Figure 2H). # ::save-date Sun Jan 17, 2016 ::file a_pmid_2488_5690_60.txt (c5 / contrast-01 :ARG1 (c / confirm-01 :ARG0 (d / detect-01 :ARG1 (l / level :quant-of (p2 / protein :name (n / name :op1 "caspase" :op2 "3") :ARG1-of (c2 / cleave-01)) :quant (c3 / considerable)) :location (c4 / cell-line :name (n2 / name :op1 "RBW-1") :ARG1-of (s / starve-01 :ARG2 (s2 / serum)))) :ARG1 (a / apoptosis)) :ARG2 (s3 / show-01 :ARG0 (t / thing :mod (a2 / all) :mod (o / other) :ARG1-of (s4 / sample-01)) :ARG1 (p / protein :ARG1-of (l2 / long-03 :degree (f / full))) :mod (o2 / only)) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure :mod "2H"))) # ::id a_pmid_2488_5690.61 ::date 2015-06-09T23:49:47 ::annotator SDL-AMR-09 ::preferred # ::snt Consistent with RKO modeling a distinct subpopulation of patients characterized by the presence of certain molecular features and the absence of others [7], no implication of p53 in apoptosis was observed (Figure 2H). # ::save-date Wed Oct 14, 2015 ::file a_pmid_2488_5690_61.txt (o / observe-01 :ARG1 (i / implicate-01 :polarity - :ARG1 (p / protein :name (n / name :op1 "p53")) :ARG2 (a / apoptosis)) :ARG1-of (c / consistent-01 :ARG2 (m / model-01 :ARG0 (c2 / cell-line :name (n2 / name :op1 "RKO")) :ARG1 (s / subpopulation :mod (p2 / patient) :mod (d / distinct) :ARG1-of (c3 / characterize-01 :ARG2 (a2 / and :op1 (h / have-03 :ARG0 s :ARG1 (f / feature :mod (m2 / molecule) :mod (c4 / certain))) :op2 (l / lack-01 :ARG0 s :ARG1 (f2 / feature :mod m2 :mod (o2 / other)))))) :ARG1-of (d2 / describe-01 :ARG0 (p3 / publication :ARG1-of (c5 / cite-01 :ARG2 7))))) :ARG1-of (d3 / describe-01 :ARG0 (f3 / figure :mod "2H"))) # ::id a_pmid_2488_5690.62 ::date 2015-06-09T23:56:19 ::annotator SDL-AMR-09 ::preferred # ::snt Since serum starvation is often used to model apoptosis mediated via the PUMA pathway [26], we also analyzed PUMA protein levels. # ::save-date Fri Feb 5, 2016 ::file a_pmid_2488_5690_62.txt (a / analyze-01 :ARG0 (w / we) :ARG1 (l / level :quant-of (p / protein :name (n / name :op1 "PUMA"))) :ARG1-of (c / cause-01 :ARG0 (u / use-01 :ARG1 (s / starve-01 :ARG2 (s2 / serum)) :frequency (o / often) :purpose (m / model-01 :ARG0 s :ARG1 (a2 / apoptosis :ARG1-of (m2 / mediate-01 :instrument (p2 / pathway :name (n2 / name :op1 "PUMA"))))) :ARG1-of (d / describe-01 :ARG0 (p3 / publication :ARG1-of (c2 / cite-01 :ARG2 26))))) :mod (a3 / also)) # ::id a_pmid_2488_5690.63 ::date 2015-06-10T00:00:07 ::annotator SDL-AMR-09 ::preferred # ::snt PUMA was found to be highly abundant specifically in serum starved RBW-1 (Figure 2H). # ::save-date Sun Jan 3, 2016 ::file a_pmid_2488_5690_63.txt (a / abundant :op1 (c / cell-line :name (n2 / name :op1 "RBW-1") :ARG1-of (s / starve-01 :ARG2 (s2 / serum))) :ARG1-of (h / high-02) :domain (p / protein :name (n / name :op1 "PUMA")) :ARG1-of (f / find-01) :ARG1-of (d / describe-01 :ARG0 (f2 / figure :mod "2H")) :ARG1-of (s3 / specific-02)) # ::id a_pmid_2488_5690.64 ::date 2015-06-10T00:05:29 ::annotator SDL-AMR-09 ::preferred # ::snt Consistent with data previously shown by others, starvation-induced apoptosis is mediated by PUMA in a p53-independent fashion in our experiments [27]. # ::save-date Sun Dec 20, 2015 ::file a_pmid_2488_5690_64.txt (m / mediate-01 :ARG0 (p / protein :name (n / name :op1 "PUMA")) :ARG1 (a / apoptosis :ARG2-of (i / induce-01 :ARG0 (s / starve-01))) :manner (d / depend-01 :polarity - :ARG1 (p2 / protein :name (n2 / name :op1 "p53"))) :time (e / experiment-01 :ARG0 (w / we)) :ARG1-of (c / consistent-01 :ARG2 (d2 / data :ARG1-of (s2 / show-01 :ARG0 (p5 / person :mod (o / other)) :time (p3 / previous)) :ARG1-of (d3 / describe-01 :ARG0 (p4 / publication :ARG1-of (c2 / cite-01 :ARG2 27)))))) # ::id a_pmid_2488_5690.65 ::date 2015-06-10T00:10:01 ::annotator SDL-AMR-09 ::preferred # ::snt Programmed cell death is a key feature of proliferation control in homeostasis and overcoming apoptosis is considered another hallmark of cancer cells [28]. # ::save-date Sun Dec 20, 2015 ::file a_pmid_2488_5690_65.txt (a / and :op1 (f / feature :ARG1-of (k / key-02 :ARG2 (d2 / die-01 :ARG1 (c / cell) :ARG1-of (p / program-01))) :part-of (c2 / control-01 :ARG1 (p2 / proliferate-01)) :prep-in (h / homeostasis)) :op2 (c3 / consider-01 :ARG1 (h2 / hallmark :mod (c4 / cell :mod (d / disease :wiki "Cancer" :name (n / name :op1 "cancer"))) :domain (o / overcome-01 :ARG1 (a2 / apoptosis)) :mod (a3 / another)) :ARG1-of (d3 / describe-01 :ARG0 (p3 / publication :ARG1-of (c6 / cite-01 :ARG2 28))))) # ::id a_pmid_2488_5690.66 ::date 2015-06-10T00:16:49 ::annotator SDL-AMR-09 ::preferred # ::snt Since virtually all malignant cancer cells show apoptosis resistance, the induction of apoptotic pathways is considered a particularly promising approach for therapeutic strategies [29]. # ::save-date Mon Feb 15, 2016 ::file a_pmid_2488_5690_66.txt (c / consider-01 :ARG1 (a / approach-02 :ARG0 (i / induce-01 :ARG2 (p3 / pathway :mod a4)) :ARG1 (s / strategy :mod (t / therapy)) :ARG2-of (p / promise-01 :degree (p2 / particular))) :ARG1-of (c2 / cause-01 :ARG0 (s2 / show-01 :ARG0 (c3 / cell :mod (a3 / all :degree (v / virtual)) :mod (d / disease :wiki "Cancer" :name (n / name :op1 "cancer") :ARG2-of (m / malignant-02))) :ARG1 (r / resist-01 :ARG0 c3 :ARG1 (a4 / apoptosis)))) :ARG1-of (d2 / describe-01 :ARG0 (p4 / publication :ARG1-of (c5 / cite-01 :ARG2 29)))) # ::id a_pmid_2488_5690.67 ::date 2015-06-10T00:22:21 ::annotator SDL-AMR-09 ::preferred # ::snt Our results show that in RKO this particular cancer cell trait is modulated by and dependent on B-RafV600E and that targeting mutant BRAF is sufficient to restore sensitivity to caspase-dependent apoptosis after serum withdrawal via p53-independent PUMA induction [27]. # ::save-date Wed Dec 9, 2015 ::file a_pmid_2488_5690_67.txt (s / show-01 :ARG0 (t4 / thing :ARG1-of (r / result-01) :poss (w / we)) :ARG1 (a / and :op1 (a2 / and :op1 (m / modulate-01 :ARG0 (e2 / enzyme :name (n3 / name :op1 "B-Raf") :ARG2-of (m2 / mutate-01 :value "V600E")) :ARG1 (t / trait :mod (c / cell :mod (d5 / disease :wiki "Cancer" :name (n / name :op1 "cancer"))) :mod (p / particular) :mod (t3 / this))) :op2 (d2 / depend-01 :ARG0 t :ARG1 e2) :location (c3 / cell-line :name (n4 / name :op1 "RKO"))) :op2 (s2 / suffice-01 :ARG0 (t2 / target-01 :ARG1 (g / gene :name (n5 / name :op1 "BRAF") :ARG2-of (m3 / mutate-01))) :ARG1 (r2 / restore-01 :ARG0 t2 :ARG1 (s3 / sensitive-03 :ARG1 (a3 / apoptosis :ARG0-of (d3 / depend-01 :ARG1 (p2 / protein :name (n6 / name :op1 "caspase"))) :time (a4 / after :op1 (w2 / withdraw-01 :ARG1 (s4 / serum))) :instrument (i / induce-01 :ARG2 (p3 / protein :name (n7 / name :op1 "PUMA")) :ARG0-of (d4 / depend-01 :polarity - :ARG1 (p4 / protein :name (n8 / name :op1 "p53"))) :ARG1-of (d / describe-01 :ARG0 (p5 / publication :ARG1-of (c4 / cite-01 :ARG2 27)))))))))) # ::id a_pmid_2488_5690.68 ::date 2015-06-10T00:40:15 ::annotator SDL-AMR-09 ::preferred # ::snt Complementing and extending previous studies, we thus provide evidence from an endogenous and quantitative genetic model of BRAF-mutant colorectal cancer cells, thereby ruling out the occurrence of artifacts caused by unspecific cellular response or incomplete knockdown in RNAi setups and, likewise, avoiding inter-species bias potentially experienced in mouse models of colorectal cancer [30]. # ::save-date Mon Dec 21, 2015 ::file a_pmid_2488_5690_68.txt (i / infer-01 :ARG1 (p / provide-01 :ARG0 (w / we) :ARG1 (e / evidence :source (m2 / model :mod (c / cell :location-of (g / gene :name (n3 / name :op1 "BRAF") :ARG2-of (m / mutate-01)) :mod (d / disease :wiki "Colorectal_cancer" :name (n / name :op1 "colorectal" :op2 "cancer"))) :mod (q / quantity) :mod (e2 / endogenous) :mod (g2 / gene))) :ARG0-of (c2 / cause-01 :ARG1 (a / and :op1 (r / rule-out-02 :ARG1 (a2 / artifact :ARG1-of (c3 / cause-01 :ARG0 (o2 / or :op1 (r2 / respond-01 :ARG0 (c4 / cell) :ARG1-of (s / specific-02 :polarity -)) :op2 (k / knock-down-02 :ARG1-of (c5 / complete-01 :polarity -) :location (s2 / setup :mod (i3 / interfere-01 :ARG1 (n2 / nucleic-acid :name (n4 / name :op1 "RNA"))))))))) :op2 (a3 / avoid-01 :ARG1 (b / bias-01 :mod (i2 / inter-species) :ARG1-of (e3 / experience-01 :ARG1-of (p2 / possible-01) :location (m3 / model :mod (d2 / disease) :mod (m4 / mouse) :ARG1-of (d3 / describe-01 :ARG0 (p3 / publication :ARG1-of (c6 / cite-01 :ARG2 30)))))))))) :ARG1-of (c7 / complement-01 :ARG2 (s3 / study-01 :time (p4 / previous))) :ARG0-of (e4 / extend-01 :ARG1 s3)) # ::id bel_pmid_1064_0734.39802 ::date 2015-04-09T03:22:23 ::annotator SDL-AMR-09 ::preferred # ::snt In this paper we demonstrate that expression of CD72 down-modulates both extracellular signal-related kinase (ERK) activation and Ca2+ mobilization induced by BCR ligation in the mouse B lymphoma line K46^mA, whereas BCR-mediated ERK activation was not reduced by the ITIM-mutated form of CD72. # ::save-date Sun Dec 20, 2015 ::file bel_pmid_1064_0734_39802.txt (d / demonstrate-01 :ARG0 (w / we) :ARG1 (d2 / downmodulate-01 :ARG1 (a / and :op1 (a2 / activate-01 :ARG1 (e4 / enzyme :name (n3 / name :op1 "extracellular" :op2 "signal-related" :op3 "kinase") :ARG1-of (d3 / describe-01 :ARG2 (e3 / enzyme :name (n4 / name :op1 "ERK"))))) :op2 (m / mobilize-01 :ARG1 (c4 / calcium :ARG1-of (i2 / ionize-01 :value "2+"))) :ARG2-of (i / induce-01 :ARG0 (l / ligate-01 :ARG1 (p3 / protein :name (n6 / name :op1 "BCR"))) :location (c / cell-line :name (n7 / name :op1 "K46^mA") :mod (m2 / mouse) :consist-of (c3 / cell :name (n / name :op1 "B") :part-of (l2 / lymphoma))))) :ARG2 (e2 / express-03 :ARG2 (p2 / protein :name (n2 / name :op1 "CD72"))) :ARG1-of (c2 / contrast-01 :ARG2 (r / reduce-01 :polarity - :ARG0 (p4 / protein :name (n8 / name :op1 "CD72") :ARG2-of (m4 / mutate-01 :ARG0 (p5 / protein-segment :name (n9 / name :op1 "ITIM")))) :ARG1 (a3 / activate-01 :ARG1 e3 :ARG1-of (m3 / mediate-01 :ARG0 p3))))) :medium (p / paper :mod (t / this))) # ::id bel_pmid_1064_0734.39804 ::date 2015-04-09T03:46:19 ::annotator SDL-AMR-09 ::preferred # ::snt Results CD72 negatively regulates both ERK activation and Ca2+ mobilization induced by BCR ligation in the K46^mk B lymphoma cells To investigate the signaling function of CD72, we assessed CD72 expression on the surface of B cell lines by flow cytometry. # ::save-date Sun Dec 20, 2015 ::file bel_pmid_1064_0734_39804.txt (m / multi-sentence :snt1 (t / thing :ARG2-of (r / result-01)) :snt1 (d / downregulate-01 :ARG1 (a / and :op1 (a2 / activate-01 :ARG1 (e2 / enzyme :name (n4 / name :op1 "ERK"))) :op2 (m2 / mobilize-01 :ARG1 (c6 / calcium :ARG1-of (i3 / ionize-01 :value "2+"))) :ARG2-of (i / induce-01 :ARG0 (l / ligate-01 :ARG1 (p2 / protein :name (n6 / name :op1 "BCR"))))) :ARG2 (p / protein :name (n3 / name :op1 "CD72")) :location (c / cell-line :name (n7 / name :op1 "K46^mk") :consist-of (c5 / cell :name (n9 / name :op1 "B") :part-of (l2 / lymphoma)))) :snt3 (a3 / assess-01 :ARG0 (w / we) :ARG1 (e3 / express-03 :ARG2 (p3 / protein :name (n8 / name :op1 "CD72")) :location (s2 / surface :part-of (c2 / cell-line :consist-of (c4 / cell :name (n / name :op1 "B"))))) :instrument (c3 / cytometry :mod (f / flow)) :purpose (i2 / investigate-01 :ARG0 w :ARG1 (f2 / function-01 :ARG0 p3 :ARG1 (s3 / signal-07))))) # ::id bel_pmid_1064_0734.39810 ::date 2015-04-09T04:01:27 ::annotator SDL-AMR-09 ::preferred # ::snt However, both of the CD72 transfectants showed reduced phosphorylation of ERK1 and ERK2 compared to that of the parent cells regardless of the duration of Ag stimulation. # ::save-date Thu Jan 7, 2016 ::file bel_pmid_1064_0734_39810.txt (h / have-concession-91 :ARG1 (s2 / show-01 :ARG0 (m / molecular-physical-entity :mod (b / both) :ARG1-of (t / transfect-01 :ARG2 (p2 / protein :name (n2 / name :op1 "CD72")))) :ARG1 (p / phosphorylate-01 :ARG1 (a / and :op1 (e / enzyme :name (n3 / name :op1 "ERK1")) :op2 (e2 / enzyme :name (n4 / name :op1 "ERK2"))) :ARG1-of (r / reduce-01 :compared-to (c3 / cell :mod (p4 / parent)) :ARG1-of (r2 / regardless-91 :ARG2 (d / duration :poss (s / stimulate-01 :ARG2 (a2 / antigen)))))))) # ::id bel_pmid_1064_0734.39812 ::date 2015-04-09T04:44:25 ::annotator SDL-AMR-09 ::preferred # ::snt Taken together, expression of CD72 most probably down-modu-lates phosphorylation of ERK induced by BCR signaling. # ::save-date Sun Dec 20, 2015 ::file bel_pmid_1064_0734_39812.txt (h / have-condition-91 :ARG1 (p3 / probable :degree (m / most) :domain (d / downmodulate-01 :ARG1 (p / phosphorylate-01 :ARG1 (e / enzyme :name (n / name :op1 "ERK")) :ARG2-of (i / induce-01 :ARG0 (s / signal-07 :ARG0 (p4 / protein :name (n3 / name :op1 "BCR"))))) :ARG2 (e2 / express-03 :ARG2 (p2 / protein :name (n2 / name :op1 "CD72"))))) :ARG2 (t / take-01 :mod (t2 / together))) # ::id bel_pmid_1064_0734.39814 ::date 2015-04-09T04:55:18 ::annotator SDL-AMR-09 ::preferred # ::snt Indeed, in vitro kinase assay showed that the activity of ERK2 in Ag-stimulated K46^mA CD72 transfectants was lower than that of Ag-stimulated K46^mA (Fig. 3). # ::save-date Thu Dec 17, 2015 ::file bel_pmid_1064_0734_39814.txt (s / show-01 :ARG0 (a / assay-01 :ARG1 (k / kinase) :manner (i / in-vitro)) :ARG1 (l / low-04 :ARG1 (a2 / activity-06 :ARG0 (e / enzyme :name (n / name :op1 "ERK2")) :location (m2 / molecular-physical-entity :part-of (c2 / cell-line :name (n4 / name :op1 "K46^mA") :ARG1-of (s2 / stimulate-01 :ARG2 (a4 / antigen))) :ARG1-of (t / transfect-01 :ARG2 (p / protein :name (n3 / name :op1 "CD72"))))) :degree (m / more) :compared-to (a3 / activity-06 :location c2)) :mod (i2 / indeed) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod 3))) # ::id bel_pmid_1064_0734.39818 ::date 2015-04-09T05:13:20 ::annotator SDL-AMR-09 ::preferred # ::snt However, the CD72 transfectants showed less increase in the intracellular Ca2+ concentration than the parent K46^mA cells did. # ::save-date Sat Jan 2, 2016 ::file bel_pmid_1064_0734_39818.txt (h / have-concession-91 :ARG1 (s / show-01 :ARG0 (m / molecular-physical-entity :ARG1-of (t / transfect-01 :ARG2 (p / protein :name (n2 / name :op1 "CD72")))) :ARG1 (i / increase-01 :ARG1 (c3 / concentrate-02 :ARG0 (c / calcium :ARG1-of (i3 / ionize-01 :value "2+")) :mod (i2 / intracellular)) :ARG2 (l / less) :compared-to (c4 / cell-line :name (n4 / name :op1 "K46^mA") :mod (p2 / parent))))) # ::id bel_pmid_1064_0734.39820 ::date 2015-04-09T05:20:31 ::annotator SDL-AMR-09 ::preferred # ::snt Thus, expression of CD72 appears to negatively regulate BCR-mediated Ca2+ mobilization in K46^mA cells. # ::save-date Mon Oct 26, 2015 ::file bel_pmid_1064_0734_39820.txt (i / infer-01 :ARG1 (a / appear-02 :ARG1 (d / downregulate-01 :ARG1 (m / mobilize-01 :ARG1 (c2 / calcium :ARG1-of (i2 / ionize-01 :value "2+")) :ARG1-of (m2 / mediate-01 :ARG0 (p2 / protein :name (n4 / name :op1 "BCR")))) :ARG2 (e / express-03 :ARG2 (p / protein :name (n / name :op1 "CD72"))) :location (c / cell-line :name (n5 / name :op1 "K46^mA"))))) # ::id bel_pmid_1064_0734.39822 ::date 2015-04-09T05:27:53 ::annotator SDL-AMR-09 ::preferred # ::snt Taken together, CD72 down-modulates both ERK activation and Ca2+ mobilization induced by BCR ligation, strongly suggesting that CD72 negatively regulates BCR signaling in K46^mA cells. # ::save-date Sun Dec 20, 2015 ::file bel_pmid_1064_0734_39822.txt (h / have-condition-91 :ARG1 (d / downmodulate-01 :ARG1 (a / and :op1 (a2 / activate-01 :ARG1 (e2 / enzyme :name (n3 / name :op1 "ERK"))) :op2 (m / mobilize-01 :ARG1 (c2 / calcium :ARG1-of (i2 / ionize-01 :value "2+"))) :ARG2-of (i / induce-01 :ARG0 (l / ligate-01 :ARG1 (p2 / protein :name (n5 / name :op1 "BCR"))))) :ARG2 (p / protein :name (n2 / name :op1 "CD72")) :ARG0-of (s2 / suggest-01 :ARG1 (d2 / downregulate-01 :ARG1 (s4 / signal-07 :ARG0 p2) :ARG2 p :location (c / cell-line :name (n6 / name :op1 "K46^mA"))) :ARG1-of (s3 / strong-02))) :ARG2 (t / take-01 :mod (t2 / together))) # ::id bel_pmid_1064_0734.39824 ::date 2015-04-09T05:35:11 ::annotator SDL-AMR-09 ::preferred # ::snt Western blotting of total cell lysates using anti-phospho-ERK Ab showed that both ERK1 and ERK2 were phosphorylated by either BCR ligation alone or coligation of BCR and CD72 (Fig. 6B). # ::save-date Sun Jan 3, 2016 ::file bel_pmid_1064_0734_39824.txt (s / show-01 :ARG0 (i / immunoblot-01 :ARG2 (l / lysate :mod (c / cell) :quant (t2 / total)) :ARG3 (a / antibody :ARG0-of (c2 / counter-01 :ARG1 (e / enzyme :name (n / name :op1 "ERK") :ARG3-of (p / phosphorylate-01))))) :ARG1 (p2 / phosphorylate-01 :ARG1 (a2 / and :op1 (e2 / enzyme :name (n3 / name :op1 "ERK1")) :op2 (e3 / enzyme :name (n4 / name :op1 "ERK2"))) :ARG2 (o / or :op1 (l2 / ligate-01 :ARG1 (p3 / protein :name (n5 / name :op1 "BCR")) :mod (a3 / alone)) :op2 (l3 / ligate-01 :ARG1 p3 :ARG3 (p4 / protein :name (n6 / name :op1 "CD72")) :mod (t3 / together)))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "6B"))) # ::id bel_pmid_1064_0734.39826 ::date 2015-04-09T05:59:50 ::annotator SDL-AMR-09 ::preferred # ::snt However, BCR ligation induced stronger ERK phosphorylation than coligation of CD72 with BCR did, indicating that BCR ligation-induced phosphorylation of ERK is down-modulated when CD72 is coligated with BCR. # ::save-date Sun Dec 20, 2015 ::file bel_pmid_1064_0734_39826.txt (h / have-concession-91 :ARG1 (i / induce-01 :ARG0 (l / ligate-01 :ARG1 (p2 / protein :name (n2 / name :op1 "BCR"))) :ARG2 (p / phosphorylate-01 :ARG1 (e / enzyme :name (n / name :op1 "ERK")) :ARG1-of (s / strong-02 :degree (m / more) :compared-to (l2 / ligate-01 :ARG1 (p3 / protein :name (n3 / name :op1 "CD72")) :ARG3 p2 :mod (t / together)))) :ARG0-of (i2 / indicate-01 :ARG1 (d / downmodulate-01 :ARG1 (p4 / phosphorylate-01 :ARG1 e :ARG2-of (i3 / induce-01 :ARG0 l)) :time l2)))) # ::id bel_pmid_1064_0734.39828 ::date 2015-04-09T06:06:35 ::annotator SDL-AMR-09 ::preferred # ::snt Phosphorylation of both ERK1 and ERK2 induced by coligation of BCR and CD72 was weaker than that induced by BCR ligation alone (Fig. 6 C), indicating that coligation with CD72 reduced BCR ligation-mediated phosphorylation of ERK in DBA/2 spleen cells. # ::save-date Sat Jan 2, 2016 ::file bel_pmid_1064_0734_39828.txt (w / weak-02 :ARG1 (p / phosphorylate-01 :ARG1 (a / and :op1 (e2 / enzyme :name (n2 / name :op1 "ERK1")) :op2 (e3 / enzyme :name (n3 / name :op1 "ERK2"))) :ARG2-of (i / induce-01 :ARG0 (l / ligate-01 :ARG1 (p2 / protein :name (n4 / name :op1 "BCR")) :ARG3 (p3 / protein :name (n5 / name :op1 "CD72")) :mod (t / together)))) :degree (m / more) :compared-to (p4 / phosphorylate-01 :ARG2-of (i2 / induce-01 :ARG0 (l2 / ligate-01 :ARG1 p2 :mod (a2 / alone)))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "6C")) :ARG0-of (i3 / indicate-01 :ARG1 (r / reduce-01 :ARG0 l :ARG1 (p5 / phosphorylate-01 :ARG1 (e / enzyme :name (n / name :op1 "ERK")) :ARG1-of (m2 / mediate-01 :ARG0 l2) :location (c / cell :part-of (s / spleen :source (o / organism :name (n6 / name :op1 "DBA/2" :op2 "mouse")))))))) # ::id bel_pmid_1064_0734.39830 ::date 2015-04-09T06:20:57 ::annotator SDL-AMR-09 ::preferred # ::snt Coligation of CD72 with BCR showed a reduced Ca2+ flux compared to that with BCR ligation alone in spleen B cells (Fig. 6D). # ::save-date Mon Oct 26, 2015 ::file bel_pmid_1064_0734_39830.txt (s / show-01 :ARG0 (l / ligate-01 :ARG1 (p / protein :name (n / name :op1 "CD72")) :ARG3 (p2 / protein :name (n2 / name :op1 "BCR")) :mod (t / together)) :ARG1 (f / flux :quant-of (c3 / calcium :ARG1-of (i / ionize-01 :value "2+")) :ARG1-of (r / reduce-01) :compared-to (f2 / flux :ARG1-of (c / cause-01 :ARG0 (l2 / ligate-01 :ARG1 p2 :mod (a / alone))))) :location (c2 / cell :name (n4 / name :op1 "B") :part-of (s3 / spleen)) :ARG1-of (d / describe-01 :ARG0 (f3 / figure :mod "6D"))) # ::id bel_pmid_1064_0734.39832 ::date 2015-04-09T06:29:32 ::annotator SDL-AMR-09 ::preferred # ::snt Taken together, these results indicate that coligation with CD72 negatively regulates BCR-induced ERK activation and Ca2+ concentration in normal spleen B cells. # ::save-date Sun Dec 20, 2015 ::file bel_pmid_1064_0734_39832.txt (h / have-condition-91 :ARG1 (i / indicate-01 :ARG0 (t / thing :ARG1-of (r / result-01) :mod (t2 / this)) :ARG1 (d / downregulate-01 :ARG1 (a2 / and :op1 (a / activate-01 :ARG1 (e / enzyme :name (n / name :op1 "ERK")) :ARG2-of (i2 / induce-01 :ARG0 (p2 / protein :name (n4 / name :op1 "BCR")))) :op2 (c / concentrate-02 :ARG1 (c3 / calcium :ARG1-of (i3 / ionize-01 :value "2+")))) :ARG2 (l / ligate-01 :ARG3 (p / protein :name (n3 / name :op1 "CD72")) :mod (t3 / together)) :location (c2 / cell :name (n6 / name :op1 "B") :ARG1-of (n2 / normal-02) :part-of (s2 / spleen)))) :ARG2 (t4 / take-01 :mod t3)) # ::id bel_pmid_1064_4693.7794 ::date 2015-04-09T06:35:04 ::annotator SDL-AMR-09 ::preferred # ::snt Furthermore, the hCdc14 phosphatases were found to dephosphorylate p53 specifically at the p34(Cdc2)/clb phosphorylation site (p53-phosphor-Ser(315)). # ::save-date Fri Jul 24, 2015 ::file bel_pmid_1064_4693_7794.txt (a / and :op2 (f / find-01 :ARG1 (d / dephosphorylate-01 :ARG1 (p3 / protein-segment :ARG1-of (p / phosphorylate-01 :ARG2 (e / enzyme :name (n3 / name :op1 "p34Cdc2/clb"))) :ARG1-of (d2 / describe-01 :ARG2 (a2 / amino-acid :mod 315 :name (n4 / name :op1 "serine") :ARG1-of p :part-of p2)) :part-of (p2 / protein :name (n / name :op1 "p53"))) :ARG2 (e2 / enzyme :name (n2 / name :op1 "hCdc14" :op2 "phosphatase")) :manner (s / specific-02)))) # ::id bel_pmid_1064_8414.21216 ::date 2015-04-09T06:47:05 ::annotator SDL-AMR-09 ::preferred # ::snt Overexpression of mutant FGFR3 resulted in IL-6 independence, decreased apoptosis, and an enhanced proliferative response to IL-6. # ::save-date Sun Jan 3, 2016 ::file bel_pmid_1064_8414_21216.txt (r / result-01 :ARG1 (o / overexpress-01 :ARG1 (p / protein :name (n / name :op1 "FGFR3") :ARG1-of (m / mutate-01))) :ARG2 (a / and :op1 (d / depend-01 :polarity - :ARG1 (p2 / protein :name (n2 / name :op1 "IL-6"))) :op2 (a2 / apoptosis :ARG1-of (d2 / decrease-01)) :op3 (r2 / respond-01 :ARG1 p2 :ARG2 (p3 / proliferate-01) :ARG1-of (e / enhance-01)))) # ::id bel_pmid_1064_8414.21218 ::date 2015-04-09T06:55:11 ::annotator SDL-AMR-09 ::preferred # ::snt B9 clones expressing either wild-type FGFR3 at high levels or mutant FGFR3 displayed increased phosphorylation of STAT3 and higher levels of bcl-x(L) expression than did parental B9 cells after cytokine withdrawal. # ::save-date Sun Jul 26, 2015 ::file bel_pmid_1064_8414_21218.txt (d / display-01 :ARG0 (c3 / clone-01 :ARG1 c2 :ARG3-of (e / express-03 :ARG2 (o / or :op1 (p2 / protein :name (n2 / name :op1 "FGFR3") :mod (w / wild-type) :degree (l / level :ARG1-of (h2 / high-02))) :op2 (p3 / protein :name (n3 / name :op1 "FGFR3") :ARG2-of (m2 / mutate-01))))) :ARG1 (a / and :op1 (p / phosphorylate-01 :ARG1 (p4 / protein :name (n4 / name :op1 "STAT3")) :ARG1-of (i / increase-01)) :op2 (l2 / level :ARG1-of (h / high-02 :degree (m / more)) :degree-of (e2 / express-03 :ARG2 (p5 / protein :name (n5 / name :op1 "bcl-xL")))) :compared-to (c2 / cell :name (n6 / name :op1 "B9") :mod (p6 / parental) :time (a2 / after :op1 (w2 / withdraw-01 :ARG1 (p7 / protein :name (n7 / name :op1 "cytokine"))))))) # ::id bel_pmid_1066_0621.6864 ::date 2015-04-09T07:11:52 ::annotator SDL-AMR-09 ::preferred # ::snt Treatment of cells expressing SRC-1 with epidermal growth factor enhanced the ligand-dependent, progesterone receptor-mediated activation of a target reporter gene. These results identify phosphorylation as a regulatory modification of SRC-1 and provide a basis upon which to identify signaling pathways that regulate SRC-1 function and, consequently, modify steroid/nuclear receptor action. # ::save-date Fri Apr 17, 2015 ::file bel_pmid_1066_0621_6864.txt (m / multi-sentence :snt1 (e / enhance-01 :ARG0 (t / treat-04 :ARG1 (c / cell :ARG3-of (e2 / express-03 :ARG2 (p3 / protein :name (n2 / name :op1 "SRC-1")))) :ARG2 (p8 / protein :name (n / name :op1 "epidermal" :op2 "growth" :op3 "factor"))) :ARG1 (a2 / activate-01 :ARG1 (g / gene :name (n4 / name :op1 "reporter" :op2 "gene") :ARG1-of (t2 / target-01)) :ARG0-of (d / depend-01 :ARG1 (l / ligand)) :ARG1-of (m2 / mediate-01 :ARG0 (p4 / protein :name (n3 / name :op1 "progesterone" :op2 "receptor"))))) :snt2 (a3 / and :op1 (i / identify-01 :ARG0 (t3 / thing :ARG1-of (r2 / result-01) :mod (t4 / this)) :ARG1 (p2 / phosphorylate-01) :ARG2 (m3 / modify-01 :ARG1 (p / protein :name (n5 / name :op1 "SRC-1")) :ARG0-of (r / regulate-01))) :op2 (p5 / provide-01 :ARG0 t3 :ARG1 (b / basis) :purpose (i2 / identify-01 :ARG1 (p6 / pathway :ARG0-of (s2 / signal-07) :ARG0-of (r3 / regulate-01 :ARG1 (f / function-01 :ARG0 p)) :ARG0-of (m4 / modify-01 :ARG1 (a4 / act-01 :ARG0 (p7 / protein :name (n6 / name :op1 "steroid/nuclear" :op2 "receptor"))) :ARG1-of (c2 / cause-01 :ARG0 r3))))))) # ::id bel_pmid_1066_0621.21334 ::date 2015-04-09T07:31:47 ::annotator SDL-AMR-09 ::preferred # ::snt Furthermore, Erk-2 phosphorylated threonine 1179 and serine 1185 (and to a lesser extent, serine 395) in vitro, suggesting the importance of this pathway for SRC-1 regulation. # ::save-date Mon Nov 2, 2015 ::file bel_pmid_1066_0621_21334.txt (a3 / and :op2 (p / phosphorylate-01 :ARG1 (a4 / and :op1 (a / amino-acid :mod 1179 :name (n / name :op1 "threonine")) :op2 (a2 / amino-acid :mod 1185 :name (n2 / name :op1 "serine")) :op3 (a5 / amino-acid :mod 395 :name (n4 / name :op1 "serine") :degree (e2 / extent :mod (l / less :degree (m / more))))) :ARG2 (e / enzyme :name (n3 / name :op1 "Erk-2")) :manner (i / in-vitro) :ARG0-of (s / suggest-01 :ARG1 (i2 / important :domain (p2 / pathway :mod (t / this)) :purpose (r / regulate-01 :ARG1 (p3 / protein :name (n5 / name :op1 "SRC-1"))))))) # ::id bel_pmid_1066_6199.2154 ::date 2015-04-09T07:44:01 ::annotator SDL-AMR-09 ::preferred # ::snt overexpressions of cyclin D1 or bcl-2 inhibited only differentiation or apoptosis, respectively # ::save-date Wed Jun 24, 2015 ::file bel_pmid_1066_6199_2154.txt (i / inhibit-01 :ARG0 (o3 / overexpress-01 :ARG1 (o4 / or :op1 (p / protein :name (n / name :op1 "cyclin" :op2 "D1")) :op2 (p2 / protein :name (n2 / name :op1 "bcl-2")))) :ARG1 (o2 / or :op1 (d / differentiate-01) :op2 (a / apoptosis)) :mod (o / only) :manner (r / respective)) # ::id bel_pmid_1066_6199.28424 ::date 2015-04-09T07:48:56 ::annotator SDL-AMR-09 ::preferred # ::snt Although STAT3 is essential for IL-6-induced macrophage differentiation of M1 cells, GATA-1 had little or no effect on tyrosine phosphorylation, DNA binding, and transcriptional activities of STAT3 in Western blot analysis, electropholic mobility shift assay (EMSA), and luciferase assays. # ::save-date Sun Jan 17, 2016 ::file bel_pmid_1066_6199_28424.txt (h / have-concession-91 :ARG1 (o2 / or :op1 (a / affect-01 :ARG0 (p2 / protein :name (n / name :op1 "GATA-1")) :ARG1 (a2 / and :op1 (p / phosphorylate-01 :ARG1 (a3 / amino-acid :name (n3 / name :op1 "tyrosine"))) :op2 (b / bind-01 :ARG1 (n2 / nucleic-acid :wiki "DNA" :name (n9 / name :op1 "DNA"))) :op3 (a4 / activity-06 :ARG0 (p3 / protein :name (n4 / name :op1 "STAT3")) :ARG1 (t / transcribe-01))) :degree (l / little)) :op2 (a6 / affect-01 :polarity - :ARG0 p2 :ARG1 a2) :time (a5 / and :op1 (i / immunoblot-01) :op2 (a7 / assay-01 :ARG1 (s / shift-01 :ARG1 (m2 / mobility :mod (e2 / elecropholic)))) :op3 (a8 / assay-01 :ARG1 (l2 / luciferase)))) :ARG2 (e / essential :domain p3 :purpose (d3 / differentiate-01 :ARG1 (c2 / cell :name (n10 / name :op1 "M1")) :ARG2-of (i2 / induce-01 :ARG0 (p4 / protein :name (n11 / name :op1 "IL-6"))) :mod (m / macrophage)))) # ::id bel_pmid_1066_6199.38222 ::date 2015-04-09T08:03:06 ::annotator SDL-AMR-09 ::preferred # ::snt During IL-6-induced macrophage differentiation of M1 cells, IL-6 down-regulated cyclin D1 expression and induced p19(INK4D) expression, leading to reduction in cdk4 activities. In contrast, sustained expression of cyclin D1 and a significantly lesser amount of p19(INK4D) induction were observed in IL-6-treated M1 cells overexpressing GATA-1. # ::save-date Sun Jan 3, 2016 ::file bel_pmid_1066_6199_38222.txt (m / multi-sentence :snt1 (a / and :op1 (d / downregulate-01 :ARG1 (e / express-03 :ARG2 (p2 / protein :name (n2 / name :op1 "cyclin" :op2 "D1"))) :ARG2 (p / protein :name (n / name :op1 "IL-6"))) :op2 (i / induce-01 :ARG0 p :ARG2 (e2 / express-03 :ARG1 (g / gene :name (n7 / name :op1 "p19(INK4D)")))) :ARG0-of (l / lead-03 :ARG2 (r / reduce-01 :ARG1 (a2 / activity-06 :ARG0 (e3 / enzyme :name (n3 / name :op1 "cdk4"))))) :time (d2 / differentiate-01 :ARG1 (c / cell :name (n4 / name :op1 "M1")) :ARG2-of (i2 / induce-01 :ARG0 p) :mod (m2 / macrophage))) :snt2 (c3 / contrast-01 :ARG2 (o / observe-01 :ARG1 (a3 / and :op1 (e4 / express-03 :ARG1 (p3 / protein :name (n6 / name :op1 "cyclin" :op2 "D1")) :ARG1-of (s / sustain-01)) :op2 (a4 / amount :mod (l2 / less :degree (s2 / significant) :degree (m3 / more)) :degree-of (i4 / induce-01 :ARG2 (g2 / gene :name (n8 / name :op1 "p19(INK4D)"))))) :location (c4 / cell :name (n9 / name :op1 "M1") :ARG1-of (t / treat-04 :ARG2 (p4 / protein :name (n10 / name :op1 "IL-6"))) :location-of (o2 / overexpress-01 :ARG1 (p5 / protein :name (n11 / name :op1 "GATA-1"))))))) # ::id bel_pmid_1067_7502.3614 ::date 2015-04-09T08:22:18 ::annotator SDL-AMR-09 ::preferred # ::snt High concentrations of stauro of up to 1 microM only partially inhibit IL-3-stimulated Bcl2 phosphorylation but completely block PKC-mediated Bcl2 phosphorylation in vitro # ::save-date Wed Mar 2, 2016 ::file bel_pmid_1067_7502_3614.txt (c / contrast-01 :ARG1 (i / inhibit-01 :ARG0 (c2 / concentrate-02 :ARG0 (s / small-molecule :name (n4 / name :op1 "stauro")) :ARG1-of (h / high-02) :quant (u / up-to :op1 (c4 / concentration-quantity :quant 1 :unit (m2 / micromolar)))) :ARG1 (p3 / phosphorylate-01 :ARG1 (p4 / protein :name (n / name :op1 "Bcl2")) :ARG1-of (s2 / stimulate-01 :ARG0 (p5 / protein :name (n2 / name :op1 "IL-3")))) :degree (p2 / part) :mod (o / only)) :ARG2 (b / block-01 :ARG0 c2 :ARG1 (p / phosphorylate-01 :ARG1 p4 :ARG1-of (m / mediate-01 :ARG0 (e / enzyme :name (n3 / name :op1 "PKC")))) :ARG1-of (c3 / complete-02) :manner (i2 / in-vitro))) # ::id bel_pmid_1067_7502.21952 ::date 2015-04-11T01:45:18 ::annotator SDL-AMR-09 ::preferred # ::snt p44MAPK/extracellular signal-regulated kinase 1 (ERK1) and p42 MAPK/ERK2 are activated by IL-3, colocalize with mitochondrial Bcl2, and can directly phosphorylate Bcl2 on Ser-70 in a stauro-resistant manner both in vitro and in vivo # ::save-date Tue Feb 2, 2016 ::file bel_pmid_1067_7502_21952.txt (a / and :op1 (a2 / activate-01 :ARG0 (p / protein :name (n6 / name :op1 "IL-3")) :ARG1 (a3 / and :op1 (e / enzyme :name (n / name :op1 "p44MAPK") :ARG1-of (m / mean-01 :ARG2 (e2 / enzyme :name (n2 / name :op1 "extracellular" :op2 "signal-regulated" :op3 "kinase" :op4 "1") :ARG1-of (d / describe-01 :ARG2 (e3 / enzyme :name (n3 / name :op1 "ERK1")))))) :op2 (e4 / enzyme :name (n4 / name :op1 "p42MAPK") :ARG1-of (m2 / mean-01 :ARG2 (e5 / enzyme :name (n5 / name :op1 "ERK2")))))) :op2 (c / colocalize-01 :ARG1 (a6 / and :op1 a3 :op2 (p2 / protein :name (n7 / name :op1 "Bcl2") :part-of (m3 / mitochondrion)))) :op3 (p3 / possible-01 :ARG1 (p4 / phosphorylate-01 :ARG1 (a4 / amino-acid :mod 70 :name (n8 / name :op1 "serine") :part-of p2) :ARG2 a3 :manner (r / resist-01 :ARG1 (s / small-molecule :name (n9 / name :op1 "stauro"))) :manner (a5 / and :op1 (i / in-vitro) :op2 (i2 / in-vivo)) :ARG1-of (d2 / direct-02)))) # ::id bel_pmid_1068_1535.5746 ::date 2015-04-11T02:11:44 ::annotator SDL-AMR-09 ::preferred # ::snt We found that TPO stimulation or Ha-Ras G12V expression led to up-regulation of cyclin D1, cyclin D2, and cyclin D3 expression. # ::save-date Sat Jan 16, 2016 ::file bel_pmid_1068_1535_5746.txt (f / find-01 :ARG0 (w / we) :ARG1 (l / lead-03 :ARG0 (o / or :op1 (s / stimulate-01 :ARG1 (p / protein :name (n / name :op1 "TPO"))) :op2 (e / express-03 :ARG2 (e5 / enzyme :name (n2 / name :op1 "Ha-Ras") :ARG2-of (m / mutate-01 :value "G12V")))) :ARG2 (u / upregulate-01 :ARG1 (a2 / and :op1 (e2 / express-03 :ARG2 (p3 / protein :name (n3 / name :op1 "cyclin" :op2 "D1"))) :op2 (e3 / express-03 :ARG2 (p4 / protein :name (n4 / name :op1 "cyclin" :op2 "D2"))) :op3 (e4 / express-03 :ARG2 (p5 / protein :name (n5 / name :op1 "cyclin" :op2 "D3"))))))) # ::id bel_pmid_1068_1535.24496 ::date 2015-04-11T02:21:10 ::annotator SDL-AMR-09 ::preferred # ::snt By using a refined model of megakaryocytic differentiation, we found that either TPO stimulation or Ha-Ras G12V expression could up-regulate the expression of cyclin D1 and cyclin D2 in addition to cyclin D3, and that, when cdc2 activity was suppressed, each of cyclin D1, cyclin D2, and cyclin D3 expression was able to induce megakaryocytic differentiation with a similar efficiency. # ::save-date Wed Jan 13, 2016 ::file bel_pmid_1068_1535_24496.txt (f / find-01 :ARG0 (w / we) :ARG1 (a / and :op1 (p2 / possible-01 :ARG1 (u / upregulate-01 :ARG1 a3 :ARG2 (o / or :op1 (s / stimulate-01 :ARG1 (p3 / protein :name (n / name :op1 "TPO"))) :op2 (e / express-03 :ARG2 (e7 / enzyme :name (n2 / name :op1 "Ha-Ras") :ARG2-of (m / mutate-01 :value "G12V")))))) :op2 (p8 / possible-01 :ARG1 (i / induce-01 :ARG0 (a3 / and :op1 (e3 / express-03 :ARG2 (p9 / protein :name (n6 / name :op1 "cyclin" :op2 "D1"))) :op2 (e4 / express-03 :ARG2 (p10 / protein :name (n7 / name :op1 "cyclin" :op2 "D2"))) :op3 (e5 / express-03 :ARG2 (p11 / protein :name (n8 / name :op1 "cyclin" :op2 "D3"))) :mod (e6 / each)) :ARG2 (d / differentiate-01 :ARG1 (c / cell :name (n10 / name :op1 "megakaryocyte"))) :ARG1-of (e2 / efficient-01 :ARG1-of (r2 / resemble-01))) :time (s2 / suppress-01 :ARG1 (a2 / activity-06 :ARG0 (e8 / enzyme :name (n9 / name :op1 "cdc2")))))) :manner (u2 / use-01 :ARG1 (m3 / model :ARG1-of (r / refine-01) :topic d))) # ::id bel_pmid_1069_9758.15770 ::date 2015-04-09T09:06:02 ::annotator SDL-AMR-09 ::preferred # ::snt which are dual-specificity (serine/threonine and tyrosine) kinases that regulate downstream responses to a broad range of mitogenic, apoptotic, and differentiation-inducing stimuli [368-372]. Interestingly, MEK1 but not MEK2 is stimulated by H2O2 treatment, suggesting that only MEK1 is redox-sensitive [154]. # ::save-date Sun Jan 3, 2016 ::file bel_pmid_1069_9758_15770.txt (m / multi-sentence :snt1 (r / regulate-01 :ARG0 (k / kinase :mod (s7 / specificity :ARG1-of (m2 / mean-01 :ARG2 (a / and :op1 (s / slash :op1 (a2 / amino-acid :wiki "Serine" :name (n / name :op1 "serine")) :op2 (a3 / amino-acid :wiki "Threonine" :name (n2 / name :op1 "threonine"))) :op2 (a4 / amino-acid :wiki "Tyrosine" :name (n3 / name :op1 "tyrosine")))) :mod (d / dual))) :ARG1 (r2 / respond-01 :ARG1 (r4 / range-01 :ARG1 (s5 / stimulus :mod (m3 / mitogenic) :mod (a5 / apoptosis) :ARG0-of (i / induce-01 :ARG2 (d3 / differentiate-01))) :ARG1-of (b / broad-02))) :direction (d2 / downstream) :ARG1-of (d4 / describe-01 :ARG0 (p / publication :ARG1-of (c / cite-01 :ARG2 (v / value-interval :op1 368 :op2 372))))) :snt2 (c2 / contrast-01 :ARG1 (s2 / stimulate-01 :ARG0 (t / treat-04 :ARG2 (s8 / small-molecule :wiki "Hydrogen_peroxide" :name (n6 / name :op1 "H2O2"))) :ARG1 (e / enzyme :wiki "MAP2K1" :name (n4 / name :op1 "MEK1"))) :ARG2 (s3 / stimulate-01 :polarity - :ARG0 t :ARG1 (e2 / enzyme :wiki "MAP2K2" :name (n5 / name :op1 "MEK2"))) :ARG2-of (i2 / interest-01) :ARG0-of (s4 / suggest-01 :ARG1 (s6 / sensitive-03 :ARG0 e :ARG1 (r3 / redox) :mod (o / only)) :ARG2-of (i3 / interest-01) :ARG1-of (d5 / describe-01 :ARG0 (p2 / publication :ARG1-of (c3 / cite-01 :ARG2 154)))))) # ::id bel_pmid_1069_9758.24188 ::date 2015-04-11T06:31:13 ::annotator SDL-AMR-09 ::preferred # ::snt Additionally, several studies have shown that antioxidant enzymes and mimics also block NF-kB activation by various stimuli. For example, overexpression of peroxiredoxin [247] or thioredoxin [111] blocks NF-kB activation by H2O2. # ::save-date Wed Oct 28, 2015 ::file bel_pmid_1069_9758_24188.txt (m / multi-sentence :snt1 (s / show-01 :ARG0 (s2 / study-01 :quant (s3 / several)) :ARG1 (b / block-01 :ARG0 (a7 / and :op1 (e2 / enzyme :mod (a2 / antioxidant)) :op2 (m2 / mimic-01)) :ARG1 (a4 / activate-01 :ARG1 (p / protein :name (n / name :op1 "NF-kB"))) :ARG3 (s4 / stimulus :mod (v / various)) :mod (a / also)) :mod (a6 / additional)) :snt2 (b3 / block-01 :ARG0 (o4 / or :op1 (o / overexpress-01 :ARG1 (e4 / enzyme :name (n2 / name :op1 "peroxiredoxin")) :ARG1-of (d / describe-01 :ARG0 (p2 / publication :ARG1-of (c / cite-01 :ARG2 247)))) :op2 (o2 / overexpress-01 :ARG1 (p4 / protein :name (n4 / name :op1 "thioredoxin")) :ARG1-of (d2 / describe-01 :ARG0 (p5 / publication :ARG1-of (c2 / cite-01 :ARG2 111))))) :ARG1 (a5 / activate-01 :ARG1 (p3 / protein :name (n3 / name :op1 "NF-kB"))) :ARG3 (s5 / small-molecule :name (n5 / name :op1 "H2O2")) :ARG0-of (e / exemplify-01))) # ::id bel_pmid_1069_9758.34686 ::date 2015-04-11T07:06:57 ::annotator SDL-AMR-09 ::preferred # ::snt Furthermore, in many types of cells, antioxidants diminish or completely eliminate NF-kB activation (Table 1). For example, H2O2, UV, and ionizing radiation have all been observed to stimulate degradation of IkB (Table 1). Conversely, antioxidants and reductants such as BHA, NGA, a-tocopherol, NAC, and PDTC decrease NF-kB activity and translocation [12,253]. # ::save-date Wed Mar 2, 2016 ::file bel_pmid_1069_9758_34686.txt (m / multi-sentence :snt1 (a / and :op2 (o / or :op1 (d / diminish-01 :ARG0 (a10 / antioxidant) :ARG1 (a2 / activate-01 :ARG1 (p / protein :name (n2 / name :op1 "NF-kB")))) :op2 (e2 / eliminate-01 :ARG1 a2 :ARG1-of (c4 / complete-02)) :location (t / type-03 :ARG1 (c / cell) :mod (m3 / many))) :ARG1-of (d2 / describe-01 :ARG0 (t2 / table :mod 1))) :snt2 (o2 / observe-01 :ARG1 (s / stimulate-01 :ARG0 (a3 / and :op1 (s2 / small-molecule :wiki "Hydrogen_peroxide" :name (n5 / name :op1 "H2O2")) :op2 (l / light :mod (u / ultraviolet)) :op3 (r / radiate-01 :ARG0-of (i / ionize-01)) :mod (a11 / all)) :ARG1 (d3 / degrade-01 :ARG1 (p4 / protein :name (n3 / name :op1 "IkB")))) :ARG1-of (d4 / describe-01 :ARG0 (t3 / table :mod 1)) :ARG0-of (e / exemplify-01)) :snt3 (c2 / contrast-01 :ARG2 (d5 / decrease-01 :ARG0 (a12 / and :op1 (a7 / antioxidant :example (a13 / and :op1 (a14 / antioxidant :name (n / name :op1 "BHA")) :op2 (a15 / antioxidant :name (n12 / name :op1 "NGA")))) :op2 (r2 / reductant :example (a6 / and :op1 (r3 / reductant :name (n4 / name :op1 "a-tocopherol")) :op2 (r4 / reductant :name (n6 / name :op1 "NAC")) :op3 (r5 / reductant :name (n7 / name :op1 "PDTC"))))) :ARG1 (a4 / and :op1 (a5 / activity-06 :ARG0 (p2 / protein :name (n11 / name :op1 "NF-kB"))) :op2 (t4 / translocate-01 :ARG1 p2)) :ARG1-of (d7 / describe-01 :ARG0 (p3 / publication :ARG1-of (c3 / cite-01 :ARG2 (a9 / and :op1 12 :op2 253))))))) # ::id bel_pmid_1069_9758.36926 ::date 2015-04-12T05:16:31 ::annotator SDL-AMR-09 ::preferred # ::snt Once activated, Raf-1 phosphorylates serines in the catalytic sites of MKK/MEK [345,367]. MKK1/MEK1 and MKK2/MEK2 activate members of the MAP kinase family (ERK-1/ERK-2), # ::save-date Mon Jan 4, 2016 ::file bel_pmid_1069_9758_36926.txt (m / multi-sentence :snt1 (p / phosphorylate-01 :ARG1 (a / amino-acid :name (n2 / name :op1 "serine") :part-of (p3 / protein-segment :part-of (s2 / slash :op1 (e5 / enzyme :name (n6 / name :op1 "MKK")) :op2 (e6 / enzyme :name (n7 / name :op1 "MEK"))) :mod (c / catalysis))) :ARG2 (e / enzyme :name (n / name :op1 "Raf-1")) :time (a2 / activate-01 :ARG1 e) :ARG1-of (d / describe-01 :ARG0 (p2 / publication :ARG1-of (c2 / cite-01 :ARG2 (a3 / and :op1 345 :op2 367))))) :snt2 (a5 / activate-01 :ARG0 (a7 / and :op1 (s3 / slash :op1 (e4 / enzyme :name (n5 / name :op1 "MKK1")) :op2 (e2 / enzyme :name (n3 / name :op1 "MEK1"))) :op2 (s5 / slash :op1 (e9 / enzyme :name (n10 / name :op1 "MKK2")) :op2 (e10 / enzyme :name (n11 / name :op1 "MEK2")))) :ARG1 (m2 / member :ARG1-of (m3 / mean-01 :ARG2 (s4 / slash :op1 (e7 / enzyme :name (n8 / name :op1 "ERK-1")) :op2 (e8 / enzyme :name (n9 / name :op1 "ERK-2")))) :ARG1-of (i / include-91 :ARG2 (p4 / protein-family :name (n4 / name :op1 "MAP" :op2 "kinase")))))) # ::id bel_pmid_1072_9607.86 ::date 2015-04-13T12:11:45 ::annotator SDL-AMR-09 ::preferred # ::snt These results are consistent with our previous data showing that PAF is able to translocate PKCa and PKCe from cytosol to plasma membrane # ::save-date Fri Feb 12, 2016 ::file bel_pmid_1072_9607_86.txt (c / consistent-01 :ARG1 (t3 / thing :ARG2-of (r / result-01) :mod (t / this)) :ARG2 (d / data :poss (w / we) :time (p2 / previous)) :ARG0-of (s / show-01 :ARG1 (p / possible-01 :ARG1 (t2 / translocate-01 :ARG0 (s2 / small-molecule :name (n / name :op1 "PAF")) :ARG1 (a / and :op1 (e / enzyme :name (n2 / name :op1 "PKCa")) :op2 (e2 / enzyme :name (n3 / name :op1 "PKCe"))) :ARG2 (m2 / membrane :mod (p3 / plasma)) :ARG3 (c2 / cytosol))))) # ::id bel_pmid_1072_9607.18666 ::date 2015-04-13T12:23:45 ::annotator SDL-AMR-09 ::preferred # ::snt Eosinophils Human Superoxide production Human Transmigration through epithelial cells Human Transmigration through Matrigel Human CD11b/CD18 (Mac-1) translocation, degranulation Human IL-8 release # ::save-date Fri Feb 12, 2016 ::file bel_pmid_1072_9607_18666.txt (m / multi-sentence :snt1 (p / produce-01 :ARG1 (s / superoxide :mod (h / human) :mod (c / cell :name (n / name :op1 "eosinophil")))) :snt2 (t / transmigrate-01 :ARG1 (c2 / cell :mod (e / epithelium)) :mod (h5 / human)) :snt3 (t2 / transmigrate-01 :ARG1 (p5 / protein :name (n3 / name :op1 "Matrigel") :mod (h3 / human)) :mod (h2 / human)) :snt4 (a / and :op1 (t4 / translocate-01 :ARG1 (m2 / macro-molecular-complex :part (p2 / protein :name (n4 / name :op1 "CD11b")) :part (p3 / protein :name (n5 / name :op1 "CD18")) :ARG1-of (m3 / mean-01 :ARG2 (s2 / small-molecule :name (n2 / name :op1 "Mac-1"))))) :op2 (d / degranulate-00 :ARG1 (r / release-01 :ARG0 (p4 / protein :name (n6 / name :op1 "IL-8") :mod (h4 / human)))))) # ::id bel_pmid_1072_9607.19486 ::date 2015-04-13T12:30:20 ::annotator SDL-AMR-09 ::preferred # ::snt Activation of tyrosine kinases Fyn and Lyn, but not Lck, also occurred within 2 min after PAF stimulation in the cells # ::save-date Fri Feb 12, 2016 ::file bel_pmid_1072_9607_19486.txt (c3 / contrast-01 :ARG1 (a3 / activate-01 :ARG1 (a / and :op1 (e / enzyme :name (n / name :op1 "tyrosine" :op2 "kinase" :op3 "Fyn")) :op2 (e2 / enzyme :name (n2 / name :op1 "tyrosine" :op2 "kinase" :op3 "Lyn"))) :time (a6 / after :op1 (s / stimulate-01 :ARG1 (s2 / small-molecule :name (n4 / name :op1 "PAF")) :location (c2 / cell)) :quant (u / up-to :op1 (t / temporal-quantity :quant 2 :unit (m2 / minute)))) :mod (a2 / also)) :ARG2 (a5 / activate-01 :polarity - :ARG1 (e3 / enzyme :name (n3 / name :op1 "Lck")))) # ::id bel_pmid_1072_9607.19488 ::date 2015-04-13T12:41:31 ::annotator SDL-AMR-09 ::preferred # ::snt PAFR promoter 2 contained AP-2 and Sp-1 binding sites we demonstrated that PAF activates p44ERK1/p42ERK2 in CHO cells stably expressing PAF receptor # ::save-date Fri Feb 12, 2016 ::file bel_pmid_1072_9607_19488.txt (m3 / multi-sentence :snt1 (c2 / contain-01 :ARG0 (m4 / molecular-physical-entity :ARG0-of (p / promote-01 :ARG1 (p6 / protein :name (n5 / name :op1 "PAFR")))) :ARG1 (b / bind-01 :ARG1 (a2 / and :op1 (p4 / protein-segment :ARG1-of (b2 / bind-01 :ARG2 (p2 / protein :name (n6 / name :op1 "AP-2")))) :op2 (p5 / protein-segment :ARG1-of (b3 / bind-01 :ARG2 (p3 / protein :name (n8 / name :op1 "Sp-1"))))))) :snt2 (d / demonstrate-01 :ARG0 (w / we) :ARG1 (a / activate-01 :ARG0 (p7 / protein :name (n / name :op1 "PAF" :op2 "receptor")) :ARG1 (m2 / macro-molecular-complex :part (e / enzyme :name (n2 / name :op1 "p44ERK1")) :part (e2 / enzyme :name (n3 / name :op1 "p42ERK2"))) :location (c / cell-line :name (n4 / name :op1 "CHO") :ARG1-of (e3 / express-03 :ARG2 p7 :ARG1-of (s / stable-03)))))) # ::id bel_pmid_1072_9607.19490 ::date 2015-04-13T13:35:19 ::annotator SDL-AMR-09 ::preferred # ::snt PAF induced tyrosine phosphorylation and activation of focal adhesion kinase (FAK) in human endothelial cells derived from vein umbilical cord # ::save-date Fri Feb 12, 2016 ::file bel_pmid_1072_9607_19490.txt (i / induce-01 :ARG0 (s / small-molecule :name (n / name :op1 "PAF")) :ARG2 (a / and :op1 (p / phosphorylate-01 :ARG1 (a2 / amino-acid :name (n2 / name :op1 "tyrosine") :part-of e)) :op2 (a3 / activate-01 :ARG1 (e / enzyme :name (n3 / name :op1 "focal" :op2 "adhesion" :op3 "kinase")))) :location (c / cell :mod (e2 / endothelium) :mod (h / human) :ARG1-of (d / derive-01 :ARG2 (c2 / cord :mod (n4 / navel) :mod (v / vein))))) # ::id bel_pmid_1072_9607.22074 ::date 2015-04-13T13:49:55 ::annotator SDL-AMR-09 ::preferred # ::snt Suppression of the PAF effects by calphostin C, a PKC inhibitor, suggests that PKC is an upstream activator of FAK # ::save-date Fri Feb 12, 2016 ::file bel_pmid_1072_9607_22074.txt (s / suggest-01 :ARG0 (s2 / suppress-01 :ARG1 (a / affect-01 :ARG0 (c / calphostin :name (n2 / name :op1 "C") :ARG1-of (m2 / mean-01 :ARG2 (m3 / molecular-physical-entity :ARG0-of (i2 / inhibit-01 :ARG1 (e2 / enzyme :name (n3 / name :op1 "PKC")))))) :ARG1 (s3 / small-molecule :name (n / name :op1 "PAF")))) :ARG1 (a2 / activate-01 :ARG0 e2 :ARG1 (e3 / enzyme :name (n4 / name :op1 "FAK")) :direction (u / upstream))) # ::id bel_pmid_1072_9607.31242 ::date 2015-04-13T14:03:47 ::annotator SDL-AMR-09 ::preferred # ::snt transforming growth factor-b2 (TGF-b2) was shown to upregulate the transcription rate of PAFR transcript 1 in Ramos human lymphoblastoid cells # ::save-date Fri Feb 12, 2016 ::file bel_pmid_1072_9607_31242.txt (s / show-01 :ARG1 (u / upregulate-01 :ARG1 (r / rate :degree-of (t2 / transcribe-01 :ARG1 (p3 / protein :name (n2 / name :op1 "PAFR" :op2 "transcript" :op3 "1")))) :ARG2 (p2 / protein :name (n3 / name :op1 "transforming" :op2 "growth" :op3 "factor-b2") :ARG1-of (m / mean-01 :ARG2 (p / protein :name (n / name :op1 "TGF-b2")))) :location (c / cell :name (n4 / name :op1 "Ramos" :op2 "human" :op3 "lymphoblastoid")))) # ::id bel_pmid_1073_7606.7132 ::date 2015-04-13T14:43:10 ::annotator SDL-AMR-09 ::preferred # ::snt We have further identified, in the GFAP promoter region, a STAT3 site at which nucleotide substitutions almost completely abolished the IL-11-induced GFAP promoter activation. # ::save-date Sun Dec 20, 2015 ::file bel_pmid_1073_7606_7132.txt (i / identify-01 :ARG0 (w / we) :ARG1 (p3 / protein-segment :part-of (p / protein :name (n / name :op1 "STAT3"))) :ARG2 (a / abolish-01 :ARG0 (s2 / substitute-01 :ARG2 (n3 / nucleotide)) :ARG1 (a3 / activate-01 :ARG1 (m2 / molecular-physical-entity :ARG0-of (p4 / promote-01 :ARG1 (p5 / protein :name (n4 / name :op1 "GFAP")))) :ARG2-of (i2 / induce-01 :ARG0 (p6 / protein :name (n5 / name :op1 "IL-11")))) :ARG1-of (c / complete-02 :degree (a2 / almost))) :degree (f / further) :location (r / region :part-of (m / molecular-physical-entity :ARG0-of (p2 / promote-01 :ARG1 p5)))) # ::id bel_pmid_1073_7606.22816 ::date 2015-04-14T08:35:13 ::annotator SDL-AMR-09 ::preferred # ::snt Activation of the GFAP gene promoter by IL-11 and related cytokines Previous studies have shown that stimulation of gp130 molecules on neuroepithelial cells by LIF, CNTF, or the IL-6/sIL-6R complex induces activation of the GFAP gene promoter (Bonni et al., 1997 ; Nakashima et al., 1999 b ). # ::save-date Sun Jan 3, 2016 ::file bel_pmid_1073_7606_22816.txt (m / multi-sentence :snt2 (s2 / show-01 :ARG0 (s3 / study-01 :time (p9 / previous)) :ARG1 (i / induce-01 :ARG0 (s / stimulate-01 :ARG0 (p5 / protein :name (n5 / name :op1 "gp130")) :ARG1 (c / cell :mod (n6 / neuroepithelium)) :ARG2 (o3 / or :op1 (p4 / protein :name (n4 / name :op1 "LIF")) :op2 (p6 / protein :name (n7 / name :op1 "CNTF")) :op3 (m3 / macro-molecular-complex :part (p7 / protein :name (n8 / name :op1 "IL-6")) :part (p8 / protein :name (n9 / name :op1 "sIL-6R"))))) :ARG2 (a3 / activate-01 :ARG1 (m4 / molecular-physical-entity :ARG0-of (p10 / promote-01 :ARG1 (g2 / gene :name (n10 / name :op1 "GFAP")))))) :ARG1-of (d3 / describe-01 :ARG0 (a7 / and :op1 (p11 / publication-91 :ARG0 (a5 / and :op1 (p12 / person :name (n11 / name :op1 "Bonni")) :op2 (p13 / person :mod (o / other))) :time (d / date-entity :year 1997)) :op2 (p14 / publication-91 :ARG0 (a6 / and :op1 (p15 / person :name (n12 / name :op1 "Nakashima")) :op2 (p16 / person :mod (o2 / other))) :time (d2 / date-entity :year 1999))))) :snt1 (a2 / activate-01 :ARG0 (a8 / and :op1 (p2 / protein :name (n2 / name :op1 "IL-11")) :op2 (p3 / protein :name (n3 / name :op1 "cytokine") :ARG1-of (r / relate-01))) :ARG1 (m2 / molecular-physical-entity :ARG0-of (p / promote-01 :ARG1 (g / gene :name (n / name :op1 "GFAP")))))) # ::id bel_pmid_1074_4722.88 ::date 2015-04-14T09:31:17 ::annotator SDL-AMR-09 ::preferred # ::snt As shown in Fig. 5B, immediately after -irradiation, the amount of threonine 68- phosphorylated Chk2 increased (lane 2), and prior treatment of cells with caffeine markedly reduced this increase (lane 4). # ::save-date Sun Apr 26, 2015 ::file bel_pmid_1074_4722_88.txt (a5 / and :op1 (i / increase-01 :ARG1 (a3 / amount :quant-of (e / enzyme :name (n2 / name :op1 "Chk2") :part (a / amino-acid :mod 68 :name (n / name :op1 "threonine") :ARG1-of (p / phosphorylate-01)))) :ARG1-of (d / describe-01 :ARG2 (l / lane :mod 2)) :time (a4 / after :op1 (i2 / irradiate-01) :mod (i3 / immediate))) :op2 (r / reduce-01 :ARG0 (t / treat-03 :ARG1 (c / cell) :ARG3 (c2 / caffeine) :time (p2 / prior)) :ARG1 i :manner (m2 / marked) :ARG1-of (d2 / describe-01 :ARG2 (l2 / lane :mod 4))) :ARG1-of (s / show-01) :location (f / figure :mod "5B")) # ::id bel_pmid_1074_4722.15494 ::date 2015-04-14T09:48:01 ::annotator SDL-AMR-09 ::preferred # ::snt As shown in Fig. 3A in normal cells, IR causes activation of Chk2/Cds1 (lane 2), and this activation is inhibited by prior treatment of cells with caffeine (lane 4). # ::save-date Sun Jan 17, 2016 ::file bel_pmid_1074_4722_15494.txt (a / and :op1 (c / cause-01 :ARG0 (r / radiate-01 :ARG0-of (i2 / ionize-01)) :ARG1 (a2 / activate-01 :ARG1 (m / macro-molecular-complex :part (e / enzyme :name (n2 / name :op1 "Chk2")) :part (e2 / enzyme :name (n3 / name :op1 "Cds1")))) :ARG1-of (d2 / describe-01 :ARG2 (l / lane :mod 2))) :op1 (i / inhibit-01 :ARG0 (t2 / treat-03 :ARG1 (c2 / cell) :ARG3 (c3 / caffeine) :time (p / prior)) :ARG1 a2 :ARG1-of (d / describe-01 :ARG2 (l2 / lane :mod 4))) :ARG1-of (s / show-01 :location (f / figure :mod "3A")) :location (c4 / cell :ARG1-of (n4 / normal-02))) # ::id bel_pmid_1074_4722.15496 ::date 2015-04-14T10:01:59 ::annotator SDL-AMR-09 ::preferred # ::snt Immediately after IR, an increase in serine 216-phosphorylated Cdc25C was observed in the nuclear fraction (Fig. 1B, lane 2), and prior treatment of cells with caffeine inhibited this increase (Fig. 1B, lane 4). # ::save-date Sun Jan 17, 2016 ::file bel_pmid_1074_4722_15496.txt (a2 / and :op1 (o / observe-01 :ARG1 (i / increase-01 :ARG1 (e / enzyme :name (n3 / name :op1 "Cdc25C") :part (a3 / amino-acid :mod 216 :name (n2 / name :op1 "serine") :ARG0-of (p / phosphorylate-01)))) :location (f / fraction-01 :mod (n4 / nucleus)) :time (a / after :op1 (r / radiate-01 :ARG0-of (i4 / ionize-01)) :mod (i2 / immediate)) :ARG1-of (d / describe-01 :ARG0 (a4 / and :op1 (f2 / figure :mod "1B") :op2 (l / lane :mod 2)))) :op2 (i3 / inhibit-01 :ARG0 (t2 / treat-03 :ARG1 (c / cell) :ARG3 (c2 / caffeine) :time (p2 / prior)) :ARG1 i :ARG1-of (d2 / describe-01 :ARG0 (a5 / and :op1 (f3 / figure :mod "1B") :op2 (l2 / lane :mod 4))))) # ::id bel_pmid_1074_4722.15498 ::date 2015-04-14T11:11:23 ::annotator SDL-AMR-09 ::preferred # ::snt As shown in Fig. 6A, ATM immunoprecipitated from irradiated cells was more active than that from unirradiated cells, and both the basal and radiationinduced ATM activities were inhibited by caffeine with an IC50 at around 200 M. # ::save-date Sun Jan 3, 2016 ::file bel_pmid_1074_4722_15498.txt (a2 / and :op1 (a3 / activity-06 :ARG0 (e / enzyme :name (n / name :op1 "ATM") :ARG1-of (i / immunoprecipitate-01 :ARG2 (c / cell :ARG1-of (i2 / irradiate-01)))) :degree (m2 / more) :compared-to (e2 / enzyme :name (n2 / name :op1 "ATM") :ARG1-of (i3 / immunoprecipitate-01 :ARG2 (c2 / cell :ARG1-of (i8 / irradiate-01 :polarity -))))) :op2 (i5 / inhibit-01 :ARG0 (c3 / caffeine :ARG1-of (h / have-percentage-maximal-inhibitory-concentration-01 :ARG2 50 :ARG4 (a / around :op1 (c4 / concentration-quantity :quant 200 :unit (m / molar))))) :ARG1 (a5 / and :op1 (a4 / activity-06 :ARG0 (e3 / enzyme :name (n3 / name :op1 "ATM")) :mod (b / basal)) :op2 (a6 / activity-06 :ARG0 e3 :ARG2-of (i6 / induce-01 :ARG0 (r / radiate-01))))) :ARG1-of (s / show-01 :location (f / figure :mod "6A"))) # ::id bel_pmid_1074_4722.15500 ::date 2015-04-14T11:32:28 ::annotator SDL-AMR-09 ::preferred # ::snt However, no such activation was found in A-T cells indicating that caffeine inhibited the ATM-dependent Chk2/Cds1 activation (Fig. 3A, lanes 6 and 8). # ::save-date Tue Apr 14, 2015 ::file bel_pmid_1074_4722_15500.txt (h / have-concession-91 :ARG1 (f / find-01 :ARG1 (a / activate-01 :polarity - :mod (s / such)) :location (c / cell :name (n / name :op1 "A-T")) :ARG0-of (i / indicate-01 :ARG1 (i2 / inhibit-01 :ARG0 (c2 / caffeine) :ARG1 (a2 / activate-01 :ARG1 (e / enzyme :name (n2 / name :op1 "ATM") :ARG0-of (d / depend-01 :ARG1 (m / macro-molecular-complex :part (e2 / enzyme :name (n3 / name :op1 "Chk2")) :part (e3 / enzyme :name (n4 / name :op1 "Cds1"))))))))) :ARG1-of (d2 / describe-01 :ARG0 (a3 / and :op1 (f2 / figure :mod "3A") :op2 (a4 / and :op1 (l / lane :op1 6) :op2 (l2 / lane :mod 8))))) # ::id bel_pmid_1074_4722.21126 ::date 2015-04-14T11:42:05 ::annotator SDL-AMR-09 ::preferred # ::snt Substitution of threonine 68 by alanine in the full-length kinase-dead Chk2 dramatically reduced but did not abolish the ATM phosphorylation of Chk2/Cds1 in vitro (Fig. 4B; threonine 68 accounts for approximately 70% of the total phosphorylation). # ::save-date Mon Dec 21, 2015 ::file bel_pmid_1074_4722_21126.txt (m / multi-sentence :snt1 (c / contrast-01 :ARG1 (r / reduce-01 :ARG0 (s / substitute-01 :ARG1 (a2 / amino-acid :name (n2 / name :op1 "alanine")) :ARG2 (a / amino-acid :name (n / name :op1 "threonine")) :location (e / enzyme :name (n3 / name :op1 "Chk2") :ARG0-of (f3 / function-01 :polarity - :ARG1 (k / kinase :ARG1-of (l / long-03 :degree (f / full)))))) :ARG1 (p3 / phosphorylate-01 :ARG1 (m2 / macro-molecular-complex :part (e2 / enzyme :name (n4 / name :op1 "Chk2")) :part (e4 / enzyme :name (n6 / name :op1 "Cds1"))) :ARG2 (e3 / enzyme :name (n5 / name :op1 "ATM")) :manner (i / in-vitro)) :manner (d2 / dramatic)) :ARG2 (a3 / abolish-01 :ARG0 s :ARG1 p3) :ARG1-of (d3 / describe-01 :ARG0 (f2 / figure :mod "4B"))) :snt2 (a4 / account-01 :ARG1 (a5 / amino-acid :mod 68 :name (n7 / name :op1 "threonine") :ARG1-of (i2 / include-91 :ARG2 (t / total-01 :ARG1 (p2 / phosphorylate-01)) :ARG3 (a7 / approximately :op1 (p / percentage-entity :value 70)))))) # ::id bel_pmid_1074_4722.21132 ::date 2015-04-14T12:32:00 ::annotator SDL-AMR-09 ::preferred # ::snt Serine 15 in the N terminus of p53 has been shown to be the preferred ATM phosphorylation site (27, 29, 30). As shown in Fig. 7A, ATM immunoprecipitated from irradiated cells was more active than that from control cells, and both ATM activities were inhibited by caffeine with IC50 at around 200 M. # ::save-date Sun Jan 3, 2016 ::file bel_pmid_1074_4722_21132.txt (m2 / multi-sentence :snt1 (s / show-01 :ARG1 (p / protein-segment :ARG1-of (p5 / phosphorylate-01 :ARG2 (e / enzyme :name (n5 / name :op1 "ATM"))) :ARG1-of (p4 / prefer-01) :domain (a3 / amino-acid :mod 15 :name (n2 / name :op1 "serine") :part-of (p2 / protein-segment :name (n3 / name :op1 "N" :op2 "terminus") :part-of (p3 / protein :name (n4 / name :op1 "p53"))))) :ARG1-of (d2 / describe-01 :ARG0 (p6 / publication :ARG1-of (c / cite-01 :ARG2 (a4 / and :op1 27 :op2 29 :op3 30))))) :snt2 (a2 / and :op1 (a7 / activity-06 :ARG0 (e2 / enzyme :name (n / name :op1 "ATM") :ARG1-of (i / immunoprecipitate-01 :ARG2 (c2 / cell :ARG1-of (i2 / irradiate-01)))) :degree (m3 / more) :compared-to (e3 / enzyme :name (n6 / name :op1 "ATM") :ARG1-of (i3 / immunoprecipitate-01 :ARG2 (c3 / cell :mod (c5 / control-01))))) :op2 (i4 / inhibit-01 :ARG0 (c4 / caffeine :ARG1-of (h / have-percentage-maximal-inhibitory-concentration-01 :ARG2 50 :ARG4 (a / around :op1 (c6 / concentration-quantity :quant 200 :unit (m / molar))))) :ARG1 (a5 / activity-06 :ARG0 (a6 / and :op1 e2 :op2 e3))) :ARG1-of (s3 / show-01 :location (f / figure :mod "7A")))) # ::id bel_pmid_1074_4722.21168 ::date 2015-04-14T13:16:27 ::annotator SDL-AMR-09 ::preferred # ::snt Both Chk1 and Chk2/Cds1 have been shown to localize to the nucleus and to phosphorylate serine 216 of Cdc25C in vitro (13, 15) (18–21). # ::save-date Sun Apr 26, 2015 ::file bel_pmid_1074_4722_21168.txt (s / show-01 :ARG1 (a2 / and :op1 (b / be-located-at-91 :ARG1 (a5 / and :op1 (e / enzyme :name (n2 / name :op1 "Chk1")) :op2 (m / macro-molecular-complex :part (e2 / enzyme :name (n3 / name :op1 "Chk2")) :part (e3 / enzyme :name (n4 / name :op1 "Cds1")))) :ARG2 (n5 / nucleus)) :op2 (p / phosphorylate-01 :ARG1 (a / amino-acid :mod 216 :name (n / name :op1 "serine") :part-of (e4 / enzyme :name (n6 / name :op1 "Cdc25C"))) :ARG2 a5 :manner (i / in-vitro))) :ARG1-of (d2 / describe-01 :ARG0 (a4 / and :op1 (p2 / publication :ARG1-of (c / cite-01 :ARG2 (a3 / and :op1 13 :op2 15))) :op2 (p3 / publication :ARG1-of (c2 / cite-01 :ARG2 (v / value-interval :op1 18 :op2 21)))))) # ::id bel_pmid_1074_4722.21170 ::date 2015-04-14T13:31:50 ::annotator SDL-AMR-09 ::preferred # ::snt As shown in the Western blot (Fig. 1A, lane 3), the phospho-S216 antibody recognized Cdc25C that was incubated with a wild type Chk2 in the in vitro kinase assay but failed to recognize unphosphorylated Cdc25C, incubated with a kinase-dead mutant (D347A) (Fig. 1A, lane 2). # ::save-date Sun Jan 3, 2016 ::file bel_pmid_1074_4722_21170.txt (c / contrast-01 :ARG1 (r / recognize-01 :ARG0 (a / antibody :ARG0-of (c2 / counter-01 :ARG1 (a5 / amino-acid :mod 216 :name (n / name :op1 "serine")))) :ARG1 (e / enzyme :name (n3 / name :op1 "Cdc25C") :ARG1-of (i / incubate-01 :ARG2 (e2 / enzyme :name (n4 / name :op1 "Chk2") :mod (w / wild-type)) :time (a3 / assay-01 :ARG1 (k / kinase) :manner (i2 / in-vitro))))) :ARG2 (f2 / fail-01 :ARG1 a :ARG2 (r2 / recognize-01 :ARG0 a :ARG1 (e3 / enzyme :name (n5 / name :op1 "Cdc25C") :ARG3-of (p / phosphorylate-01 :polarity -) :ARG1-of (i3 / incubate-01 :ARG2 (m2 / molecular-physical-entity :ARG2-of (m / mutate-01 :value "D347A") :ARG0-of (f / function-01 :polarity - :ARG1 (k2 / kinase)))))) :ARG1-of (d / describe-01 :ARG0 (a2 / and :op1 (f3 / figure :mod "1A") :op2 (l / lane :mod 2)))) :ARG1-of (s / show-01 :ARG0 (i4 / immunoblot-01 :ARG1-of (d2 / describe-01 :ARG0 (a4 / and :op1 (f4 / figure :mod "1A") :op2 (l2 / lane :mod 3)))))) # ::id bel_pmid_1074_7872.20016 ::date 2015-04-14T14:11:40 ::annotator SDL-AMR-09 ::preferred # ::snt We found that STAT3, but not STAT5, was activated in response to IGF-I in 293T cells cotransfected with IGF-IR and STAT expression vectors. Moreover, tyrosine phosphorylation of STAT3, JAK1, and JAK2 was increased upon IGF-I stimulation of endogenous IGF-IR in 293T cells transfected with the respective STAT or JAK expression vector. # ::save-date Sun Jan 17, 2016 ::file bel_pmid_1074_7872_20016.txt (m / multi-sentence :snt2 (a4 / and :op2 (i / increase-01 :ARG1 (p / phosphorylate-01 :ARG1 (a5 / and :op1 (a6 / amino-acid :name (n7 / name :op1 "tyrosine") :part-of (p6 / protein :name (n8 / name :op1 "STAT3"))) :op2 (a7 / amino-acid :name (n16 / name :op1 "tyrosine") :part-of (e7 / enzyme :name (n9 / name :op1 "JAK1"))) :op3 (a8 / amino-acid :name (n17 / name :op1 "tyrosine") :part-of (e8 / enzyme :name (n10 / name :op1 "JAK2"))))) :time (s / stimulate-01 :ARG0 (p9 / protein :name (n11 / name :op1 "IGF-I")) :ARG1 (p8 / protein :name (n12 / name :op1 "IGF-IR") :mod (m2 / monocot) :location (c3 / cell-line :name (n13 / name :op1 "293T") :ARG1-of (t / transfect-01 :ARG2 (o / or :op1 (v3 / vector :ARG1-of (e5 / express-03 :ARG2 (p10 / protein :name (n14 / name :op1 "STAT") :mod (r2 / respective)))) :op2 (v2 / vector :ARG1-of (e4 / express-03 :ARG2 (e6 / enzyme :name (n15 / name :op1 "JAK"))))))))))) :snt1 (f / find-01 :ARG0 (w / we) :ARG1 (c / contrast-01 :ARG1 (a / activate-01 :ARG1 (p2 / protein :name (n / name :op1 "STAT3")) :ARG2-of (r / respond-01 :ARG1 (p3 / protein :name (n2 / name :op1 "IGF-I") :location (c2 / cell-line :name (n3 / name :op1 "293T") :ARG1-of (c4 / cotransfect-01 :ARG2 (a2 / and :op1 (p7 / protein :name (n4 / name :op1 "IGF-IR")) :op2 (v / vector :ARG1-of (e2 / express-03 :ARG2 (p4 / protein :name (n5 / name :op1 "STAT")))))))))) :ARG2 (a3 / activate-01 :polarity - :ARG1 (p5 / protein :name (n6 / name :op1 "STAT5")) :ARG2-of r)))) # ::id bel_pmid_1074_7872.21236 ::date 2015-04-14T14:46:59 ::annotator SDL-AMR-09 ::preferred # ::snt tyrosine phosphorylation of STAT3, JAK1, and JAK2 was increased upon IGF-I stimulation of endogenous IGF-IR in 293T cells transfected with the respective STAT or JAK expression vector. # ::save-date Sun Jan 17, 2016 ::file bel_pmid_1074_7872_21236.txt (i / increase-01 :ARG1 (p / phosphorylate-01 :ARG1 (a2 / and :op1 (a / amino-acid :name (n / name :op1 "tyrosine") :part-of (p2 / protein :name (n2 / name :op1 "STAT3"))) :op2 (a3 / amino-acid :name (n10 / name :op1 "tyrosine") :part-of (e6 / enzyme :name (n3 / name :op1 "JAK1"))) :op3 (a4 / amino-acid :name (n11 / name :op1 "tyrosine") :part-of (e5 / enzyme :name (n9 / name :op1 "JAK2"))))) :time (s / stimulate-01 :ARG0 (p4 / protein :name (n4 / name :op1 "IGF-I")) :ARG1 (p3 / protein :name (n5 / name :op1 "IGF-IR") :mod (m / monocot) :location (c / cell-line :name (n6 / name :op1 "293T") :ARG1-of (t / transfect-01 :ARG2 (o / or :op1 (v2 / vector :ARG1-of (e3 / express-03 :ARG2 (p5 / protein :name (n7 / name :op1 "STAT") :mod (r / respective)))) :op2 (v / vector :ARG1-of (e2 / express-03 :ARG2 (e4 / enzyme :name (n8 / name :op1 "JAK")))))))))) # ::id bel_pmid_1074_7872.21238 ::date 2015-04-14T14:54:49 ::annotator SDL-AMR-09 ::preferred # ::snt STAT3, but not STAT5, was activated in response to IGF-I in 293T cells cotransfected with IGF-IR and STAT expression vectors. # ::save-date Sun Jan 3, 2016 ::file bel_pmid_1074_7872_21238.txt (c / contrast-01 :ARG1 (a / activate-01 :ARG1 (p / protein :name (n / name :op1 "STAT3")) :ARG2-of (r / respond-01 :ARG1 (p2 / protein :name (n2 / name :op1 "IGF-I") :location (c2 / cell-line :name (n3 / name :op1 "293T") :ARG1-of (c3 / cotransfect-01 :ARG2 (a2 / and :op1 (v2 / vector :ARG1-of (e2 / express-03 :ARG2 (p3 / protein :name (n4 / name :op1 "IGF-IR")))) :op2 (v / vector :ARG1-of (e / express-03 :ARG2 (p4 / protein :name (n5 / name :op1 "STAT")))))))))) :ARG2 (a3 / activate-01 :polarity - :ARG1 (p5 / protein :name (n6 / name :op1 "STAT5")) :ARG2-of r)) # ::id bel_pmid_1074_7872.21262 ::date 2015-04-14T14:59:38 ::annotator SDL-AMR-09 ::preferred # ::snt Dominant-negative JAK1 or JAK2 was able to block the IGF-IR-mediated tyrosine phosphorylation of STAT3 in 293T cells. # ::save-date Sun Jan 3, 2016 ::file bel_pmid_1074_7872_21262.txt (p3 / possible-01 :ARG1 (b / block-01 :ARG0 (o / or :op1 (e2 / enzyme :name (n / name :op1 "JAK1") :ARG2-of (m2 / mutate-01 :mod "-/-")) :op2 (e / enzyme :name (n7 / name :op1 "JAK2") :ARG2-of (m3 / mutate-01 :mod "-/-"))) :ARG1 (p2 / phosphorylate-01 :ARG0 (a2 / amino-acid :name (n4 / name :op1 "tyrosine")) :ARG1 (p6 / protein :name (n5 / name :op1 "STAT3")) :location (c / cell-line :name (n6 / name :op1 "293T")) :ARG1-of (m / mediate-01 :ARG0 (p5 / protein :name (n3 / name :op1 "IGF-IR")))))) # ::id bel_pmid_1077_7583.7596 ::date 2015-04-16T05:24:23 ::annotator SDL-AMR-09 ::preferred # ::snt Inhibition of SHP2 activation leads to increased SOCS3-mRNA levels, whereas increased expression of SOCS3 results in a reduction of SHP2 phosphorylation after activation of the interleukin-6 signal transduction pathway. # ::save-date Tue Jan 19, 2016 ::file bel_pmid_1077_7583_7596.txt (c / contrast-01 :ARG1 (l / lead-03 :ARG0 (i / inhibit-01 :ARG1 (a / activate-01 :ARG1 (e3 / enzyme :name (n3 / name :op1 "SHP2")))) :ARG2 (l2 / level :ARG1-of (i2 / increase-01) :quant-of (n5 / nucleic-acid :name (n / name :op1 "mRNA") :mod (p / protein :name (n2 / name :op1 "SOCS3"))))) :ARG2 (r2 / result-01 :ARG1 (e / express-03 :ARG2 p :ARG1-of (i3 / increase-01)) :ARG2 (r3 / reduce-01 :ARG0 e :ARG2 (p3 / phosphorylate-01 :ARG1 e3)) :time (a2 / after :op1 (a3 / activate-01 :ARG1 (p4 / pathway :ARG2-of (t / transduce-01 :ARG1 (s / signal-07 :ARG1 (p2 / protein :name (n4 / name :op1 "interleukin-6"))))))))) # ::id bel_pmid_1079_1191.20850 ::date 2015-04-17T04:02:44 ::annotator SDL-AMR-09 ::preferred # ::snt In situ end-labeling detection showed that apoptotic cell death was significantly increased in cells with 5-day treatment of antisense H-ras oligodeoxynucleotide (34.0 +/- 4.5%) in comparing with cells without treatment (2.5 +/- 1.2%, t = 13.434, P < 0.01) or treated with non-specific antisense oligodeoxynucleotide (4.8 +/- 1.4%, t = 12.453, P < 0.01) at the corresponding time. # ::save-date Fri Feb 12, 2016 ::file bel_pmid_1079_1191_20850.txt (s / show-01 :ARG0 (d / detect-01 :ARG2 (l / label-01 :mod (e2 / end)) :mod (i / in-situ)) :ARG1 (i2 / increase-01 :ARG1 (c / cell :mod (a / apoptosis) :ARG0-of (f / function-01 :polarity -)) :ARG2 (s2 / significant-02) :location (c2 / cell :ARG1-of (t / treat-04 :ARG2 (s7 / small-molecule :name (n / name :op1 "oligodeoxynucleotide") :mod (e / enzyme :name (n2 / name :op1 "H-ras") :mod (a2 / antisense)) :quant (c6 / concentration-quantity :quant 34 :unit (m3 / micromolar)) :quant (p2 / percentage-entity :value 4.5)) :duration (t2 / temporal-quantity :quant 5 :unit (d3 / day)))) :compared-to (o / or :op1 (c3 / cell :ARG1-of (t3 / treat-04 :polarity - :ARG1-of (s4 / statistical-test-91 :ARG2 (l2 / less-than :op1 0.01))) :quant (t6 / temperature-quantity :value 13.434) :quant (p4 / percentage-entity :value 1.2)) :op2 (c4 / cell :ARG1-of (t4 / treat-04 :ARG2 (s6 / small-molecule :name (n3 / name :op1 "oligodeoxynucleotide") :mod (a3 / antisense :ARG1-of (s3 / specific-02 :polarity -)) :quant (p3 / percentage-entity :value 1.4) :quant (c7 / concentration-quantity :quant 12.453 :unit (m4 / micromolar))) :ARG1-of (s5 / statistical-test-91 :ARG2 l2))) :time (t5 / time :ARG1-of (c5 / correspond-02))))) # ::id bel_pmid_1084_2184.19138 ::date 2015-04-16T19:28:31 ::annotator SDL-AMR-09 ::preferred # ::snt \"Negative regulation of growth hormone receptor/JAK2 signaling by signal regulatory protein alpha.\" # ::save-date Sun Jan 3, 2016 ::file bel_pmid_1084_2184_19138.txt (d / downregulate-01 :ARG1 (m / macro-molecular-complex :part (p / protein :name (n2 / name :op1 "growth" :op2 "hormone" :op3 "receptor")) :part (e / enzyme :name (n3 / name :op1 "JAK2"))) :ARG2 (p3 / protein :name (n / name :op1 "signal" :op2 "regulatory" :op3 "protein" :op4 "alpha")) :ARG2-of (c / cite-01)) # ::id bel_pmid_1085_1026.6144 ::date 2015-04-16T14:12:34 ::annotator SDL-AMR-09 ::preferred # ::snt FGFs activate the endogenous FGFRs leading to the formation of a Grb2/FRS2/Shp2 complex and activation of MAP kinase. # ::save-date Wed Jan 13, 2016 ::file bel_pmid_1085_1026_6144.txt (a / activate-01 :ARG0 (p / protein :name (n / name :op1 "FGF")) :ARG1 (p2 / protein :name (n2 / name :op1 "FGFR") :mod (m2 / monocot) :ARG0-of (l / lead-03 :ARG2 (a2 / and :op1 (f / form-01 :ARG0 p2 :ARG1 (m / macro-molecular-complex :part (p3 / protein :name (n3 / name :op1 "Grb2")) :part (p4 / protein :name (n4 / name :op1 "FRS2")) :part (e / enzyme :name (n5 / name :op1 "Shp2")))) :op2 (a3 / activate-01 :ARG0 p2 :ARG1 (k / kinase :name (n6 / name :op1 "MAP"))))))) # ::id bel_pmid_1085_1026.8692 ::date 2015-04-16T14:25:22 ::annotator SDL-AMR-09 ::preferred # ::snt However, immature osteoblasts respond to FGF treatment with increased proliferation, whereas in differentiating cells FGF does not induce DNA synthesis but causes apoptosis. # ::save-date Sun Dec 20, 2015 ::file bel_pmid_1085_1026_8692.txt (h / have-concession-91 :ARG1 (c2 / contrast-01 :ARG1 (r / respond-01 :ARG0 (o / osteoblast :ARG1-of (m / mature-02 :polarity -)) :ARG1 (t / treat-04 :ARG1 o :ARG2 (p / protein :name (n / name :op1 "FGF"))) :ARG2 (p2 / proliferate-01 :ARG0 o :ARG1-of (i2 / increase-01))) :ARG2 (c3 / contrast-01 :ARG1 (i / induce-01 :polarity - :ARG0 p :ARG2 (s / synthesize-01 :ARG1 (n2 / nucleic-acid :wiki "DNA" :name (n3 / name :op1 "DNA"))) :time (d2 / differentiate-01 :ARG0 p :ARG1 (c5 / cell))) :ARG2 (c4 / cause-01 :ARG0 p :ARG1 (a / apoptosis))))) # ::id bel_pmid_1085_1026.8694 ::date 2015-04-16T17:01:37 ::annotator SDL-AMR-09 ::preferred # ::snt When either primary or OB1 osteoblasts are induced to differentiate, FGF signaling inhibits expression of alkaline phosphatase, and blocks mineralization. # ::save-date Sun Jan 3, 2016 ::file bel_pmid_1085_1026_8694.txt (a / and :op1 (i2 / inhibit-01 :ARG0 (p2 / protein :name (n / name :op1 "FGF" :op2 "signaling")) :ARG1 (e2 / express-03 :ARG1 (e3 / enzyme :name (n3 / name :op1 "alkaline" :op2 "phosphatase")))) :op2 (b / block-01 :ARG0 p2 :ARG1 (m / mineralize-01)) :time (i / induce-01 :ARG1 (o / or :op1 (o3 / osteoblast :mod (p / primary)) :op2 (o2 / osteoblast :mod (d2 / dna-sequence :name (n2 / name :op1 "OB1"))) :mod (e / either)) :ARG2 (d / differentiate-01 :ARG0 o))) # ::id bel_pmid_1085_1055.19244 ::date 2015-04-16T17:42:59 ::annotator SDL-AMR-09 ::preferred # ::snt IL-2-mediated hetero-dimerization of its receptor triggers a rapid increase in the recruitment of Jak3 and activation of both Jak1 and Jak3 # ::save-date Sun Jan 3, 2016 ::file bel_pmid_1085_1055_19244.txt (t / trigger-01 :ARG0 (h2 / heterodimerize-01 :ARG1 (r3 / receptor :poss p3) :ARG1-of (m / mediate-01 :ARG0 (p3 / protein :name (n2 / name :op1 "IL-2")))) :ARG1 (i / increase-01 :ARG1 (a / and :op1 (r2 / recruit-01 :ARG1 (e2 / enzyme :name (n / name :op1 "Jak3"))) :op2 (a2 / activate-01 :ARG1 (a3 / and :op1 (e / enzyme :name (n3 / name :op1 "Jak1")) :op2 e2))) :manner (r / rapid))) # ::id bel_pmid_1088_0513.7274 ::date 2015-04-16T13:17:28 ::annotator SDL-AMR-09 ::preferred # ::snt We show that IL-6 triggers selective activation of SHP2 and its association with RAFTK in Dex-treated MM cells. # ::save-date Fri Feb 12, 2016 ::file bel_pmid_1088_0513_7274.txt (s / show-01 :ARG0 (w / we) :ARG1 (t / trigger-01 :ARG0 (p / protein :name (n2 / name :op1 "IL-6")) :ARG1 (a / and :op1 (a2 / activate-01 :ARG0 p :ARG1 (e / enzyme :name (n / name :op1 "SHP2")) :mod (s2 / selective)) :op2 (a3 / associate-01 :ARG1 e :ARG2 (e2 / enzyme :name (n3 / name :op1 "RAFTK")) :location (c / cell :ARG1-of (t2 / treat-04 :ARG2 (s3 / small-molecule :name (n4 / name :op1 "Dex"))) :mod (d / disease :name (n5 / name :op1 "multiple" :op2 "myeloma"))))))) # ::id bel_pmid_1088_0513.23686 ::date 2015-04-16T13:27:35 ::annotator SDL-AMR-09 ::preferred # ::snt We and others have shown that IL-6 induces growth in MM cells via the MAPK pathway, which includes activation of protein-tyrosine phosphatase SHP2 (16, 28) # ::save-date Sun Jan 3, 2016 ::file bel_pmid_1088_0513_23686.txt (s / show-01 :ARG0 (a2 / and :op1 (w / we) :op2 (p2 / person :mod (o / other))) :ARG1 (i2 / induce-01 :ARG0 (p3 / protein :name (n / name :op1 "IL-6")) :ARG2 (g / grow-01 :ARG1 (c2 / cell :mod (d2 / disease :name (n4 / name :op1 "multiple" :op2 "myeloma"))) :instrument (p4 / pathway :name (n3 / name :op1 "MAPK") :ARG2-of (i / include-01 :ARG1 (a3 / activate-01 :ARG1 (p6 / protein-tyrosine-phosphatase :name (n6 / name :op1 "SHP2"))))))) :ARG1-of (d / describe-01 :ARG0 (p / publication :ARG1-of (c / cite-01 :ARG2 (a / and :op1 16 :op2 28))))) # ::id bio-exp_0001.1 ::date 2014-09-16T11:13:45 ::annotator SDL-AMR-09 ::preferred # ::snt We next examined the mechanisms accounting for the increase in HER3 by MAPK pathway inhibitors in BRAF mutant thyroid cell lines . # ::save-date Mon Feb 9, 2015 ::file bio-exp_0001_1.txt (e / examine-01 :ARG0 (w / we) :ARG1 (m / mechanism :ARG0-of (a / account-01 :ARG1 (i / increase-01 :ARG0 (m2 / molecular-physical-entity :ARG0-of (i2 / inhibit-01 :ARG1 (p / pathway :name (n3 / name :op1 "MAPK")) :location (c / cell-line :source (t / thyroid) :ARG1-of (e3 / encode-01 :ARG0 (n5 / nucleic-acid :wiki "DNA" :name (n6 / name :op1 "DNA") :part (g / gene :name (n4 / name :op1 "BRAF") :ARG2-of (m3 / mutate-01))))))) :ARG1 (e2 / enzyme :name (n2 / name :op1 "HER3"))))) :time (n / next)) # ::id bio-exp_0001.2 ::date 2014-09-26T12:18:16 ::annotator SDL-AMR-09 ::preferred # ::snt Upregulation of HER3 has been found to mediate resistance to PI3K/AKT ( 26 ) or HER2 ( 27 ) inhibitors in HER2-amplified breast cancer cell lines , which is caused in part through a FoxO3A-dependent induction of HER3 gene transcription . # ::save-date Sun Jan 17, 2016 ::file bio-exp_0001_2.txt (f / find-01 :ARG1 (m / mediate-01 :ARG0 (u / upregulate-01 :ARG1 (e / enzyme :name (n / name :op1 "HER3"))) :ARG1 (r / resist-01 :ARG1 (m2 / molecular-physical-entity :ARG0-of (i / inhibit-01 :ARG1 (o / or :op1 (p / pathway :name (n2 / name :op1 "PI3K/AKT") :ARG1-of (d2 / describe-01 :ARG0 (p5 / publication :ARG1-of (c4 / cite-01 :ARG2 26)))) :op2 (e3 / enzyme :name (n3 / name :op1 "HER2") :ARG1-of (d3 / describe-01 :ARG0 (p6 / publication :ARG1-of (c5 / cite-01 :ARG2 27))))))) :location (c / cell-line :ARG0-of (a / amplify-01 :ARG1 e3) :source (d4 / disease :wiki "Breast_cancer" :name (n5 / name :op1 "breast" :op2 "cancer")))) :ARG1-of (c3 / cause-01 :ARG0 (i2 / induce-01 :ARG2 (t / transcribe-01 :ARG1 (g / gene :ARG0-of (e2 / encode-01 :ARG1 e))) :ARG0-of (d / depend-01 :ARG1 (p4 / protein :name (n4 / name :op1 "FoxO3A")))) :degree (p3 / part)))) # ::id bio-exp_0001.3 ::date 2014-09-26T12:18:43 ::annotator SDL-AMR-09 ::preferred # ::snt As shown in Fig. 5A, PLX4032 treatment increased HER3 and HER2 mRNAs in all six BRAF-mutant thyroid cancer cell lines tested . # ::save-date Sun Jan 17, 2016 ::file bio-exp_0001_3.txt (i / increase-01 :ARG0 (t / treat-04 :ARG2 (s2 / small-molecule :name (n / name :op1 "PLX4032"))) :ARG1 (n8 / nucleic-acid :name (n9 / name :op1 "mRNA") :ARG0-of (e / encode-01 :ARG1 (a / and :op1 (e3 / enzyme :name (n2 / name :op1 "HER3")) :op2 (e4 / enzyme :name (n3 / name :op1 "HER2"))))) :ARG1-of (s / show-01 :location (f / figure :mod "5A")) :location (c / cell-line :ARG1-of (e2 / encode-01 :ARG0 (n5 / nucleic-acid :wiki "DNA" :name (n6 / name :op1 "DNA") :part (g / gene :name (n4 / name :op1 "BRAF") :ARG2-of (m2 / mutate-01)))) :ARG1-of (i2 / include-91 :ARG2 (c3 / cell-line :quant 6 :ARG1-of (t3 / test-01)) :ARG3 (a2 / all)) :source (d / disease :wiki "Thyroid_cancer" :name (n7 / name :op1 "thyroid" :op2 "cancer")))) # ::id bio-exp_0001.4 ::date 2015-01-23T04:12:10 ::annotator SDL-AMR-09 ::preferred # ::snt Similar results were found following treatment with the MEK inhibitor AZD6244 ( not shown ) . # ::save-date Sat Jan 16, 2016 ::file bio-exp_0001_4.txt (f / find-01 :ARG1 (t / thing :ARG2-of (r / result-01) :ARG1-of (r2 / resemble-01) :ARG1-of (s / show-01 :polarity -)) :ARG1-of (f2 / follow-01 :ARG2 (t2 / treat-04 :ARG2 (s2 / small-molecule :name (n2 / name :op1 "AZD6244") :ARG0-of (i / inhibit-01 :ARG1 (p / protein-family :name (n / name :op1 "MEK"))))))) # ::id bio-exp_0001.5 ::date 2015-02-07T10:09:52 ::annotator SDL-AMR-09 ::preferred # ::snt The effects of the MEK inhibitor on total HER2 , HER3 protein and on pHER3 were dose dependent , and inversely associated with the degree of inhibition of pERK ( Fig. 5B ) . # ::save-date Sat Jan 16, 2016 ::file bio-exp_0001_5.txt (a / and :op1 (d / depend-01 :ARG0 (a2 / affect-01 :ARG0 (m / molecular-physical-entity :ARG0-of (i / inhibit-01 :ARG1 (p2 / protein-family :name (n / name :op1 "MEK")))) :ARG1 (a3 / and :op1 (e2 / enzyme :name (n2 / name :op1 "HER2") :mod (t / total)) :op2 (e3 / enzyme :name (n3 / name :op1 "HER3")) :op3 (e4 / enzyme :name (n4 / name :op1 "HER3") :ARG3-of (p / phosphorylate-01)))) :ARG1 (d2 / dose-01)) :op2 (a4 / associate-01 :ARG1 a2 :ARG2 (t2 / thing :degree-of (i2 / inhibit-01 :ARG1 (e5 / enzyme :name (n5 / name :op1 "ERK") :ARG3-of p))) :manner (i3 / inverse)) :ARG1-of (d3 / describe-01 :ARG0 (f / figure :mod "5B"))) # ::id bio-exp_0001.6 ::date 2015-02-07T10:17:49 ::annotator SDL-AMR-09 ::preferred # ::snt RAF or MEK inhibitors induced luciferase activity of a HER3 promoter construct spanning ~ 1 kb upstream of the transcriptional start site in 8505C cells . # ::save-date Sat Jan 16, 2016 ::file bio-exp_0001_6.txt (i / induce-01 :ARG0 (o / or :op1 (m / molecular-physical-entity :ARG0-of (i2 / inhibit-01 :ARG1 (p3 / protein-family :wiki "RAF_kinase" :name (n / name :op1 "RAF")))) :op2 (m2 / molecular-physical-entity :ARG0-of (i3 / inhibit-01 :ARG1 (p4 / protein-family :wiki "Mitogen-activated_protein_kinase_kinase" :name (n2 / name :op1 "MEK"))))) :ARG2 (a / activity-06 :ARG0 (c / construct-01 :ARG0-of (p / promote-01 :ARG1 (e3 / enzyme :wiki "ERBB3" :name (n3 / name :op1 "HER3"))) :ARG0-of (s / span-01 :ARG1 (r / relative-position :op1 (p2 / protein-segment :location-of (s3 / start-01 :ARG1 (t / transcribe-01))) :direction (u / upstream)) :location (c2 / cell-line :wiki - :name (n4 / name :op1 "8505C")) :quant (a2 / approximately :op1 (d / distance-quantity :quant 1 :unit (k / kilo-base-pair))))) :ARG1 (l / luciferase))) # ::id bio-exp_0001.7 ::date 2015-02-07T10:25:54 ::annotator SDL-AMR-09 ::preferred # ::snt Serial deletions identified a minimal HER3 promoter retaining transcriptional response to vemurafenib and AZD6244 , which was located between -401 and -42 bp ( Fig. 5C ) . # ::save-date Thu Jun 4, 2015 ::file bio-exp_0001_7.txt (i / identify-01 :ARG0 (d / delete-01 :manner (s2 / serial)) :ARG1 (m / molecular-physical-entity :ARG0-of (p / promote-01 :ARG1 (e / enzyme :name (n / name :op1 "HER3"))) :ARG1-of (m2 / minimal-02) :ARG0-of (r / retain-01 :ARG1 (t / thing :ARG2-of (r2 / respond-01 :ARG1 (a / and :op1 (s3 / small-molecule :name (n3 / name :op1 "vemurafenib")) :op2 (s / small-molecule :name (n2 / name :op1 "AZD6244"))))) :mod (t2 / transcribe-01)) :location (b / between :op1 (d2 / distance-quantity :quant "-401" :unit (b2 / base-pair)) :op2 (d3 / distance-quantity :quant "-42" :unit (b3 / base-pair)))) :ARG1-of (d4 / describe-01 :ARG0 (f / figure :mod "5C"))) # ::id bio-exp_0001.8 ::date 2015-01-28T02:52:22 ::annotator SDL-AMR-09 ::preferred # ::snt This region does not contain any predicted FoxO binding sites . # ::save-date Fri Feb 6, 2015 ::file bio-exp_0001_8.txt (c / contain-01 :polarity - :ARG0 (r / region :mod (t / this)) :ARG1 (p3 / protein-segment :mod (a / any) :ARG1-of (p / predict-01) :ARG1-of (b / bind-01 :ARG2 (p2 / protein :name (n / name :op1 "FoxO"))))) # ::id bio-exp_0001.9 ::date 2015-02-07T10:41:21 ::annotator SDL-AMR-09 ::preferred # ::snt Moreover , PLX4032 led to an increase in phosphorylation of FoxO1/3A between 4 – 10 h after addition of compound ( not shown ) , which is known to promote its dissociation from DNA , and likely discards involvement of these factors as transcriptional regulators of HER3 in response to MAPK pathway inhibition . # ::save-date Wed Jun 24, 2015 ::file bio-exp_0001_9.txt (a / and :op2 (l / lead-03 :ARG0 (s / small-molecule :name (n / name :op1 "PLX4032")) :ARG1 (i / increase-01 :ARG1 (p / phosphorylate-01 :ARG1 (p2 / protein :name (n2 / name :op1 "FoxO1/3A"))) :time (a2 / after :op1 (a3 / add-02 :ARG1 (c / compound)) :quant (b / between :op1 (t / temporal-quantity :quant 4 :unit (h / hour)) :op2 (t2 / temporal-quantity :quant 10 :unit (h2 / hour)))) :ARG1-of (s2 / show-01 :polarity -) :ARG0-of (p3 / promote-01 :ARG1 (d / dissociate-01 :ARG1 p2 :ARG2 (n5 / nucleic-acid :wiki "DNA" :name (n6 / name :op1 "DNA"))) :ARG1-of (k / know-01)) :ARG0-of (d3 / discard-01 :ARG1 (i2 / involve-01 :ARG1 (f / factor :mod (t3 / this)) :mod (m / molecular-physical-entity :ARG0-of (r / regulate-01 :ARG1 (e / enzyme :name (n3 / name :op1 "HER3"))) :ARG0-of (t4 / transcribe-01))) :ARG1-of (l2 / likely-01) :ARG2-of (r2 / respond-01 :ARG1 (i3 / inhibit-01 :ARG1 (p4 / pathway :name (n4 / name :op1 "MAPK")))))))) # ::id bio-exp_0001.10 ::date 2015-02-07T10:47:07 ::annotator SDL-AMR-09 ::preferred # ::snt The minimal HER3 promoter region regulated by MAPK inhibitors overlaps with sequences previously described to be immunoprecipitated using antibodies against the ZFN217 transcription factor and CtBP1/CtBP2 corepressors ( 28–30 ) . # ::save-date Mon Jan 4, 2016 ::file bio-exp_0001_10.txt (o / overlap-01 :ARG0 (r / region :part (m / molecular-physical-entity :ARG0-of (p2 / promote-01 :ARG1 (e / enzyme :name (n / name :op1 "HER3"))) :ARG1-of (m2 / minimal-02)) :ARG1-of (r2 / regulate-01 :ARG0 (m3 / molecular-physical-entity :ARG0-of (i / inhibit-01 :ARG1 (p / pathway :name (n2 / name :op1 "MAPK")))))) :ARG1 (s / sequence :ARG1-of (i2 / immunoprecipitate-01 :ARG2-of (u / use-01 :ARG1 (a / antibody :ARG0-of (o2 / oppose-01 :ARG1 (a2 / and :op1 (f / factor :ARG0-of (t / transcribe-01 :ARG1 (e2 / enzyme :name (n3 / name :op1 "ZFN217")))) :op2 (m4 / molecular-physical-entity :ARG0-of (r3 / repress-01 :ARG1 (o3 / or :op1 (p5 / protein :name (n4 / name :op1 "CtBP1")) :op2 (p6 / protein :name (n5 / name :op1 "CtBP2"))))))))) :ARG1-of (d / describe-01 :time (p3 / previous)))) :ARG1-of (d2 / describe-01 :ARG0 (p4 / publication :ARG1-of (c3 / cite-01 :ARG2 (v / value-interval :op1 28 :op2 30))))) # ::id bio-exp_0001.11 ::date 2015-02-07T11:00:42 ::annotator SDL-AMR-09 ::preferred # ::snt CtBPs have also been described to negatively regulate transcriptional activity of the HER3 promoter in breast carcinoma cell lines ( 30 ) . # ::save-date Mon Jan 4, 2016 ::file bio-exp_0001_11.txt (d / describe-01 :ARG1 (p / protein :name (n2 / name :op1 "CtBP")) :ARG2 (d2 / downregulate-01 :ARG1 (a / activity-06 :ARG0 (m / molecular-physical-entity :ARG0-of (p2 / promote-01 :ARG1 (e / enzyme :name (n / name :op1 "HER3")))) :ARG1 (t / transcribe-01)) :ARG2 p) :location (c / cell-line :mod (m2 / medical-condition :name (n3 / name :op1 "carcinoma") :mod (b / breast))) :mod (a2 / also) :ARG1-of (d3 / describe-01 :ARG0 (p3 / publication :ARG1-of (c3 / cite-01 :ARG2 30)))) # ::id bio-exp_0001.12 ::date 2015-02-05T12:19:53 ::annotator SDL-AMR-09 ::preferred # ::snt Silencing of CtBP1 , and to a lesser extent CtBP2 , increased basal HER3 in 8505C cells , and markedly potentiated the effects of PLX4032 ( Fig. 5D and 5E ) . # ::save-date Sun Jan 17, 2016 ::file bio-exp_0001_12.txt (a / and :op1 (i / increase-01 :ARG0 (s / silence-01 :ARG1 (a2 / and :op1 (p / protein :name (n2 / name :op1 "CtBP1")) :op2 (p2 / protein :name (n3 / name :op1 "CtBP2") :degree (l / less :degree (m / more))))) :ARG1 (e / enzyme :name (n / name :op1 "HER3") :mod (b / basal)) :location (c / cell-line :name (n4 / name :op1 "8505C"))) :op2 (p3 / potentiate-01 :ARG1 (a3 / affect-01 :ARG0 (s2 / small-molecule :name (n5 / name :op1 "PLX4032"))) :ARG2 s :ARG3 (m2 / marked)) :ARG1-of (d / describe-01 :ARG0 (a4 / and :op1 (f / figure :mod "5D") :op2 (f2 / figure :mod "5E")))) # ::id bio-exp_0001.13 ::date 2015-02-07T09:16:39 ::annotator SDL-AMR-09 ::preferred # ::snt Knockdown of these factors modestly increased basal and PLX4032 - induced HER2 levels , which likely contributes to the remarkable increase in pHER3 we observed ( Fig. 5D and 5E ) . # ::save-date Fri Jul 24, 2015 ::file bio-exp_0001_13.txt (i / increase-01 :ARG0 (k / knock-down-02 :ARG1 (f / factor :mod (t / this))) :ARG1 (a / and :op1 (l / level :quant-of (e / enzyme :name (n / name :op1 "HER2") :mod (b / basal))) :op2 (l2 / level :quant-of (e2 / enzyme :name (n2 / name :op1 "HER2") :ARG2-of (i2 / induce-01 :ARG0 (s / small-molecule :name (n3 / name :op1 "PLX4032")))))) :degree (m / modest) :ARG0-of (c / contribute-01 :ARG1 (i3 / increase-01 :ARG1 (e3 / enzyme :name (n4 / name :op1 "HER3") :ARG3-of (p / phosphorylate-01)) :ARG1-of (o / observe-01 :ARG0 (w / we)) :ARG1-of (r / remarkable-02)) :ARG1-of (l3 / likely-01)) :ARG1-of (d / describe-01 :ARG0 (a2 / and :op1 (f2 / figure :mod "5D") :op2 (f3 / figure :mod "5E")))) # ::id bio-exp_0001.14 ::date 2015-02-07T11:19:08 ::annotator SDL-AMR-09 ::preferred # ::snt Finally , CtBP1 and CtBP2 chromatin immunoprecipitation assays showed decreased binding to the HER3 promoter after treatment with PLX4032 ( Fig. 5F ) . # ::save-date Fri Oct 23, 2015 ::file bio-exp_0001_14.txt (s / show-01 :li "-1" :ARG0 (a / assay-01 :ARG1 (i / immunoprecipitate-01 :ARG1 (a2 / and :op1 (p / protein :name (n2 / name :op1 "CtBP1")) :op2 (p2 / protein :name (n3 / name :op1 "CtBP2"))) :mod (c / chromatin))) :ARG1 (b / bind-01 :ARG2 (m / molecular-physical-entity :ARG0-of (p3 / promote-01 :ARG1 (e / enzyme :name (n / name :op1 "HER3")))) :ARG1-of (d / decrease-01 :time (a3 / after :op1 (t / treat-04 :ARG2 (s2 / small-molecule :name (n4 / name :op1 "PLX4032")))))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "5F"))) # ::id bio-exp_0001.15 ::date 2015-02-05T12:14:53 ::annotator SDL-AMR-09 ::preferred # ::snt These findings were confirmed in a second cell line ( Supplementary Fig. S5A ) . # ::save-date Sun Feb 8, 2015 ::file bio-exp_0001_15.txt (c / confirm-01 :ARG1 (t2 / thing :ARG1-of (f / find-01) :mod (t / this)) :location (c2 / cell-line :ord (o / ordinal-entity :value 2)) :ARG1-of (d / describe-01 :ARG0 (f2 / figure :mod "S5A" :ARG2-of (s / supplement-01)))) # ::id bio-kappa_0001.1 ::date 2014-09-19T16:48:49 ::annotator SDL-AMR-09 ::preferred # ::snt Activation of Raf occurs via a complex , yet incompletely understood mechanism requiring membrane translocation , regulatory phosphorylation / dephosphorylation events and , crucially , allosteric activation in the context of a side-to-side dimer comprising two Raf molecules or a Raf and a Ksr molecule . # ::save-date Wed Mar 2, 2016 ::file bio-kappa_0001_1.txt (a / activate-01 :ARG1 (e / enzyme :name (n / name :op1 "Raf")) :manner (m / mechanism :mod (c / complex) :ARG1-of (u / understand-01 :ARG1-of (c2 / complete-02 :polarity -)) :ARG0-of (r / require-01 :ARG1 (a2 / and :op1 (t / translocate-01 :ARG2 (m2 / membrane)) :op2 (p2 / phosphorylate-01 :ARG0-of (r2 / regulate-01)) :op3 (d / dephosphorylate-01 :ARG0-of (r3 / regulate-01)) :op4 (a3 / activate-01 :mod (a4 / allosteric) :mod (c3 / crucial) :condition (h / have-part-91 :ARG1 (d2 / dimer :mod (s / side :prep-to (s2 / side)) :ARG1-of (c5 / comprise-01 :ARG2 (o / or :op1 (m3 / molecule :quant 2 :mod e) :op2 (a5 / and :op1 (m4 / molecule :mod e) :op2 (m5 / molecule :mod (e4 / enzyme :name (n4 / name :op1 "Ksr"))))))))))))) # ::id bio-kappa_0001.2 ::date 2014-09-26T12:38:07 ::annotator SDL-AMR-09 ::preferred # ::snt Of the three Raf kinases , only B-Raf is able to function as an allosteric activator in the context of the Raf heterodimers , a role independent of B-Raf kinase activity . # ::save-date Sun Jan 17, 2016 ::file bio-kappa_0001_2.txt (p / possible-01 :ARG1 (a / activate-01 :ARG0 (k / kinase :name (n / name :op1 "B-Raf") :ARG1-of (i / include-91 :ARG2 (k2 / kinase :quant 3 :name (n2 / name :op1 "Raf"))) :mod (o / only)) :mod (a2 / allosteric) :condition (h2 / have-part-91 :ARG1 (h / heterodimer :part (e / enzyme :name (n3 / name :op1 "Raf"))) :ARG2 k) :ARG0-of (d / depend-01 :polarity - :ARG1 (a3 / activity-06 :ARG0 k)))) # ::id bio-kappa_0001.3 ::date 2014-09-27T15:35:13 ::annotator SDL-AMR-09 ::preferred # ::snt The molecular basis for this has recently been elucidated by the Shaw lab , who has shown that the ability of acting as an activator depends on the presence of negative charges in the Raf N-terminal acidic motif . # ::save-date Thu Feb 4, 2016 ::file bio-kappa_0001_3.txt (e / elucidate-01 :ARG0 (l / lab :name (n / name :op1 "Shaw") :ARG0-of (s / show-01 :ARG1 (d / depend-01 :ARG0 (p / possible-01 :ARG1 (a / activate-01)) :ARG1 (p2 / present-02 :ARG1 (c / charge :ARG2-of (n2 / negative-06) :location (m3 / motif :mod (a2 / acid) :part-of (p3 / protein-segment :name (n3 / name :op1 "N-terminus") :part-of (e2 / enzyme :name (n4 / name :op1 "Raf"))))))))) :ARG1 (b / base-02 :ARG1 (t / this) :mod (m2 / molecule)) :time (r / recent)) # ::id bio-kappa_0001.4 ::date 2015-01-19T06:33:33 ::annotator SDL-AMR-09 ::preferred # ::snt In B-Raf , this motif is negatively charged due to the constitutive phosphorylation of Ser446 and/or 447 , and to the presence of two aspartates at position 448/9 ( Fig. 2A ) . # ::save-date Thu Feb 4, 2016 ::file bio-kappa_0001_4.txt (c / charge-03 :ARG1 (m / motif :mod (t / this) :part-of (e2 / enzyme :name (n6 / name :op1 "B-Raf"))) :ARG2-of (n / negative-06) :ARG1-of (c2 / cause-01 :ARG0 (a / and :op1 (p / phosphorylate-01 :ARG1 (a6 / and-or :op1 (a2 / amino-acid :mod 446 :name (n2 / name :op1 "serine")) :op2 (a3 / amino-acid :mod 447 :name (n3 / name :op1 "serine"))) :mod (c3 / constitutive)) :op2 (p4 / present-02 :ARG1 (a4 / amino-acid :quant 2 :name (n4 / name :op1 "aspartate")) :ARG2 (a5 / and :op1 (p2 / protein-segment :mod 448) :op2 (p3 / protein-segment :mod 449))))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "2A"))) # ::id bio-kappa_0001.5 ::date 2015-01-20T00:43:24 ::annotator SDL-AMR-09 ::preferred # ::snt Allosteric activation by B-Raf induces cis-autophosporylation in the activation loop of the receiver kinase , i.e. C-Raf , and renders it able to phosphorylate Mek . # ::save-date Wed Jun 3, 2015 ::file bio-kappa_0001_5.txt (a3 / and :op1 (i / induce-01 :ARG0 (a / activate-01 :ARG0 (e / enzyme :name (n / name :op1 "B-Raf")) :mod (a2 / allosteric)) :ARG2 (p / phosphorylate-01 :ARG1 k :ARG2 k :subevent-of (l / loop :ARG0-of (a4 / activate-01 :ARG1 (k / kinase :ARG0-of (r2 / receive-01) :ARG1-of (m / mean-01 :ARG2 (e2 / enzyme :name (n2 / name :op1 "C-Raf")))))))) :op2 (r / render-01 :ARG0 a :ARG1 (p2 / possible-01 :ARG1 (p3 / phosphorylate-01 :ARG1 (e3 / enzyme :name (n3 / name :op1 "Mek")) :ARG2 e2)))) # ::id bio-kappa_0001.6 ::date 2015-01-20T01:34:52 ::annotator SDL-AMR-09 ::preferred # ::snt Mek , in turn , phosphorylates the N-terminal acidic motif in C-Raf , converting it to an allosteric activator of other Rafs ( Fig. 2B and C ) . # ::save-date Tue Jan 27, 2015 ::file bio-kappa_0001_6.txt (p / phosphorylate-01 :ARG1 (m / motif :mod (a / acid) :part-of (p2 / protein-segment :name (n2 / name :op1 "N-terminus") :part-of (e2 / enzyme :name (n3 / name :op1 "C-Raf") :ARG1-of (c2 / convert-01 :ARG0 e :ARG2 (e3 / enzyme :ARG0-of (a2 / activate-01 :ARG1 (e4 / enzyme :name (n4 / name :op1 "Raf") :mod (o / other)) :mod (a3 / allosteric))))))) :ARG2 (e / enzyme :name (n / name :op1 "Mek")) :ARG1-of (d / describe-01 :ARG0 (a4 / and :op1 (f / figure :mod "2B") :op2 (f2 / figure :mod "2C"))) :mod (i / in-turn)) # ::id bio-kappa_0001.7 ::date 2015-01-20T01:58:10 ::annotator SDL-AMR-09 ::preferred # ::snt This model explains why C-Raf mutants devoid of kinase activity cannot function as activators , and why B-Raf can activate Mek directly as a homodimer . # ::save-date Fri Jul 24, 2015 ::file bio-kappa_0001_7.txt (e / explain-01 :ARG0 (m / model :mod (t3 / this)) :ARG1 (t2 / thing :ARG0-of (c2 / cause-01 :ARG1 (a6 / and :op1 (p / possible-01 :polarity - :ARG1 (a2 / activate-01 :ARG0 (e2 / enzyme :name (n / name :op1 "C-Raf") :ARG2-of (m2 / mutate-01) :ARG1-of (v / void-03 :ARG2 (a / activity-06 :ARG0 (k / kinase)))))) :op2 (p2 / possible-01 :ARG1 (a4 / activate-01 :ARG0 (e3 / enzyme :name (n2 / name :op1 "B-Raf") :ARG0-of (a5 / act-01 :ARG1 (h / homodimer))) :ARG1 (e4 / enzyme :name (n3 / name :op1 "Mek")) :ARG1-of (d / direct-02))))))) # ::id bio-kappa_0001.8 ::date 2015-01-20T02:34:12 ::annotator SDL-AMR-09 ::preferred # ::snt Phosphorylated Ksr can also function as a transactivator ; however , since Raf binding to Ksr induces limited kinase activity , in quiescent cells the constitutive association of Ksr with B-Raf may serve to prevent C-Raf binding to B-Raf , safeguarding against undue activation of the pathway . # ::save-date Fri Jan 1, 2016 ::file bio-kappa_0001_8.txt (p / possible-01 :ARG1 (t2 / transactivate-01 :ARG2 (e / enzyme :name (n / name :op1 "Ksr") :ARG3-of (p2 / phosphorylate-01)) :mod (a / also) :concession-of (p3 / possible-01 :ARG1 (s / serve-01 :ARG0 (a3 / associate-01 :ARG1 e :ARG2 (e3 / enzyme :name (n3 / name :op1 "B-Raf")) :mod (c2 / constitutive)) :ARG1 (p4 / prevent-01 :ARG0 a3 :ARG1 (b / bind-01 :ARG1 (e4 / enzyme :name (n4 / name :op1 "C-Raf")) :ARG2 e3) :ARG0-of (s2 / safeguard-01 :ARG2 (a4 / activate-01 :ARG1 (p5 / pathway) :mod (d / due :polarity -))))) :location (c / cell :mod (q / quiescent)) :ARG1-of (c3 / cause-01 :ARG0 (i / induce-01 :ARG0 (b2 / bind-01 :ARG1 (e6 / enzyme :name (n6 / name :op1 "Raf")) :ARG2 e) :ARG2 (a2 / activity-06 :ARG1 (k / kinase) :ARG1-of (l / limit-01))))))) # ::id bio-kappa_0001.9 ::date 2015-01-20T03:20:23 ::annotator SDL-AMR-09 ::preferred # ::snt PSPs dephosphorylate phosphoserine and phosphothreonine residues . # ::save-date Fri Feb 6, 2015 ::file bio-kappa_0001_9.txt (d / dephosphorylate-01 :ARG1 (a / and :op1 (r / residue :mod (a2 / amino-acid :name (n / name :op1 "serine") :ARG3-of (p2 / phosphorylate-01))) :op2 (r2 / residue :mod (a3 / amino-acid :name (n2 / name :op1 "threonine") :ARG3-of (p4 / phosphorylate-01)))) :ARG2 (s / small-molecule :name (n3 / name :op1 "PSP"))) # ::id bio-kappa_0001.10 ::date 2015-01-20T03:41:50 ::annotator SDL-AMR-09 ::preferred # ::snt One of the most abundantly expressed PSPs , protein phosphatase 2A ( PP2A ) , can regulate the Raf / Mek / Erk pathway both positively and negatively . # ::save-date Fri Feb 6, 2015 ::file bio-kappa_0001_10.txt (p / possible-01 :ARG1 (a3 / and :op1 (u / upregulate-01 :ARG1 (p3 / pathway :name (n3 / name :op1 "Raf/Mek/Erk")) :ARG2 (e2 / enzyme :name (n2 / name :op1 "protein" :op2 "phosphatase" :op3 "2A") :ARG1-of (i / include-91 :ARG2 (s / small-molecule :name (n / name :op1 "PSP") :ARG2-of (e / express-03 :degree (a / abundant :degree (m2 / most))))))) :op2 (d / downregulate-01 :ARG1 p3 :ARG2 e2))) # ::id bio-kappa_0001.11 ::date 2015-01-20T04:54:37 ::annotator SDL-AMR-09 ::preferred # ::snt As a positive regulator , PP2A associates with C-Raf and Ksr1 and dephosphorylates negative regulatory sites on both proteins , allowing their recruitment to the membrane and leading to Mek and Erk activation . # ::save-date Fri Feb 6, 2015 ::file bio-kappa_0001_11.txt (a / and :op1 (a7 / associate-01 :ARG1 (e / enzyme :name (n / name :op1 "PP2A")) :ARG2 (a2 / and :op1 (e2 / enzyme :name (n2 / name :op1 "C-Raf")) :op2 (e3 / enzyme :name (n3 / name :op1 "Ksr1")))) :op2 (d / dephosphorylate-01 :ARG1 (p2 / protein-segment :ARG0-of (d2 / downregulate-01) :part-of (a3 / and :op1 e2 :op2 e3)) :ARG2 e) :ARG0-of (a4 / allow-01 :ARG1 (r / recruit-01 :ARG1 a2 :destination (m / membrane))) :ARG0-of (l / lead-03 :ARG2 (a5 / activate-01 :ARG1 (a6 / and :op1 (e4 / enzyme :name (n5 / name :op1 "Mek")) :op2 (e5 / enzyme :name (n6 / name :op1 "Erk"))))) :condition (u / upregulate-01 :ARG2 e)) # ::id bio-kappa_0001.12 ::date 2015-01-20T05:30:27 ::annotator SDL-AMR-09 ::preferred # ::snt A similar role in C-Raf activation has been described for the catalytic subunit of PP1C , which associates with C-Raf in Ras- and growth factor - stimulated cells . # ::save-date Wed Feb 24, 2016 ::file bio-kappa_0001_12.txt (d / describe-01 :ARG1 (r / role :ARG1-of (r2 / resemble-01) :purpose (a / activate-01 :ARG1 (e / enzyme :name (n / name :op1 "C-Raf")))) :topic (p / protein-segment :ARG0-of (c / catalyze-01) :part-of (e2 / enzyme :name (n2 / name :op1 "PP1C")) :ARG1-of (b / bind-01 :ARG2 e :location (c2 / cell :ARG1-of (s / stimulate-01 :ARG0 (a2 / and :op1 (e3 / enzyme :name (n3 / name :op1 "Ras")) :op2 (g / growth-factor))))))) # ::id bio-kappa_0001.13 ::date 2015-01-20T06:02:25 ::annotator SDL-AMR-09 ::preferred # ::snt In addition to promoting C-Raf activation , PP2A is also able to dephosphorylate Erk - dependent sites on C-Raf . # ::save-date Tue Jan 27, 2015 ::file bio-kappa_0001_13.txt (a / and :op1 (p3 / promote-02 :ARG0 e :ARG1 (a2 / activate-01 :ARG1 e3)) :op2 (p / possible-01 :ARG1 (d / dephosphorylate-01 :ARG1 (p2 / protein-segment :ARG0-of (d2 / depend-01 :ARG1 (e2 / enzyme :name (n2 / name :op1 "Erk"))) :part-of (e3 / enzyme :name (n3 / name :op1 "C-Raf"))) :ARG2 (e / enzyme :name (n / name :op1 "PP2A"))) :mod (a3 / also))) # ::id bio-kappa_0001.14 ::date 2015-01-20T06:22:13 ::annotator SDL-AMR-09 ::preferred # ::snt Since the sites have been described alternatively as negative regulatory or activating , the significance of these dephosphorylation events for Raf activation is unclear . # ::save-date Fri May 29, 2015 ::file bio-kappa_0001_14.txt (c / clear-06 :polarity - :ARG0 (d2 / describe-01 :ARG1 (p / protein-segment) :ARG2 (o / or :op1 (d3 / downregulate-01 :ARG2 p) :op2 (a2 / activate-01 :ARG0 p)) :manner (a / alternative)) :ARG1 (s / significance :topic (a3 / activate-01 :ARG1 (e2 / enzyme :name (n2 / name :op1 "Raf"))) :mod (d / dephosphorylate-01 :mod (t / this)))) # ::id bio-kappa_0001.15 ::date 2015-01-20T06:38:55 ::annotator SDL-AMR-09 ::preferred # ::snt As a negative regulator of the pathway , PP2A can dephosphorylate the adapter protein Shc , required downstream of some tyrosine kinase receptors for the activation of the Raf / Mek / Erk module ; and it can dephosphorylate Mek and Erk proteins , thus inhibiting the cascade directly . # ::save-date Sat Jan 16, 2016 ::file bio-kappa_0001_15.txt (a / and :op1 (p6 / possible-01 :ARG1 (d / dephosphorylate-01 :ARG1 (p2 / protein :name (n2 / name :op1 "Shc") :mod (a2 / adapter) :ARG1-of (r / require-01 :ARG0 (a3 / activate-01 :ARG1 (p3 / pathway :name (n3 / name :op1 "Raf/Mek/Erk")) :location (r3 / relative-position :op1 (p / protein :name (n7 / name :op1 "tyrosine" :op2 "kinase" :op3 "receptor") :quant (s / some)) :direction (d2 / downstream))))) :ARG2 (e / enzyme :name (n / name :op1 "PP2A")) :condition (d5 / downregulate-01 :ARG1 (p4 / pathway) :ARG2 e))) :op2 (p7 / possible-01 :ARG1 (d4 / dephosphorylate-01 :ARG1 (a4 / and :op1 (p5 / protein-family :name (n4 / name :op1 "Mek")) :op2 (p8 / protein-family :name (n5 / name :op1 "Erk"))) :ARG2 e :ARG0-of (i / inhibit-01 :ARG1 p3 :ARG1-of (d3 / direct-02))))) # ::id bio-kappa_0001.16 ::date 2015-01-20T07:03:49 ::annotator SDL-AMR-09 ::preferred # ::snt A further negative regulator of the cascade , at the level of C-Raf , is Protein phosphatase 5 ( PP5 ) , which associates with C-Raf via its N-terminal tetratricopeptide ( TPR ) domain in growth factor stimulated cells . # ::save-date Wed Feb 24, 2016 ::file bio-kappa_0001_16.txt (d3 / downregulate-01 :ARG0 (e3 / enzyme :name (n / name :op1 "Protein" :op2 "phosphatase" :op3 "5") :ARG1-of (a / associate-01 :ARG2 (e2 / enzyme :name (n2 / name :op1 "C-Raf")) :location (c / cell :ARG1-of (s / stimulate-01 :ARG0 (g / growth-factor))) :instrument (p2 / protein-segment :name (n4 / name :op1 "tetratricopeptide" :op2 "domain") :part-of (p / protein-segment :name (n3 / name :op1 "N-terminal") :part-of e2))) :mod (f / further)) :ARG1 (c2 / cascade :location e2)) # ::id bio-kappa_0001.17 ::date 2015-01-20T07:23:45 ::annotator SDL-AMR-09 ::preferred # ::snt This interaction leads to the activation of PP5 catalytic activity and to the selective dephosphorylation of the activating serine residue at position 338 , terminating the signal . # ::save-date Mon Jul 6, 2015 ::file bio-kappa_0001_17.txt (l / lead-03 :ARG0 (i2 / interact-01 :mod (t / this)) :ARG2 (a3 / and :op1 (a / activate-01 :ARG1 (a2 / activity-06 :ARG0 (e / enzyme :name (n / name :op1 "PP5")) :ARG1 (c2 / catalyze-01))) :op2 (d / dephosphorylate-01 :ARG1 (r / residue :mod 338 :mod (a4 / amino-acid :name (n2 / name :op1 "serine")) :ARG0-of (a5 / activate-01)) :mod (s / selective)) :ARG0-of (t2 / terminate-01 :ARG1 (s3 / signal)))) # ::id bio-kappa_0001.18 ::date 2015-01-20T07:43:07 ::annotator SDL-AMR-09 ::preferred # ::snt Following ligand binding , Sos is brought from the cytoplasm to the activated receptor in a phosphotyrosine - dependent manner through adapter proteins such as Grb2 . # ::save-date Fri Feb 6, 2015 ::file bio-kappa_0001_18.txt (b / bring-01 :ARG1 (p3 / protein :name (n3 / name :op1 "Sos")) :ARG2 (r / receptor :ARG1-of (a / activate-01)) :ARG4 (c / cytoplasm) :manner (d / depend-01 :ARG0 b :ARG1 (a2 / amino-acid :name (n / name :op1 "tyrosine") :ARG3-of (p4 / phosphorylate-01))) :instrument (p / protein :example (p2 / protein :name (n2 / name :op1 "Grb2")) :mod (a3 / adapter)) :ARG1-of (f / follow-01 :ARG2 (b2 / bind-01 :ARG1 (l / ligand)))) # ::id bio-kappa_0001.19 ::date 2015-01-20T08:00:15 ::annotator SDL-AMR-09 ::preferred # ::snt Grb2 contains SH3 domains that are bound constitutively to a carboxy - terminal proline - rich region of Sos , and the Grb2 '96 Sos complex is recruited to activated receptors by interactions between the SH2 domain of Grb2 and phosphotyrosine residues on the receptor . # ::save-date Sat Jun 13, 2015 ::file bio-kappa_0001_19.txt (a / and :op1 (c / contain-01 :ARG0 (p / protein :name (n / name :op1 "Grb2")) :ARG1 (p2 / protein-segment :name (n2 / name :op1 "SH3" :op2 "domain") :ARG1-of (b / bind-01 :ARG2 (r4 / region :mod (r6 / rich :topic (a3 / amino-acid :name (n3 / name :op1 "proline"))) :part-of (p5 / protein-segment :name (n4 / name :op1 "carboxy-terminus") :part-of (p6 / protein :name (n5 / name :op1 "Sos")))) :mod (c2 / constitutive)))) :op2 (r5 / recruit-01 :ARG0 (i / interact-01 :ARG0 (a5 / and :op1 (p7 / protein-segment :name (n7 / name :op1 "SH2" :op2 "domain") :part-of p) :op2 (r2 / residue :location (r3 / receptor) :mod (a4 / amino-acid :name (n6 / name :op1 "tyrosine") :ARG3-of (p3 / phosphorylate-01))))) :ARG1 (m2 / macro-molecular-complex :part p :part p6) :destination (r / receptor :ARG1-of (a2 / activate-01)))) # ::id bio-kappa_0001.20 ::date 2015-01-20T08:03:03 ::annotator SDL-AMR-09 ::preferred # ::snt The guanine nucleotide-binding switch in three dimensions . # ::save-date Wed Jan 21, 2015 ::file bio-kappa_0001_20.txt (s / switch :mod (p / protein :name (n / name :op1 "guanine" :op2 "nucleotide-binding")) :prep-in (d / dimension :quant 3)) # ::id bio-kappa_0001.21 ::date 2015-01-20T08:10:38 ::annotator SDL-AMR-09 ::preferred # ::snt Activation requires dissociation of protein - bound GDP , an intrinsically slow process that is accelerated by guanine nucleotide '96 exchange factors ( GEFs ) . # ::save-date Wed Nov 11, 2015 ::file bio-kappa_0001_21.txt (r / require-01 :ARG0 (a / activate-01) :ARG1 (d / dissociate-01 :ARG1 (s / small-molecule :name (n / name :op1 "GDP") :ARG1-of (b / bind-01 :ARG2 (p / protein))) :ARG1-of (s2 / slow-05 :mod (i / intrinsic)) :ARG1-of (a2 / accelerate-01 :ARG0 (p2 / protein :name (n2 / name :op1 "guanine" :op2 "nucleotide" :op3 "exchange" :op4 "factor"))))) # ::id bio-kappa_0001.22 ::date 2015-01-20T08:17:10 ::annotator SDL-AMR-09 ::preferred # ::snt This switch - ON process involves the exchange of GDP for GTP , and is , at least in principle , reversible . # ::save-date Mon Jul 13, 2015 ::file bio-kappa_0001_22.txt (a / and :op1 (i2 / involve-01 :ARG0 (p / process-02 :ARG1 (a3 / activate-01) :mod (t / this)) :ARG1 (e / exchange-01 :ARG1 (s / small-molecule :name (n / name :op1 "GDP")) :ARG3 (s2 / small-molecule :name (n2 / name :op1 "GTP")))) :op2 (p3 / possible-01 :ARG1 (r / reverse-01 :ARG1 p) :mod (i / in-principle :mod (a2 / at-least)))) # ::id bio-kappa_0001.23 ::date 2015-01-20T08:30:46 ::annotator SDL-AMR-09 ::preferred # ::snt The switch - OFF process is entirely different and involves hydrolysis of GTP to GDP , the guanosine triphosphatase ( GTPase ) reaction , which is basically irreversible . # ::save-date Mon Jul 13, 2015 ::file bio-kappa_0001_23.txt (a / and :op1 (d2 / differ-02 :ARG1 (p / process-02 :ARG1 (d / deactivate-01)) :degree (e / entire)) :op2 (i / involve-01 :ARG1 (h / hydrolyze-01 :ARG1 (s / small-molecule :name (n / name :op1 "GTP")) :ARG3 (s2 / small-molecule :name (n2 / name :op1 "GDP")) :ARG2-of (r / react-01 :ARG0 (e2 / enzyme :name (n3 / name :op1 "guanosine" :op2 "triphosphatase")) :ARG1-of (r2 / reverse-01 :ARG1-of (p2 / possible-01 :polarity - :mod (b / basic))))) :ARG2 p)) # ::id bio-kappa_0001.24 ::date 2015-01-20T08:41:56 ::annotator SDL-AMR-09 ::preferred # ::snt It is also intrinsically very slow and thus has to be accelerated by GTPase - activating proteins ( GAPs ) . # ::save-date Wed Nov 11, 2015 ::file bio-kappa_0001_24.txt (s / slow-05 :ARG1 (i / it) :degree (v / very) :mod (i2 / intrinsic) :mod (a4 / also) :ARG0-of (c / cause-01 :ARG1 (o2 / obligate-01 :ARG2 (a / accelerate-01 :ARG0 (p / protein :ARG0-of (a3 / activate-01 :ARG1 (e / enzyme :name (n / name :op1 "GTPase")))) :ARG1 i)))) # ::id bio-kappa_0001.25 ::date 2015-01-20T09:07:33 ::annotator SDL-AMR-09 ::preferred # ::snt The mechanism of GEF action involves a series of fast reaction steps , which lead from a binary protein - nucleotide complex via a trimeric GNBP - nucleotide - GEF complex to a binary nucleotide - free complex , which is stable in the absence of nucleotide . # ::save-date Wed Jan 20, 2016 ::file bio-kappa_0001_25.txt (i / involve-01 :ARG1 (s / series :consist-of (s2 / step :ARG1-of (f / fast-02) :mod (r / react-01) :ARG0-of (t3 / turn-02 :ARG2 (c2 / complex :ARG1-of (f2 / free-04 :ARG2 (n3 / nucleotide)) :ARG1-of (s3 / stable-03 :condition (a2 / absent-01 :ARG1 n3))) :ARG3 (m2 / macro-molecular-complex :part (p2 / protein) :part n3 :mod (b2 / binary)) :path (m3 / macro-molecular-complex :mod (t2 / trimeric) :part (p3 / protein :name (n2 / name :op1 "GNBP")) :part n3 :part p)))) :ARG2 (m / mechanism :mod (a / act-02 :ARG0 (p / protein :name (n / name :op1 "GEF"))))) # ::id bio-kappa_0001.26 ::date 2015-01-20T09:08:43 ::annotator SDL-AMR-09 ::preferred # ::snt This series of reactions is reversed by rebinding of nucleotide , predominantly GTP , because of its higher concentration in the cell . # ::save-date Sun Jul 26, 2015 ::file bio-kappa_0001_26.txt (r / reverse-01 :ARG0 (b / bind-01 :ARG1 (n / nucleotide :ARG1-of (m2 / mean-01 :ARG2 (s2 / small-molecule :name (n2 / name :op1 "GTP")) :mod (p / predominant :ARG1-of (c / cause-01 :ARG0 (c2 / concentrate-02 :ARG1 s2 :ARG1-of (h / high-02 :degree (m / more)) :location (c3 / cell)))))) :mod (a / again)) :ARG1 (s / series :mod (t / this) :consist-of (r2 / react-01))) # ::id bio-kappa_0001.27 ::date 2015-01-20T09:16:31 ::annotator SDL-AMR-09 ::preferred # ::snt In principle , these reactions are fast and fully reversible , so that the GEF merely acts as a catalyst to increase the rate at which equilibrium between the GDP- and GTP - bound forms of the protein is reached . # ::save-date Wed Jan 20, 2016 ::file bio-kappa_0001_27.txt (a / and :op1 (f / fast-02 :ARG1 (r / react-01 :mod (t / this))) :op2 (p / possible-01 :ARG1 (r2 / reverse-01 :ARG1 r :degree (f2 / full))) :mod (i2 / in-principle) :ARG0-of (c / cause-01 :ARG1 (a2 / act-01 :ARG0 (p3 / protein :name (n / name :op1 "GEF")) :ARG1 (c2 / catalyze-01) :degree (m / mere) :purpose (i / increase-01 :ARG0 p3 :ARG1 (r3 / rate :degree-of (r4 / reach-01 :ARG1 (e / equilibrate-01 :ARG1 (a4 / and :op1 (p2 / protein :ARG1-of (b / bind-01 :ARG2 (s / small-molecule :name (n2 / name :op1 "GDP")))) :op2 (p5 / protein :ARG1-of (b2 / bind-01 :ARG2 (s2 / small-molecule :name (n3 / name :op1 "GTP")))))))))))) # ::id bio.bel_0002.1 ::date 2014-09-29T14:32:03 ::annotator SDL-AMR-09 ::preferred # ::snt Protein kinase A-dependent phosphorylation of serine 43 within the regulatory domain of Raf-1 reciprocally potentiates its interaction with Rheb and decreases its interaction with H-Ras. # ::save-date Tue Jun 16, 2015 ::file bio_bel_0002_1.txt (a / and :op1 (p / potentiate-01 :ARG1 (i / interact-01 :ARG0 e2 :ARG1 (p2 / protein :name (n / name :op1 "Rheb"))) :ARG2 (p3 / phosphorylate-01 :ARG1 (a2 / amino-acid :mod 43 :name (n5 / name :op1 "serine") :part-of (d2 / domain :mod (r / regulate-01) :part-of (e2 / enzyme :name (n3 / name :op1 "Raf-1")))) :ARG0-of (d3 / depend-01 :ARG1 (e3 / enzyme :name (n4 / name :op1 "protein" :op2 "kinase" :op3 "A")))) :mod (r2 / reciprocal)) :op2 (d / decrease-01 :ARG0 p3 :ARG1 (i2 / interact-01 :ARG0 e2 :ARG1 (e / enzyme :name (n2 / name :op1 "H-Ras"))))) # ::id bio.bel_0002.2 ::date 2014-09-29T14:54:34 ::annotator SDL-AMR-09 ::preferred # ::snt We show that wild-type B-RAF forms a complex with C-RAF in a RAS-dependent manner, whereas the mutants bind independently of RAS. # ::save-date Mon Feb 9, 2015 ::file bio_bel_0002_2.txt (s / show-01 :ARG0 (w / we) :ARG1 (f / form-01 :ARG1 (m / macro-molecular-complex :part (e4 / enzyme :name (n / name :op1 "B-RAF") :mod (w2 / wild-type)) :part (e / enzyme :name (n2 / name :op1 "C-RAF"))) :ARG0-of (d / depend-01 :ARG1 (e3 / enzyme :name (n3 / name :op1 "RAS"))) :ARG1-of (c / contrast-01 :ARG2 (b / bind-01 :ARG1 (e5 / enzyme :name (n4 / name :op1 "B-RAF") :ARG2-of (m2 / mutate-01)) :ARG2 (e2 / enzyme :name (n5 / name :op1 "C-RAF") :ARG2-of (m3 / mutate-01)) :ARG0-of (d2 / depend-01 :polarity - :ARG1 e3))))) # ::id bio.bel_0002.3 ::date 2014-09-29T15:10:36 ::annotator SDL-AMR-09 ::preferred # ::snt Importantly, we show that wild-type B-RAF can also activate C-RAF. # ::save-date Wed Dec 10, 2014 ::file bio_bel_0002_3.txt (s / show-01 :ARG0 (w / we) :ARG1 (p / possible-01 :ARG1 (a / activate-01 :ARG0 (e2 / enzyme :name (n / name :op1 "B-RAF") :mod (w2 / wild-type)) :ARG1 (e / enzyme :name (n2 / name :op1 "C-RAF")) :mod (a2 / also))) :mod (i / important)) # ::id bio.bel_0002.4 ::date 2015-02-05T10:13:38 ::annotator SDL-AMR-09 ::preferred # ::snt The homologous site on B-Raf, S445, is constitutively phosphorylated, accounting for the higher basal activity of B-Raf. # ::save-date Sun Jul 26, 2015 ::file bio_bel_0002_4.txt (p / phosphorylate-01 :ARG1 (a3 / amino-acid :mod 445 :name (n3 / name :op1 "serine") :part-of (e / enzyme :name (n4 / name :op1 "B-Raf")) :mod (h2 / homologue)) :mod (c / constitutive) :ARG0-of (a / account-01 :ARG1 (a2 / activity-06 :ARG0 e :mod (b / basal) :ARG1-of (h / high-02 :degree (m / more))))) # ::id bio.bel_0002.5 ::date 2015-01-23T02:19:50 ::annotator SDL-AMR-09 ::preferred # ::snt In addition, introduction of B-Raf enhances and sustains integrin-mediated activation of ERK in wild-type primary fibroblasts # ::save-date Fri Feb 6, 2015 ::file bio_bel_0002_5.txt (a4 / and :op2 (a / and :op1 (e / enhance-01 :ARG0 (i / introduce-02 :ARG1 (e2 / enzyme :name (n / name :op1 "B-Raf"))) :ARG1 (a2 / activate-01 :ARG1 (e3 / enzyme :name (n2 / name :op1 "ERK")) :location (f / fibroblast :mod (w / wild-type) :mod (p / primary)) :ARG1-of (m / mediate-01 :ARG0 (i2 / integrin)))) :op2 (s / sustain-01 :ARG0 i :ARG1 a2))) # ::id bio.bel_0002.6 ::date 2015-02-05T10:37:17 ::annotator SDL-AMR-09 ::preferred # ::snt siRNA-mediated depletion of B-Raf reduced cell proliferation by up to 65% through the inhibition of ERK1/2 activation, irrespective of the mutational status of B-Raf. # ::save-date Thu Jan 7, 2016 ::file bio_bel_0002_6.txt (r / reduce-01 :ARG0 (d / deplete-01 :ARG1 (e / enzyme :name (n2 / name :op1 "B-Raf")) :ARG1-of (m / mediate-01 :ARG0 (n4 / nucleic-acid :name (n / name :op1 "siRNA")))) :ARG1 (p2 / proliferate-01 :ARG0 (c / cell)) :ARG2 (u / up-to :op1 (p / percentage-entity :value 65)) :manner (i / inhibit-01 :ARG1 (a / activate-01 :ARG1 (e2 / enzyme :name (n3 / name :op1 "ERK1/2")))) :ARG1-of (r2 / regardless-91 :ARG2 (s / status :poss e :mod (m2 / mutate-01)))) # ::id bio.bel_0002.7 ::date 2015-02-05T10:59:48 ::annotator SDL-AMR-09 ::preferred # ::snt Following expression of BRAFV600E in melanocytes, the majority of cells became senescent (Figure 1D and data not shown), consistent with previous studies (Michaloglou et al., 2005) # ::save-date Mon Feb 9, 2015 ::file bio_bel_0002_7.txt (b / become-01 :ARG1 (c / cell :quant (m / majority)) :ARG2 (s / senescent :domain c) :ARG1-of (f / follow-01 :ARG2 (e / express-03 :ARG2 (e2 / enzyme :name (n / name :op1 "B-Raf") :ARG2-of (m2 / mutate-01 :value "V600E")) :ARG3 (m3 / melanocyte))) :ARG1-of (d2 / describe-01 :ARG0 (a / and :op1 (f2 / figure :mod "1D") :op2 (d3 / data :ARG1-of (s2 / show-01 :polarity -)))) :ARG1-of (c3 / consistent-01 :ARG2 (s3 / study :time (p / previous) :ARG1-of (d4 / describe-01 :ARG0 (p2 / publication-91 :ARG0 (a2 / and :op1 (p3 / person :name (n2 / name :op1 "Michaloglou")) :op2 (p4 / person :mod (o / other))) :time (d / date-entity :year 2005)))))) # ::id bio.bel_0002.8 ::date 2015-01-23T02:59:24 ::annotator SDL-AMR-09 ::preferred # ::snt disruption of the KSR1/CK2 interaction or inhibition of CK2 activity significantly reduces the growth-factor-induced phosphorylation of C-Raf and B-Raf on the activating serine site in the negative-charge regulatory region (N-region). # ::save-date Wed Feb 24, 2016 ::file bio_bel_0002_8.txt (r / reduce-01 :ARG0 (o / or :op1 (d / disrupt-01 :ARG1 (i / interact-01 :ARG0 (e3 / enzyme :name (n4 / name :op1 "KSR1")) :ARG1 (e4 / enzyme :name (n5 / name :op1 "CK2")))) :op2 (i2 / inhibit-01 :ARG1 (a3 / activity-06 :ARG0 e4))) :ARG1 (p / phosphorylate-01 :ARG1 (p2 / protein-segment :ARG0-of (a2 / activate-01) :mod (a4 / amino-acid :name (n7 / name :op1 "serine")) :part-of (r2 / region :ARG0-of (r3 / regulate-01) :ARG1-of (c / charge-03 :ARG2-of (n3 / negative-06)) :part-of (a / and :op1 (e / enzyme :name (n / name :op1 "C-Raf")) :op2 (e2 / enzyme :name (n2 / name :op1 "B-Raf"))))) :ARG2-of (i3 / induce-01 :ARG0 (g / growth-factor))) :ARG2 (s / significant-02)) # ::id bio.bel_0002.9 ::date 2015-01-23T03:54:56 ::annotator SDL-AMR-09 ::preferred # ::snt Sorafenib is a potent TKI of VEGFR-2, VEGFR-3, B-RAF, and PDGFR-B # ::save-date Thu Feb 5, 2015 ::file bio_bel_0002_9.txt (i / inhibit-01 :ARG0 (s2 / small-molecule :name (n2 / name :op1 "Sorafenib")) :ARG1 (a / and :op1 (k / kinase :name (n / name :op1 "VEGFR-2")) :op2 (k2 / kinase :name (n3 / name :op1 "VEGFR-3")) :op3 (k3 / kinase :name (n4 / name :op1 "B-RAF")) :op4 (k4 / kinase :name (n5 / name :op1 "PDGFR-B"))) :mod (p / potent)) # ::id bio.bel_0002.10 ::date 2015-01-23T03:55:41 ::annotator SDL-AMR-09 ::preferred # ::snt In addition, we found that Rheb inhibits the association of B-Raf with H-Ras. # ::save-date Fri Feb 6, 2015 ::file bio_bel_0002_10.txt (a3 / and :op2 (f / find-01 :ARG0 (w / we) :ARG1 (i / inhibit-01 :ARG0 (p / protein :name (n / name :op1 "Rheb")) :ARG1 (a2 / associate-01 :ARG1 (e2 / enzyme :name (n2 / name :op1 "B-Raf")) :ARG2 (e3 / enzyme :name (n3 / name :op1 "H-Ras")))))) # ::id bio.bel_0002.11 ::date 2015-01-23T04:01:28 ::annotator SDL-AMR-09 ::preferred # ::snt hKSR-2 selectively inhibited the Cot-mediated activation of MEK by 60%. # ::save-date Mon Feb 9, 2015 ::file bio_bel_0002_11.txt (i / inhibit-01 :ARG0 (e / enzyme :name (n / name :op1 "hKSR-2")) :ARG1 (a / activate-01 :ARG1 (e2 / enzyme :name (n2 / name :op1 "MEK")) :ARG1-of (m / mediate-01 :ARG0 (e3 / enzyme :name (n3 / name :op1 "Cot")))) :manner (s / selective) :quant (p / percentage-entity :value 60)) # ::id bio.bel_0002.12 ::date 2015-02-05T12:05:33 ::annotator SDL-AMR-09 ::preferred # ::snt In contrast, hKSR-2 up-regulated the Rafmediated MEK activation by up to 70%. # ::save-date Thu Feb 5, 2015 ::file bio_bel_0002_12.txt (c / contrast-01 :ARG2 (u / upregulate-01 :ARG1 (a / activate-01 :ARG1 (e / enzyme :name (n / name :op1 "MEK")) :ARG1-of (m / mediate-01 :ARG0 (e2 / enzyme :name (n2 / name :op1 "Raf")))) :ARG2 (e3 / enzyme :name (n3 / name :op1 "hKSR-2")) :quant (u2 / up-to :op1 (p / percentage-entity :value 70)))) # ::id bio.bel_0002.13 ::date 2015-02-07T09:19:06 ::annotator SDL-AMR-09 ::preferred # ::snt GSK PI3K Phase 2, part 1: List of non-position specific phosphorylation effects on parent protein's activity, derived from existing causal assertions of position-specific phosphorylations on the parent protein activity. # ::save-date Fri Jan 1, 2016 ::file bio_bel_0002_13.txt (a4 / and :op1 (e / enzyme :name (n / name :op1 "GSK")) :op2 (e2 / enzyme :name (n2 / name :op1 "PI3K")) :mod (p8 / phase :mod 2 :part (p9 / part :mod 1 :topic (l / list-01 :ARG1 (a / affect-01 :ARG0 (p / phosphorylate-01 :ARG1-of (s / specific-02 :polarity - :ARG2 (p2 / position-01))) :ARG1 (a2 / activity-06 :ARG0 (p3 / protein :mod (p4 / parent)))) :ARG1-of (d / derive-01 :ARG2 (a3 / assert-03 :ARG1 (p5 / phosphorylate-01 :mod (p6 / position :ARG1-of s)) :ARG0-of (c / cause-01) :topic a2 :ARG1-of (e3 / exist-01))))))) # ::id bio.bmtr_0001.1 ::date 2014-12-03T18:05:22 ::annotator SDL-AMR-09 ::preferred # ::snt Sasaki et al., “Ubiquitination of Ras enhances activation and facilitates binding to select downstream effectors” (PMC3437993) # ::save-date Wed Dec 10, 2014 ::file bio_bmtr_0001_1.txt (p / publication-91 :ARG0 (a / and :op1 (p2 / person :name (n / name :op1 "Sasaki")) :op2 (p3 / person :mod (o / other))) :ARG1 (a2 / and :op1 (e / enhance-01 :ARG0 (u / ubiquitinate-01 :ARG1 (e3 / enzyme :name (n2 / name :op1 "Ras"))) :ARG1 (a3 / activate-01)) :op2 (f / facilitate-01 :ARG0 u :ARG1 (b / bind-01 :ARG2 (e2 / effector :location (d / downstream) :mod (s2 / select))))) :ARG8 "PMC3437993") # ::id bio.bmtr_0001.2 ::date 2014-12-03T21:45:59 ::annotator SDL-AMR-09 ::preferred # ::snt We utilized an unbiased mass spectrometry-based approach to identify ubiquitination sites of Ras. # ::save-date Wed Dec 10, 2014 ::file bio_bmtr_0001_2.txt (u / utilize-01 :ARG0 (w / we) :ARG1 (a / approach-02 :ARG1-of (b / base-02 :ARG2 (s / spectrometry :mod (m / mass))) :ARG1-of (b2 / bias-01 :polarity -)) :purpose (i / identify-01 :ARG0 w :ARG1 (p / protein-segment :part-of (e / enzyme :name (n / name :op1 "Ras")) :ARG1-of (u2 / ubiquitinate-01)))) # ::id bio.bmtr_0001.3 ::date 2014-12-03T21:53:14 ::annotator SDL-AMR-09 ::preferred # ::snt His-tagged ubiquitin and Flag-tagged K-Ras4B (K-Ras hereafter) were expressed in HEK293T cells at levels similar to endogenous K-Ras (Fig. 1B) and subjected to sequential affinity chromatography. # ::save-date Wed Dec 10, 2014 ::file bio_bmtr_0001_3.txt (a3 / and :op1 (e / express-03 :ARG2 (a / and :op1 (p / protein :name (n2 / name :op1 "ubiquitin") :ARG1-of (t / tag-01 :ARG2 (p3 / protein-segment :part (a2 / amino-acid :name (n5 / name :op1 "histidine"))))) :op2 (e5 / enzyme :name (n3 / name :op1 "K-Ras4B") :name (n4 / name :op1 "K-Ras") :ARG1-of (t2 / tag-01 :ARG2 (p4 / protein-segment :name (n6 / name :op1 "Flag"))))) :ARG3 (c / cell-line :name (n / name :op1 "HEK293T")) :degree (l / level :ARG1-of (r / resemble-01 :ARG2 (l2 / level :degree-of (e3 / express-03 :ARG2 (e4 / enzyme :name (n7 / name :op1 "K-Ras") :mod (e2 / endogenous)) :ARG3 c)))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "1B"))) :op2 (s2 / subject-01 :ARG1 a :ARG2 (c2 / chromatography :mod (a4 / affinity) :mod (s3 / sequence)))) # ::id bio.bmtr_0001.4 ::date 2014-12-09T14:55:44 ::annotator SDL-AMR-09 ::preferred # ::snt His-ubiquitinated proteins were purified by Co2+ metal affinity chromatography in 8M urea denaturing conditions. # ::save-date Mon Oct 26, 2015 ::file bio_bmtr_0001_4.txt (p / purify-01 :ARG1 (p2 / protein :ARG3-of (u / ubiquitinate-01 :mod (a / amino-acid :name (n / name :op1 "histidine")))) :manner (c / chromatography :mod (a2 / affinity :topic (c3 / copper :ARG1-of (i / ionize-01 :value "2+"))) :condition (d / denature-01 :ARG1 p2 :ARG4 (s / small-molecule :name (n3 / name :op1 "urea") :mod (c2 / concentration-quantity :quant 8 :unit (m2 / molar)))))) # ::id bio.bmtr_0001.5 ::date 2014-12-09T22:13:53 ::annotator SDL-AMR-09 ::preferred # ::snt His-ubiquitinated K-Ras was subsequently purified with anti-Flag resin. # ::save-date Tue Dec 9, 2014 ::file bio_bmtr_0001_5.txt (p / purify-01 :ARG1 (e / enzyme :name (n / name :op1 "K-Ras") :ARG3-of (u / ubiquitinate-01 :mod (a / amino-acid :name (n2 / name :op1 "histidine")))) :time (s / subsequent) :instrument (r / resin :ARG0-of (c / counter-01 :ARG1 (p2 / protein-segment :name (n3 / name :op1 "Flag"))))) # ::id bio.bmtr_0001.6 ::date 2014-12-09T22:40:15 ::annotator SDL-AMR-09 ::preferred # ::snt Following purification, mono- and di- ubiquitinated K-Ras appeared to be the major ubiquitination forms, which is consistent with the endogenous K-Ras ubiquitination pattern (Fig. 1, A and B). # ::save-date Fri Jan 1, 2016 ::file bio_bmtr_0001_6.txt (a / appear-02 :ARG1 (f4 / form :mod (u3 / ubiquitinate-01) :mod (m2 / major) :domain (a3 / and :op1 (u4 / ubiquitinate-01 :quant 1 :ARG1 (e / enzyme :name (n / name :op1 "K-Ras"))) :op2 (u5 / ubiquitinate-01 :quant 2 :ARG1 e)) :ARG1-of (c / consistent-01 :ARG2 (p2 / pattern :topic (u2 / ubiquitinate-01 :ARG1 (e2 / enzyme :name (n2 / name :op1 "K-Ras") :mod (e3 / endogenous)))))) :ARG1-of (d / describe-01 :ARG0 (a2 / and :op1 (f2 / figure :mod "1A") :op2 (f3 / figure :mod "1B"))) :ARG1-of (f / follow-01 :ARG2 (p / purify-01 :ARG1 e))) # ::id bio.bmtr_0001.7 ::date 2014-12-09T22:54:17 ::annotator SDL-AMR-09 ::preferred # ::snt H-Ras ubiquitination sites were also determined by the same approach. # ::save-date Wed Nov 4, 2015 ::file bio_bmtr_0001_7.txt (d / determine-01 :ARG1 (p / protein-segment :ARG1-of (u / ubiquitinate-01) :part-of (e / enzyme :name (n / name :op1 "H-Ras"))) :manner (a / approach-02 :ARG1-of (s / same-01)) :mod (a2 / also)) # ::id bio.bmtr_0001.8 ::date 2014-12-05T20:16:13 ::annotator SDL-AMR-09 ::preferred # ::snt Tandem mass spectrometric analysis of tryptic fragments from the bands migrating at the positions expected for mono- and di-ubiquitinated Ras revealed ubiquitination at Lys residues 104 and 147 of K-Ras, and Lys residues 117, 147 and 170 for H-Ras (fig. S1C). # ::save-date Sun Jul 5, 2015 ::file bio_bmtr_0001_8.txt (r / reveal-01 :ARG0 (a / analyze-01 :ARG1 (p3 / protein-segment :ARG3-of (h / hydrolyze-01 :ARG2 (e2 / enzyme :name (n2 / name :op1 "trypsin"))) :source (b / band :ARG0-of (m / migrate-01 :ARG2 (p / position :ARG2-of (b2 / be-located-at-91 :ARG1 (e5 / enzyme :name (n / name :op1 "Ras") :ARG3-of (u / ubiquitinate-01 :quant (o / or :op1 1 :op2 2))) :ARG1-of (e / expect-01)))))) :manner (s / spectrometry :mod (m2 / mass) :mod (t / tandem))) :ARG1 (u2 / ubiquitinate-01 :ARG1 (a2 / and :op1 (a8 / and :op1 (r2 / residue :mod (a3 / amino-acid :mod 104 :name (n3 / name :op1 "lysine"))) :op2 (r3 / residue :mod (a4 / amino-acid :mod 147 :name (n4 / name :op1 "lysine"))) :part-of (e4 / enzyme :name (n5 / name :op1 "K-Ras"))) :op2 (a9 / and :op1 (r4 / residue :mod (a5 / amino-acid :mod 117 :name (n6 / name :op1 "lysine"))) :op2 (r5 / residue :mod (a6 / amino-acid :mod 147 :name (n7 / name :op1 "lysine"))) :op3 (r6 / residue :mod (a7 / amino-acid :mod 170 :name (n8 / name :op1 "lysine"))) :part-of (e3 / enzyme :name (n9 / name :op1 "H-Ras"))))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "S1C"))) # ::id bio.bmtr_0001.9 ::date 2014-12-09T22:57:04 ::annotator SDL-AMR-09 ::preferred # ::snt The tryptic peptide with ubiquitination at Lys147 (K147) was the most frequently observed peptide for both K-Ras and H-Ras, while Lys117 appeared as a secondary major ubiquitination site in H-Ras. # ::save-date Fri Jan 1, 2016 ::file bio_bmtr_0001_9.txt (c / contrast-01 :ARG1 (p / peptide :ARG1-of (o / observe-01 :ARG1-of (f / frequent-02 :degree (m / most))) :part-of (e2 / enzyme :mod (o2 / or :op1 (e3 / enzyme :name (n3 / name :op1 "K-Ras")) :op2 (e4 / enzyme :name (n4 / name :op1 "H-Ras")))) :domain (p2 / peptide :part (a / amino-acid :mod 147 :name (n / name :op1 "lysine") :ARG3-of (u / ubiquitinate-01)) :ARG3-of (h / hydrolyze-01 :ARG2 (e / enzyme :name (n2 / name :op1 "trypsin"))) :part-of e2)) :ARG2 (a3 / appear-01 :ARG1 (p3 / protein-segment :ARG1-of (u2 / ubiquitinate-01) :ARG1-of (m2 / major-02) :mod (s / secondary) :domain (a2 / amino-acid :mod 117 :name (n6 / name :op1 "lysine")) :part-of e4))) # ::id bio.bmtr_0001.10 ::date 2014-12-18T10:39:24 ::annotator SDL-AMR-09 ::preferred # ::snt To examine the effect of ubiquitination on GTP loading, we purified wild-type K-Ras, oncogenic G12V-K-Ras mutant or the ubiquitinated subfraction of wild-type K-Ras from 32P-orthophosphate labeled cells and utilized thin layer chromatography (TLC) and high performance liquid chromatography (HPLC) to assess the ratio of 32P-GTP to 32P-GDP that co-purified with each form of K-Ras. # ::save-date Wed Dec 9, 2015 ::file bio_bmtr_0001_10.txt (a2 / and :op1 (p / purify-01 :ARG0 (w / we) :ARG1 (a / and :op1 (o / or :op1 (e / enzyme :name (n2 / name :op1 "K-Ras") :mod (w2 / wild-type)) :op2 (e2 / enzyme :name (n3 / name :op1 "K-Ras") :ARG0-of (c / cause-01 :ARG1 (d / disease :wiki "Cancer" :name (n8 / name :op1 "cancer"))) :ARG2-of (m / mutate-01 :value "G12V")) :op3 (e3 / enzyme :name (n4 / name :op1 "K-Ras") :mod (w3 / wild-type) :ARG3-of (u / ubiquitinate-01) :mod (s2 / subfraction))) :op2 s4 :op3 s5) :source (c3 / cell :ARG1-of (l / label-01 :ARG2 (s3 / small-molecule :name (n5 / name :op1 "orthophosphate") :part (p2 / phosphorus :mod (m2 / molecular-mass :value 32)))))) :op2 (u2 / utilize-01 :ARG0 w :ARG1 (a5 / and :op1 (c4 / chromatography :mod (l3 / layer :ARG1-of (t / thin-03))) :op2 (c5 / chromatography :mod (l4 / liquid :ARG0-of (p3 / perform-02 :ARG1-of (h / high-02))))) :purpose (a3 / assess-01 :ARG0 w :ARG1 (r / ratio-of :op1 (s4 / small-molecule :name (n6 / name :op1 "GTP") :part (p4 / phosphorus :mod (m3 / molecular-mass :value 32))) :op2 (s5 / small-molecule :name (n7 / name :op1 "GDP") :part (p5 / phosphorus :mod (m4 / molecular-mass :value 32)))))) :purpose (e4 / examine-01 :ARG0 w :ARG1 (a4 / affect-01 :ARG0 (u3 / ubiquitinate-01) :ARG1 (l2 / load-01 :ARG2 (s / small-molecule :name (n / name :op1 "GTP")))))) # ::id bio.bmtr_0001.11 ::date 2014-12-18T12:35:31 ::annotator SDL-AMR-09 ::preferred # ::snt As expected based on previous studies, wild-type K-Ras bound primarily 32P-GDP, while G12V-Ras bound 32P-GTP (Fig.2, A and B). # ::save-date Mon Dec 22, 2014 ::file bio_bmtr_0001_11.txt (c / contrast-01 :ARG1 (b / bind-01 :ARG1 (e / enzyme :name (n / name :op1 "K-Ras") :mod (w / wild-type)) :ARG2 (s / small-molecule :name (n2 / name :op1 "GDP") :part (p / phosphorus :mod (m / molecular-mass :value 32))) :mod (p2 / primary)) :ARG2 (b2 / bind-01 :ARG1 (e2 / enzyme :name (n3 / name :op1 "Ras") :ARG2-of (m2 / mutate-01 :value "G12V")) :ARG2 (s2 / small-molecule :name (n4 / name :op1 "GTP") :part (p3 / phosphorus :mod (m3 / molecular-mass :value 32)))) :ARG1-of (d / describe-01 :ARG0 (a / and :op1 (f / figure :mod "2A") :op2 (f2 / figure :mod "2B"))) :ARG1-of (e3 / expect-01 :ARG1-of (b3 / base-02 :ARG2 (s4 / study :time (p4 / previous))))) # ::id bio.bmtr_0001.12 ::date 2014-12-18T17:04:39 ::annotator SDL-AMR-09 ::preferred # ::snt Interestingly, the ubiquitinated subfraction of wild-type K-Ras retained a significant amount of 32P-GTP. # ::save-date Tue May 26, 2015 ::file bio_bmtr_0001_12.txt (r / retain-01 :ARG0 (e / enzyme :name (n / name :op1 "K-Ras") :mod (w / wild-type) :ARG3-of (u / ubiquitinate-01) :mod (s2 / subfraction)) :ARG1 (s / small-molecule :name (n2 / name :op1 "GTP") :part (p / phosphorus :mod (m / molecular-mass :value 32)) :quant (a / amount :ARG1-of (s3 / significant-02))) :ARG2-of (i / interest-01)) # ::id bio.bmtr_0001.13 ::date 2014-12-18T17:10:57 ::annotator SDL-AMR-09 ::preferred # ::snt These results are consistent with a model in which ubiquitination of Lys147 (or Lys117), destabilizes GDP binding, allowing spontaneous GDP/GTP exchange. # ::save-date Fri Jan 1, 2016 ::file bio_bmtr_0001_13.txt (c / consistent-01 :ARG1 (t / thing :ARG2-of (r / result-01) :mod (t2 / this)) :ARG2 (m / model :topic (d / destabilize-01 :ARG0 (u / ubiquitinate-01 :ARG1 (o / or :op1 (a / amino-acid :mod 147 :name (n2 / name :op1 "lysine")) :op2 (a3 / amino-acid :mod 117 :name (n5 / name :op1 "lysine")))) :ARG1 (b / bind-01 :ARG2 (s / small-molecule :name (n / name :op1 "GDP"))) :ARG0-of (a2 / allow-01 :ARG1 (e / exchange-01 :ARG1 s :ARG3 (s4 / small-molecule :name (n4 / name :op1 "GTP")) :mod (s2 / spontaneous)))))) # ::id bio.bmtr_0001.14 ::date 2014-12-22T16:19:51 ::annotator SDL-AMR-09 ::preferred # ::snt It could be argued that GTP loading occurs prior to ubiquitination and that the GTP bound form of K-Ras, via interaction with effectors, is preferentially mono-ubiquitinated via a feedback mechanism. # ::save-date Fri Jan 1, 2016 ::file bio_bmtr_0001_14.txt (p / possible-01 :ARG1 (a / argue-01 :ARG1 (a2 / and :op1 (l / load-01 :ARG2 (s / small-molecule :name (n / name :op1 "GTP")) :time (p2 / prior :op1 (u / ubiquitinate-01))) :op2 (u2 / ubiquitinate-01 :quant 1 :ARG1 (e / enzyme :name (n2 / name :op1 "K-Ras") :ARG1-of (b / bind-01 :ARG2 s)) :ARG1-of (p3 / prefer-01) :manner (i / interact-01 :ARG0 e :ARG1 (e2 / effector)) :manner (f / feedback))))) # ::id bio.bmtr_0001.15 ::date 2014-12-22T16:27:59 ::annotator SDL-AMR-09 ::preferred # ::snt While it is difficult to eliminate this possibility, it is unlikely since, as shown in fig. S1B, the T35 mutant of K-Ras, which fails to interact with downstream effectors (fig. S1B) undergoes comparable monobuiquitination to wild type Ras. # ::save-date Wed Jul 8, 2015 ::file bio_bmtr_0001_15.txt (c / contrast-01 :ARG1 (d / difficult :domain (e3 / eliminate-01 :ARG1 (t / this :ARG1-of (p / possible-01)))) :ARG2 (l / likely-01 :polarity - :ARG1 t :ARG1-of (c2 / cause-01 :ARG0 (u / ubiquitinate-01 :quant 1 :ARG1 (e / enzyme :name (n / name :op1 "K-Ras") :ARG2-of (m / mutate-01 :value "T35") :ARG0-of (i / interact-01 :polarity - :ARG1 (e4 / effector :location (d2 / downstream)) :ARG1-of (d3 / describe-01 :ARG0 f))) :ARG1-of (s / show-01 :ARG0 (f / figure :mod "S1B")) :ARG1-of (c3 / comparable-03 :ARG2 (u2 / ubiquitinate-01 :ARG1 (e2 / enzyme :name (n2 / name :op1 "Ras") :mod (w / wild-type)))))))) # ::id bio.bmtr_0001.16 ::date 2014-12-22T16:52:11 ::annotator SDL-AMR-09 ::preferred # ::snt These results, along with the crystal structure, support a model in which mono-ubiquitination at a Lys residue directly involved in GDP binding either enhances nucleotide exchange on K-Ras, impairs GTP hydrolysis, or both. # ::save-date Fri Jul 24, 2015 ::file bio_bmtr_0001_16.txt (s3 / support-01 :ARG0 (a / and :op1 (t / thing :mod (t2 / this) :ARG2-of (r / result-01)) :op2 (s4 / structure :poss (c / crystal))) :ARG1 (m / model :topic (o / or :op1 (e2 / enhance-01 :ARG0 (u / ubiquitinate-01 :quant 1 :ARG1 (r2 / residue :mod (a2 / amino-acid :name (n4 / name :op1 "lysine")) :ARG1-of (i / involve-01 :ARG2 (b / bind-01 :ARG2 (s / small-molecule :name (n / name :op1 "GDP"))) :ARG1-of (d / direct-02)))) :ARG1 (e3 / exchange-01 :ARG1 (n5 / nucleotide) :ARG4 (e / enzyme :name (n2 / name :op1 "K-Ras")))) :op2 (i2 / impair-01 :ARG0 u :ARG1 (h / hydrolyze-01 :ARG1 (s2 / small-molecule :name (n3 / name :op1 "GTP")))) :op3 (a3 / and :op1 e2 :op2 i2)))) # ::id bio.bmtr_0001.17 ::date 2014-12-22T15:12:07 ::annotator SDL-AMR-09 ::preferred # ::snt To corroborate this finding, we measure the activity of Ras by the GST-RBD pull-down assay. # ::save-date Fri Jan 1, 2016 ::file bio_bmtr_0001_17.txt (m / measure-01 :ARG0 (w / we) :ARG1 (a / activity-06 :ARG0 (e / enzyme :name (n / name :op1 "Ras"))) :ARG2 (a2 / assay-01 :ARG1 (p / pull-down-08 :ARG1 (p2 / protein :name (n2 / name :op1 "GST-RBD")))) :purpose (c / corroborate-01 :ARG0 m :ARG1 (t / thing :ARG1-of (f / find-01) :mod (t2 / this)))) # ::id bio.bmtr_0001.18 ::date 2014-12-22T15:16:55 ::annotator SDL-AMR-09 ::preferred # ::snt To ensure that ubiquitinated Ras was being detected, the protein pulled down by GST-RBD was subjected to a second affinity purification on a cobalt column to purify the Flag-His-tagged K-Ras. # ::save-date Fri Jan 1, 2016 ::file bio_bmtr_0001_18.txt (s / subject-01 :ARG1 (p / protein :ARG1-of (p2 / pull-down-08 :ARG3 (p3 / protein :name (n3 / name :op1 "GST-RBD")))) :ARG2 (p4 / purify-01 :ARG1 p :ord (o / ordinal-entity :value 2) :mod (a / affinity) :location (c / column :consist-of (c2 / cobalt)) :purpose (p5 / purify-01 :ARG0 p4 :ARG1 (e2 / enzyme :name (n2 / name :op1 "K-Ras") :ARG1-of (t / tag-01 :ARG2 (a2 / and :op1 (p6 / protein-segment :name (n4 / name :op1 "Flag")) :op2 (p7 / protein-segment :part (a3 / amino-acid :name (n5 / name :op1 "histidine")))))))) :purpose (e3 / ensure-01 :ARG0 s :ARG1 (d / detect-01 :ARG1 (e / enzyme :name (n / name :op1 "Ras") :ARG3-of (u / ubiquitinate-01))))) # ::id bio.bmtr_0001.19 ::date 2014-12-22T15:30:38 ::annotator SDL-AMR-09 ::preferred # ::snt As predicted, only a very small fraction of wild-type K-Ras was pulled down by the GST-RBD (Fig. 2C and fig. S1D), consistent with very little wild-type K-Ras being in the GTP state under these conditions (Fig.2, A and B). # ::save-date Fri Jan 1, 2016 ::file bio_bmtr_0001_19.txt (p / pull-down-08 :ARG1 (e / enzyme :name (n / name :op1 "K-Ras") :mod (w / wild-type) :quant (f / fraction :mod (s2 / small :degree (v / very)) :mod (o / only))) :ARG3 (p2 / protein :name (n3 / name :op1 "GST-RBD")) :ARG1-of (p3 / predict-01) :ARG1-of (d / describe-01 :ARG0 (a / and :op1 (f2 / figure :mod "2C") :op2 (f3 / figure :mod "S1D"))) :ARG1-of (c / consistent-01 :ARG2 (b / bind-01 :ARG1 (e2 / enzyme :name (n4 / name :op1 "K-Ras") :quant (l / little :degree (v2 / very)) :mod w) :ARG2 (s / small-molecule :name (n2 / name :op1 "GTP")) :condition (t / this) :ARG1-of (d2 / describe-01 :ARG0 (a2 / and :op1 (f4 / figure :mod "2A") :op2 (f5 / figure :mod "2B")))))) # ::id bio.bmtr_0001.20 ::date 2014-12-22T15:36:10 ::annotator SDL-AMR-09 ::preferred # ::snt However, a much greater fraction of the ubiquitinated-K-Ras was pulled down by the GST-RBD (Fig. 2C and fig. S1D). # ::save-date Tue Jun 16, 2015 ::file bio_bmtr_0001_20.txt (c / contrast-01 :ARG2 (p / pull-down-08 :ARG1 (e / enzyme :name (n / name :op1 "K-Ras") :ARG3-of (u / ubiquitinate-01) :quant (f / fraction :mod (g / great :degree (m / more) :quant (m2 / much)))) :ARG3 (p2 / protein :name (n2 / name :op1 "GST-RBD")) :ARG1-of (d / describe-01 :ARG0 (a / and :op1 (f2 / figure :mod "2C") :op2 (f3 / figure :mod "S1D"))))) # ::id bio.bmtr_0001.21 ::date 2014-12-22T14:32:40 ::annotator SDL-AMR-09 ::preferred # ::snt These results are consistent with a greater fraction of ubiquitinated K-Ras being in the GTP state (Fig. 2, A and B). # ::save-date Mon Dec 22, 2014 ::file bio_bmtr_0001_21.txt (c / consistent-01 :ARG1 (t / thing :ARG2-of (r / result-01) :mod (t2 / this)) :ARG2 (b / bind-01 :ARG1 (e / enzyme :name (n / name :op1 "K-Ras") :ARG3-of (u / ubiquitinate-01) :degree (f3 / fraction :mod (g / great :degree (m / more)))) :ARG2 (s / small-molecule :name (n2 / name :op1 "GTP"))) :ARG1-of (d / describe-01 :ARG0 (a / and :op1 (f / figure :mod "2A") :op2 (f2 / figure :mod "2B")))) # ::id bio.bmtr_0002.1 ::date 2014-12-10T12:17:16 ::annotator SDL-AMR-09 ::preferred # ::snt Turke et al. “MEK inhibition leads to PI3K/AKT activation by relieving a negative feedback on ERBB receptors” (PMC3515079) # ::save-date Thu Feb 4, 2016 ::file bio_bmtr_0002_1.txt (p / publication-91 :ARG0 (a / and :op1 (p2 / person :name (n / name :op1 "Turke")) :op2 (p3 / person :mod (o / other))) :ARG1 (l / lead-03 :ARG0 (i / inhibit-01 :ARG1 (e / enzyme :name (n2 / name :op1 "MEK"))) :ARG2 (a2 / activate-01 :ARG1 (p4 / pathway :name (n3 / name :op1 "PI3K/AKT"))) :manner (r / relieve-01 :ARG0 i :ARG1 (f / feedback :ARG0-of (n4 / negative-03 :ARG1 (r2 / receptor :name (n5 / name :op1 "ERBB")))))) :ARG8 "PMC3515079") # ::id bio.bmtr_0002.2 ::date 2014-12-14T20:21:31 ::annotator SDL-AMR-09 ::preferred # ::snt We hypothesized that the MEK/ERK pathway may suppress trans-phosphorylation of ERBB3 by directly phosphorylating the JM domains of EGFR and HER2, and that this could be a dominant MEK inhibitor-induced feedback leading to AKT activation in these cancers. # ::save-date Sat Jan 16, 2016 ::file bio_bmtr_0002_2.txt (h / hypothesize-01 :ARG0 (w / we) :ARG1 (a / and :op1 (p / possible-01 :ARG1 (s / suppress-01 :ARG0 (p2 / pathway :name (n / name :op1 "MEK/ERK")) :ARG1 (p3 / phosphorylate-01 :ARG1 (e / enzyme :name (n2 / name :op1 "ERBB3"))) :manner (p4 / phosphorylate-01 :ARG0 p2 :ARG1 (a2 / and :op1 (p5 / protein-segment :name (n3 / name :op1 "JM" :op2 "domain") :part-of (e2 / enzyme :name (n4 / name :op1 "EGFR"))) :op2 (p6 / protein-segment :name (n5 / name :op1 "JM" :op2 "domain") :part-of (e3 / enzyme :name (n6 / name :op1 "HER2")))) :ARG1-of (d / direct-02)))) :op2 (p7 / possible-01 :ARG1 (f / feedback :ARG2-of (i / induce-01 :ARG0 (m / molecular-physical-entity :ARG0-of (i2 / inhibit-01 :ARG1 (p8 / protein-family :name (n7 / name :op1 "MEK"))))) :ARG0-of (d2 / dominate-01) :ARG0-of (l / lead-03 :ARG2 (a3 / activate-01 :ARG1 (e5 / enzyme :name (n8 / name :op1 "AKT")) :location (d3 / disease :wiki "Cancer" :name (n9 / name :op1 "cancer") :mod (t / this)))) :domain s)))) # ::id bio.bmtr_0002.3 ::date 2014-12-14T20:37:51 ::annotator SDL-AMR-09 ::preferred # ::snt We used tandem mass spectrometry to measure the effects of AZD6244 on phosphorylation of this JM domain threonine residue in both EGFR-mutant and HER2- amplified cancer models. # ::save-date Wed Dec 9, 2015 ::file bio_bmtr_0002_3.txt (u / use-01 :ARG0 (w / we) :ARG1 (s / spectrometry :mod (m / mass) :mod (t / tandem)) :ARG2 (m2 / measure-01 :ARG0 w :ARG1 (a / affect-01 :ARG0 (s2 / small-molecule :name (n / name :op1 "AZD6244")) :ARG1 (p / phosphorylate-01 :ARG1 (r / residue :mod (a2 / amino-acid :name (n2 / name :op1 "threonine")) :part-of (p2 / protein-segment :name (n3 / name :op1 "JM" :op2 "domain")) :mod (t2 / this))) :condition (a4 / and :op1 (m3 / model :topic (d / disease :wiki "Cancer" :name (n6 / name :op1 "cancer") :mod (m4 / mutate-01 :ARG1 (e / enzyme :name (n4 / name :op1 "EGFR"))))) :op2 (m5 / model :topic (d2 / disease :wiki "Cancer" :name (n7 / name :op1 "cancer") :mod (a3 / amplify-01 :ARG1 (e2 / enzyme :name (n5 / name :op1 "HER2"))))))))) # ::id bio.bmtr_0002.4 ::date 2014-12-14T20:53:57 ::annotator SDL-AMR-09 ::preferred # ::snt Targeting both the phosphorylated and non-phosphorylated peptide forms, we detected a 66% average decrease in EGFR T669 phosphorylation and a 75% decrease in HER2 T677 phosphorylation upon treatment with AZD6244 (Figure 5B, Supplemental Figure 8). # ::save-date Mon Dec 15, 2014 ::file bio_bmtr_0002_4.txt (d / detect-01 :ARG0 (w / we) :ARG1 (a / and :op1 (d2 / decrease-01 :ARG1 (p / phosphorylate-01 :ARG1 (a3 / amino-acid :mod 669 :name (n / name :op1 "threonine") :part-of (e / enzyme :name (n2 / name :op1 "EGFR")))) :ARG2 (p2 / percentage-entity :value 66 :ARG2-of (a2 / average-01))) :op2 (d3 / decrease-01 :ARG1 (p3 / phosphorylate-01 :ARG1 (a4 / amino-acid :mod 677 :name (n3 / name :op1 "threonine") :part-of (e2 / enzyme :name (n4 / name :op1 "HER2")))) :ARG2 (p4 / percentage-entity :value 75))) :ARG2 (t2 / target-01 :ARG0 w :ARG1 (a6 / and :op1 (p5 / protein-segment :ARG3-of (p7 / phosphorylate-01)) :op2 (p6 / protein-segment :ARG3-of (p8 / phosphorylate-01 :polarity -)))) :condition (t / treat-04 :ARG2 (s / small-molecule :name (n5 / name :op1 "AZD6244"))) :ARG1-of (d4 / describe-01 :ARG0 (a5 / and :op1 (f / figure :mod "5B") :op2 (f2 / figure :mod 8 :ARG2-of (s2 / supplement-01))))) # ::id bio.bmtr_0002.5 ::date 2014-12-14T21:08:29 ::annotator SDL-AMR-09 ::preferred # ::snt Phospho-specific antibodies confirmed that treatment with AZD6244 inhibited phosphorylation of T669 of EGFR and the analogous T677 of HER2 (Figure 5A). # ::save-date Fri Jul 24, 2015 ::file bio_bmtr_0002_5.txt (c / confirm-01 :ARG0 (a / antibody :ARG1-of (s / specific-02 :ARG2 (p / phosphorylate-01))) :ARG1 (i / inhibit-01 :ARG0 (t / treat-04 :ARG2 (s2 / small-molecule :name (n / name :op1 "AZD6244"))) :ARG1 (a3 / and :op1 (p2 / phosphorylate-01 :ARG1 (a2 / amino-acid :mod 669 :name (n2 / name :op1 "threonine") :part-of (e / enzyme :name (n3 / name :op1 "EGFR")))) :op2 (p3 / phosphorylate-01 :ARG1 (a4 / amino-acid :mod 677 :name (n4 / name :op1 "threonine") :mod (a5 / analogous :topic a2) :part-of (e2 / enzyme :name (n5 / name :op1 "HER2")))))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "5A"))) # ::id bio.bmtr_0002.6 ::date 2014-12-14T21:17:43 ::annotator SDL-AMR-09 ::preferred # ::snt Together these data indicate that loss of this inhibitory threonine phosphorylation on the JM domains of EGFR and HER2 occurs in cancer cell lines following MEK inhibition, presumably due to differential subcellular localization and/or binding proteins. # ::save-date Wed Dec 9, 2015 ::file bio_bmtr_0002_6.txt (i / indicate-01 :ARG0 (d / data :mod (t / this) :mod (t2 / together)) :ARG1 (l / lose-01 :ARG1 (p / phosphorylate-01 :ARG1 (a / amino-acid :name (n / name :op1 "threonine") :part-of (p2 / protein-segment :name (n2 / name :op1 "JM" :op2 "domain") :part-of (o / or :op1 (e / enzyme :name (n3 / name :op1 "EGFR")) :op2 (e2 / enzyme :name (n4 / name :op1 "HER2"))))) :ARG0-of (i2 / inhibit-01) :mod (t3 / this)) :location (c / cell-line :mod (d4 / disease :wiki "Cancer" :name (n6 / name :op1 "cancer"))) :ARG1-of (f / follow-01 :ARG2 (i3 / inhibit-01 :ARG1 (e3 / enzyme :name (n5 / name :op1 "MEK")))) :ARG1-of (c3 / cause-01 :ARG0 (a2 / and-or :op1 (l2 / location :location (c4 / cell) :ARG1-of (d2 / differ-02)) :op2 (p4 / protein :ARG1-of (b / bind-01) :ARG1-of (d3 / differ-02))) :ARG1-of (p3 / presume-01)))) # ::id bio.bmtr_0002.7 ::date 2014-12-15T14:06:48 ::annotator SDL-AMR-09 ::preferred # ::snt Mutation of T669 and T677 abrogates MEK inhibitor-induced suppression of ERBB3 Activation # ::save-date Sat Jan 16, 2016 ::file bio_bmtr_0002_7.txt (a / abrogate-01 :ARG0 (m / mutate-01 :ARG1 (a2 / and :op1 (a3 / amino-acid :mod 669 :name (n / name :op1 "threonine")) :op2 (a4 / amino-acid :mod 677 :name (n2 / name :op1 "threonine")))) :ARG1 (s / suppress-01 :ARG1 (a5 / activate-01 :ARG1 (e / enzyme :name (n3 / name :op1 "ERBB3"))) :ARG2-of (i / induce-01 :ARG0 (m2 / molecular-physical-entity :ARG0-of (i2 / inhibit-01 :ARG1 (p / protein-family :name (n4 / name :op1 "MEK"))))))) # ::id bio.bmtr_0002.8 ::date 2014-12-15T14:16:53 ::annotator SDL-AMR-09 ::preferred # ::snt We hypothesized that MEK inhibition activates AKT by inhibiting ERK activity, which blocks an inhibitory threonine phosphorylation on the JM domains of EGFR and HER2, thereby increasing ERBB3 phosphorylation. # ::save-date Mon Jul 6, 2015 ::file bio_bmtr_0002_8.txt (h / hypothesize-01 :ARG0 (w / we) :ARG1 (a / activate-01 :ARG0 (i / inhibit-01 :ARG1 (e / enzyme :name (n / name :op1 "MEK"))) :ARG1 (e2 / enzyme :name (n2 / name :op1 "AKT")) :manner (i2 / inhibit-01 :ARG0 i :ARG1 (a2 / activity-06 :ARG0 (e3 / enzyme :name (n3 / name :op1 "ERK"))) :ARG0-of (b / block-01 :ARG1 (p / phosphorylate-01 :ARG1 (a3 / amino-acid :name (n4 / name :op1 "threonine") :part-of (p2 / protein-segment :name (n5 / name :op1 "JM" :op2 "domain") :part-of (o / or :op1 (e4 / enzyme :name (n6 / name :op1 "EGFR")) :op2 (e5 / enzyme :name (n7 / name :op1 "HER2"))))) :ARG0-of (i3 / inhibit-01)) :ARG0-of (i4 / increase-01 :ARG1 (p3 / phosphorylate-01 :ARG1 (e6 / enzyme :name (n8 / name :op1 "ERBB3")))))))) # ::id bio.bmtr_0002.9 ::date 2014-12-15T14:52:21 ::annotator SDL-AMR-09 ::preferred # ::snt To test this hypothesis, we transiently transfected CHO-KI cells, which do not express ERBB receptors endogenously, with wild-type ERBB3 with either wild-type EGFR or EGFR T669A. # ::save-date Fri Jul 24, 2015 ::file bio_bmtr_0002_9.txt (t / transfect-01 :ARG0 (w / we) :ARG1 (c / cell :source (c2 / cell-line :name (n / name :op1 "CHO-KI")) :ARG3-of (e3 / express-03 :polarity - :ARG2 (r / receptor :name (n4 / name :op1 "ERBB")) :mod (e4 / endogenous))) :ARG2 (a / and :op1 (e5 / enzyme :name (n5 / name :op1 "ERBB3") :mod (w3 / wild-type)) :op2 (o / or :op1 (e / enzyme :name (n2 / name :op1 "EGFR") :mod (w2 / wild-type)) :op2 (e2 / enzyme :name (n3 / name :op1 "EGFR") :ARG2-of (m / mutate-01 :value "T669A")))) :ARG1-of (t2 / transient-02) :purpose (t3 / test-01 :ARG0 w :ARG1 (t5 / thing :ARG1-of (h / hypothesize-01) :mod (t4 / this)))) # ::id bio.bmtr_0002.10 ::date 2014-12-15T15:05:31 ::annotator SDL-AMR-09 ::preferred # ::snt In cells transfected with wild-type EGFR, MEK inhibition led to feedback activation of phospho-ERBB3 and phosho-EGFR, recapitulating the results we had observed in our panel of cancer cell lines (Figure 6A). # ::save-date Wed Dec 9, 2015 ::file bio_bmtr_0002_10.txt (l / lead-03 :ARG0 (i / inhibit-01 :ARG1 (e / enzyme :name (n / name :op1 "MEK"))) :ARG2 (a / activate-01 :ARG1 (a2 / and :op1 (e3 / enzyme :name (n3 / name :op1 "ERBB3") :ARG3-of (p / phosphorylate-01)) :op2 (e4 / enzyme :name (n4 / name :op1 "EGFR") :ARG3-of (p2 / phosphorylate-01))) :subevent-of (f / feedback)) :location (c / cell :ARG1-of (t / transfect-01 :ARG2 (e2 / enzyme :name (n2 / name :op1 "EGFR") :mod (w / wild-type)))) :ARG0-of (r / recapitulate-01 :ARG1 (t2 / thing :ARG2-of (r2 / result-01) :ARG1-of (o / observe-01 :ARG0 (w2 / we) :location (p3 / panel :consist-of (c2 / cell-line :mod (d2 / disease :wiki "Cancer" :name (n5 / name :op1 "cancer"))) :poss w2)))) :ARG1-of (d / describe-01 :ARG0 (f2 / figure :mod "6A"))) # ::id bio.bmtr_0002.11 ::date 2014-12-17T01:40:22 ::annotator SDL-AMR-09 ::preferred # ::snt In contrast, the EGFR T669A mutant increased both basal EGFR and ERBB3 tyrosine phosphorylation that was not augmented by MEK inhibition. # ::save-date Wed Dec 17, 2014 ::file bio_bmtr_0002_11.txt (c / contrast-01 :ARG2 (i / increase-01 :ARG0 (e4 / enzyme :name (n4 / name :op1 "EGFR") :ARG2-of (m / mutate-01 :value "T669A")) :ARG1 (a / and :op1 (p2 / phosphorylate-01 :ARG1 (a2 / amino-acid :name (n5 / name :op1 "tyrosine") :part-of (e / enzyme :name (n / name :op1 "EGFR"))) :mod (b / basal)) :op2 (p3 / phosphorylate-01 :ARG1 (a3 / amino-acid :name (n6 / name :op1 "tyrosine")) :part-of (e2 / enzyme :name (n2 / name :op1 "ERBB3")) :mod b) :ARG1-of (a4 / augment-01 :ARG0 (i2 / inhibit-01 :ARG1 (e3 / enzyme :name (n3 / name :op1 "MEK"))) :polarity -)))) # ::id bio.bmtr_0002.12 ::date 2014-12-15T15:37:12 ::annotator SDL-AMR-09 ::preferred # ::snt As a control, we treated CHO-KI cells expressing EGFR T669A with HRG ligand to induce maximal ERBB3 phosphorylation (Figure 6A), indicating that the lack of induction of phospho-ERBB3 in EGFR T669A expressing cells following MEK inhibition was not simply due to the saturation of the system with phospho-ERBB3. # ::save-date Wed Jun 3, 2015 ::file bio_bmtr_0002_12.txt (t / treat-04 :ARG0 (w / we) :ARG1 (c / cell :source (c2 / cell-line :name (n / name :op1 "CHO-KI")) :ARG3-of (e / express-03 :ARG2 (e2 / enzyme :name (n2 / name :op1 "EGFR") :ARG2-of (m / mutate-01 :value "T669A")))) :ARG2 (l / ligand :name (n3 / name :op1 "HRG")) :purpose (i / induce-01 :ARG0 w :ARG2 (p / phosphorylate-01 :ARG1 (e3 / enzyme :name (n4 / name :op1 "ERBB3")) :degree (m2 / maximum)) :ARG0-of (i2 / indicate-01 :ARG1 (c3 / cause-01 :polarity - :ARG0 (l2 / lack-01 :ARG1 (i3 / induce-01 :ARG2 (p3 / phosphorylate-01 :ARG1 e3) :location (c4 / cell :ARG3-of (e5 / express-03 :ARG2 (e6 / enzyme :name (n6 / name :op1 "EGFR") :ARG2-of (m3 / mutate-01 :value "T669A")))) :ARG2-of (f2 / follow-01 :ARG1 (i4 / inhibit-01 :ARG1 (e7 / enzyme :name (n7 / name :op1 "MEK")))))) :ARG1 (s / saturate-01 :ARG1 (s2 / system) :ARG2 (e4 / enzyme :name (n5 / name :op1 "ERBB3") :ARG3-of (p2 / phosphorylate-01))) :mod (s3 / simple)))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "6A")) :ARG2-of (c5 / control-01)) # ::id bio.bmtr_0002.13 ::date 2014-12-15T18:12:14 ::annotator SDL-AMR-09 ::preferred # ::snt We observed analogous results in CHO-KI cells expressing wild-type ERBB3 in combination with wild-type or T677A mutant HER2 (Figure 6B). # ::save-date Wed Dec 17, 2014 ::file bio_bmtr_0002_13.txt (o / observe-01 :ARG0 (w / we) :ARG1 (t / thing :ARG2-of (r / result-01 :ARG1 (c / cell :source (c2 / cell-line :name (n / name :op1 "CHO-KI")) :ARG3-of (e / express-03 :ARG2 (e2 / enzyme :name (n2 / name :op1 "ERBB3") :mod (w2 / wild-type) :accompanier (o2 / or :op1 (e3 / enzyme :name (n3 / name :op1 "HER2") :mod (w3 / wild-type)) :op2 (e4 / enzyme :name (n4 / name :op1 "HER2") :ARG2-of (m / mutate-01 :value "T677A"))))))) :mod (a / analogous)) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "6B"))) # ::id bio.bmtr_0002.14 ::date 2014-12-15T18:52:18 ::annotator SDL-AMR-09 ::preferred # ::snt Together these results support the hypothesis that inhibition of ERK-mediated phosphorylation of a conserved JM domain threonine residue leads to feedback activation of EGFR, HER2, and ERBB3 (Figure 7). # ::save-date Fri Dec 19, 2014 ::file bio_bmtr_0002_14.txt (s / support-01 :ARG0 (t / thing :ARG2-of (r / result-01) :mod (t2 / together) :mod (t3 / this)) :ARG1 (h / hypothesize-01 :ARG1 (l / lead-03 :ARG0 (i / inhibit-01 :ARG1 (p / phosphorylate-01 :ARG1 (r2 / residue :mod (a3 / amino-acid :name (n5 / name :op1 "threonine")) :part-of (p2 / protein-segment :name (n6 / name :op1 "JM" :op2 "domain") :ARG1-of (c / conserve-01))) :ARG1-of (m / mediate-01 :ARG0 (e4 / enzyme :name (n4 / name :op1 "ERK"))))) :ARG2 (a / activate-01 :ARG1 (a2 / and :op1 (e / enzyme :name (n / name :op1 "EGFR")) :op2 (e2 / enzyme :name (n2 / name :op1 "HER2")) :op3 (e3 / enzyme :name (n3 / name :op1 "ERBB3"))) :subevent-of (f / feedback)))) :ARG1-of (d / describe-01 :ARG0 (f2 / figure :mod 7))) # ::id bio.bmtr_0002.15 ::date 2015-01-21T16:11:03 ::annotator SDL-AMR-09 ::preferred # ::snt To determine if this feedback model explains the activation of PI3K signaling in EGFR-mutant cancers, we used shRNA to knockdown endogenous EGFR (which carries an exon 19 deletion) in the HCC827 NSCLC cell line and replaced with either EGFR (exon 19del) wild-type at T669, or EGFR (exon 19del) carrying a T669A mutation. # ::save-date Sun Jan 17, 2016 ::file bio_bmtr_0002_15.txt (a / and :op1 (u / use-01 :ARG0 (w / we) :ARG1 (n10 / nucleic-acid :name (n / name :op1 "shRNA")) :ARG2 (k / knock-down-02 :ARG0 w :ARG1 (e / enzyme :name (n2 / name :op1 "EGFR") :mod (e2 / endogenous) :location (c2 / cell-line :name (n3 / name :op1 "HCC827") :mod (d4 / disease :name (n11 / name :op1 "NSCLC"))) :ARG2-of (d / delete-01 :ARG1 (e3 / exon :mod 19))))) :op2 (r / replace-01 :ARG0 w :ARG1 e :ARG2 (o / or :op1 (e4 / enzyme :name (n4 / name :op1 "EGFR") :mod (w2 / wild-type) :ARG0-of (c / carry-01) :part (a2 / amino-acid :mod 669 :name (n5 / name :op1 "threonine"))) :op2 (e5 / enzyme :name (n6 / name :op1 "EGFR") :ARG2-of d :part (m2 / mutate-01 :value "T669A")))) :purpose (d2 / determine-01 :ARG0 w :ARG1 (e6 / explain-01 :mode interrogative :ARG0 (m3 / model :mod (f / feedback) :mod (t / this)) :ARG1 (a4 / activate-01 :ARG1 (p / pathway :name (n7 / name :op1 "PI3K") :ARG0-of (s / signal-07)) :condition (d3 / disease :wiki "Cancer" :name (n9 / name :op1 "cancer") :mod (m4 / mutate-01 :ARG1 (e7 / enzyme :name (n8 / name :op1 "EGFR")))))))) # ::id bio.bmtr_0002.16 ::date 2015-01-21T16:49:26 ::annotator SDL-AMR-09 ::preferred # ::snt Of note, this is the same EGFR-mutant cell line in which we observed that EGFR T669 is phosphorylated in MEK-dependent manner (Figure 5, Supplemental Figure 8A). # ::save-date Mon Feb 9, 2015 ::file bio_bmtr_0002_16.txt (n / note-02 :ARG1 (s / same-01 :ARG1 (t / this) :ARG2 (c / cell-line :consist-of (e3 / enzyme :name (n2 / name :op1 "EGFR") :ARG2-of (m / mutate-01)) :location-of (p / phosphorylate-01 :ARG1 (a / amino-acid :mod 669 :name (n3 / name :op1 "threonine") :part-of (e / enzyme :name (n4 / name :op1 "EGFR"))) :ARG0-of (d / depend-01 :ARG1 (e2 / enzyme :name (n5 / name :op1 "MEK"))) :ARG1-of (o / observe-01 :ARG0 (w / we)))) :ARG1-of (d2 / describe-01 :ARG0 (a2 / and :op1 (f / figure :mod 5) :op2 (f2 / figure :mod "8A" :ARG2-of (s2 / supplement-01)))))) # ::id bio.bmtr_0002.17 ::date 2015-01-21T17:03:45 ::annotator SDL-AMR-09 ::preferred # ::snt When endogenous EGFR was replaced with EGFR (exon19del) wild-type at T669, MEK inhibition led to significant feedback activation of ERBB3/PI3K/AKT signaling (Figure 6C). # ::save-date Sun May 24, 2015 ::file bio_bmtr_0002_17.txt (l / lead-03 :ARG0 (i / inhibit-01 :ARG1 (e / enzyme :name (n / name :op1 "MEK"))) :ARG2 (a / activate-01 :ARG1 (p / pathway :name (n2 / name :op1 "ERBB3/PI3K/AKT") :ARG0-of (s / signal-07)) :subevent-of (f / feedback) :ARG1-of (s2 / significant-02)) :ARG1-of (d / describe-01 :ARG0 (f2 / figure :mod "6C")) :time (r / replace-01 :ARG1 (e2 / enzyme :name (n3 / name :op1 "EGFR") :mod (e4 / endogenous)) :ARG2 (e3 / enzyme :name (n4 / name :op1 "EGFR") :mod (w / wild-type) :ARG2-of (d2 / delete-01 :ARG1 (e5 / exon :mod 19)) :part (a2 / amino-acid :mod 669 :name (n5 / name :op1 "threonine"))))) # ::id bio.bmtr_0002.18 ::date 2015-01-21T17:32:05 ::annotator SDL-AMR-09 ::preferred # ::snt However, replacement with the EGFR (exon19 del) T669A mutant led to increased tyrosine phosphorylation of both EGFR and ERBB3, and activation of PI3K/AKT signaling, mimicking the effect of MEK inhibition (Figure 6C). # ::save-date Thu Feb 5, 2015 ::file bio_bmtr_0002_18.txt (l / lead-03 :ARG0 (r / replace-01 :ARG2 (e / enzyme :name (n / name :op1 "EGFR") :ARG2-of (m / mutate-01 :value "T669A") :ARG2-of (d / delete-01 :ARG1 (e2 / exon :mod 19)))) :ARG2 (a6 / and :op1 (i / increase-01 :ARG1 (a / and :op1 (p / phosphorylate-01 :ARG1 (a2 / amino-acid :name (n2 / name :op1 "tyrosine") :part-of (e3 / enzyme :name (n3 / name :op1 "EGFR")))) :op2 (p3 / phosphorylate-01 :ARG1 (a3 / amino-acid :name (n4 / name :op1 "tyrosine") :part-of (e4 / enzyme :name (n7 / name :op1 "ERBB3")))))) :op2 (a4 / activate-01 :ARG1 (p2 / pathway :name (n5 / name :op1 "PI3K/AKT") :ARG0-of (s / signal-07))) :ARG1-of (m2 / mimic-01 :ARG0 (a5 / affect-01 :ARG0 (i2 / inhibit-01 :ARG1 (e5 / enzyme :name (n6 / name :op1 "MEK")))))) :ARG1-of (h / have-concession-91) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "6C"))) # ::id bio.bmtr_0002.19 ::date 2015-01-21T17:56:39 ::annotator SDL-AMR-09 ::preferred # ::snt As expected, addition of AZD6244 failed to further augment ERBB3 and AKT phosphorylation in cells expressing the 669A mutant. # ::save-date Sun Jan 17, 2016 ::file bio_bmtr_0002_19.txt (a4 / augment-01 :polarity - :ARG0 (a / add-02 :ARG1 (s / small-molecule :name (n / name :op1 "AZD6244"))) :ARG1 (p / phosphorylate-01 :ARG1 (a3 / and :op1 (e / enzyme :name (n2 / name :op1 "ERBB3")) :op2 (e4 / enzyme :name (n3 / name :op1 "AKT"))) :location (c / cell :ARG3-of (e2 / express-03 :ARG2 (a2 / amino-acid :mod 669 :ARG2-of (m / mutate-01))))) :degree (f2 / further) :ARG1-of (e3 / expect-01)) # ::id bio.bmtr_0002.20 ::date 2015-01-21T18:15:45 ::annotator SDL-AMR-09 ::preferred # ::snt These results demonstrate that EGFR T669 phosphorylation is necessary for MEK/ERK to suppress EGFR-mediated activation of ERBB3. # ::save-date Thu Feb 5, 2015 ::file bio_bmtr_0002_20.txt (d / demonstrate-01 :ARG0 (t / thing :mod (t2 / this) :ARG2-of (r / result-01)) :ARG1 (n / need-01 :ARG0 (s / suppress-01 :ARG0 (p2 / pathway :name (n4 / name :op1 "MEK/ERK")) :ARG1 (a2 / activate-01 :ARG1 (e2 / enzyme :name (n5 / name :op1 "ERBB3")) :ARG1-of (m / mediate-01 :ARG0 (e3 / enzyme :name (n6 / name :op1 "EGFR"))))) :ARG1 (p / phosphorylate-01 :ARG1 (a / amino-acid :mod 669 :name (n2 / name :op1 "threonine") :part-of (e / enzyme :name (n3 / name :op1 "EGFR")))))) # ::id bio.bmtr_0002.21 ::date 2015-01-21T18:24:17 ::annotator SDL-AMR-09 ::preferred # ::snt This supports the hypothesis that a dominant ERK feedback on ERBB3/PI3K/AKT is mediated though phosphorylation of T669 on EGFR (or T677 HER2). # ::save-date Thu Feb 5, 2015 ::file bio_bmtr_0002_21.txt (s / support-01 :ARG0 (t / this) :ARG1 (h / hypothesize-01 :ARG1 (m / mediate-01 :ARG0 (o2 / or :op1 (p2 / phosphorylate-01 :ARG1 (a / amino-acid :mod 669 :name (n3 / name :op1 "threonine") :part-of (e2 / enzyme :name (n4 / name :op1 "EGFR")))) :op2 (p3 / phosphorylate-01 :ARG1 (a2 / amino-acid :mod 677 :name (n5 / name :op1 "threonine") :part-of (e3 / enzyme :name (n6 / name :op1 "HER2"))))) :ARG1 (f / feedback :ARG0-of (d / dominate-01) :destination (p / pathway :name (n / name :op1 "ERBB3/PI3K/AKT")) :mod (e / enzyme :name (n2 / name :op1 "ERK")))))) # ::id bio.bmtr_0003.1 ::date 2015-01-21T23:22:38 ::annotator SDL-AMR-09 ::preferred # ::snt Montero-Conde et al. “Relief of feedback inhibition of HER3 transcription by RAF and MEK inhibitors attenuates their antitumor effects in BRAF mutant thyroid carcinomas.” (PMC3651738) # ::save-date Sat Jan 16, 2016 ::file bio_bmtr_0003_1.txt (p / publication-91 :ARG0 (a / and :op1 (p2 / person :name (n / name :op1 "Montero-Conde")) :op2 (p3 / person :mod (o / other))) :ARG1 (a3 / attenuate-01 :ARG0 (r / relieve-01 :ARG1 (i / inhibit-01 :ARG0 (m / molecular-physical-entity :ARG0-of (i2 / inhibit-01 :ARG1 (a2 / and :op1 (p4 / protein-family :name (n3 / name :op1 "RAF")) :op2 (p5 / protein-family :name (n4 / name :op1 "MEK"))))) :ARG1 (t / transcribe-01 :ARG1 (e / enzyme :name (n2 / name :op1 "HER3"))) :subevent-of (f / feedback))) :ARG1 (a4 / affect-01 :ARG0 m :ARG2 (c / counter-01 :ARG1 (t2 / tumor)) :location (m3 / medical-condition :name (n8 / name :op1 "carcinoma") :mod (t3 / thyroid) :mod (e4 / enzyme :name (n5 / name :op1 "BRAF") :ARG2-of (m2 / mutate-01))))) :ARG8 "PMC3651738") # ::id bio.bmtr_0003.2 ::date 2015-01-23T13:38:34 ::annotator SDL-AMR-09 ::preferred # ::snt We next examined the mechanisms accounting for the increase in HER3 by MAPK pathway inhibitors in BRAF mutant thyroid cell lines. # ::save-date Mon Feb 9, 2015 ::file bio_bmtr_0003_2.txt (e / examine-01 :ARG0 (w / we) :ARG1 (m / mechanism :ARG0-of (a / account-01 :ARG1 (i / increase-01 :ARG0 (m2 / molecular-physical-entity :ARG0-of (i2 / inhibit-01 :ARG1 (p / pathway :name (n2 / name :op1 "MAPK")))) :ARG1 (e2 / enzyme :name (n / name :op1 "HER3")) :location (c / cell-line :source (t / thyroid) :ARG1-of (e3 / encode-01 :ARG0 (n5 / nucleic-acid :wiki "DNA" :name (n6 / name :op1 "DNA") :part (g / gene :name (n3 / name :op1 "BRAF") :ARG2-of (m3 / mutate-01)))))))) :time (n4 / next)) # ::id bio.bmtr_0003.3 ::date 2015-01-23T14:45:30 ::annotator SDL-AMR-09 ::preferred # ::snt Upregulation of HER3 has been found to mediate resistance to PI3K/AKT (26) or HER2 (27) inhibitors in HER2-amplified breast cancer cell lines, which is caused in part through a FoxO3A-dependent induction of HER3 gene transcription. # ::save-date Wed Dec 9, 2015 ::file bio_bmtr_0003_3.txt (f / find-01 :ARG1 (m / mediate-01 :ARG0 (u / upregulate-01 :ARG1 (e / enzyme :name (n / name :op1 "HER3"))) :ARG1 (r / resist-01 :ARG1 (m2 / molecular-physical-entity :ARG0-of (i / inhibit-01 :ARG1 (o / or :op1 (p / pathway :name (n2 / name :op1 "PI3K/AKT") :ARG1-of (d / describe-01 :ARG0 (p2 / publication :ARG1-of (c / cite-01 :ARG2 26)))) :op2 (e2 / enzyme :name (n3 / name :op1 "HER2") :ARG1-of (d2 / describe-01 :ARG1-of (c2 / cite-01 :ARG2 27)))))) :location (c3 / cell-line :mod (a / amplify-01 :ARG0 e2) :source (d4 / disease :wiki "Breast_cancer" :name (n5 / name :op1 "breast" :op2 "cancer")))) :ARG1-of (c5 / cause-01 :ARG0 (i2 / induce-01 :ARG2 (t / transcribe-01 :ARG1 (g / gene :ARG0-of (e3 / encode-01 :ARG1 e))) :ARG0-of (d3 / depend-01 :ARG1 (p3 / protein :name (n4 / name :op1 "FoxO3A")))) :degree (p4 / part)))) # ::id bio.bmtr_0003.4 ::date 2015-01-23T15:09:03 ::annotator SDL-AMR-09 ::preferred # ::snt As shown in Fig. 5A, PLX4032 treatment increased HER3 and HER2 mRNAs in all six BRAF-mutant thyroid cancer cell lines tested. # ::save-date Fri Jan 1, 2016 ::file bio_bmtr_0003_4.txt (i / increase-01 :ARG0 (t / treat-04 :ARG2 (s / small-molecule :name (n / name :op1 "PLX4032"))) :ARG1 (n8 / nucleic-acid :name (n9 / name :op1 "mRNA") :ARG0-of (e / encode-01 :ARG1 (a / and :op1 (e2 / enzyme :name (n2 / name :op1 "HER3")) :op2 (e3 / enzyme :name (n3 / name :op1 "HER2"))))) :location (c / cell-line :quant 6 :source (t2 / thyroid :ARG1-of (e4 / encode-01 :ARG0 (n5 / nucleic-acid :wiki "DNA" :name (n6 / name :op1 "DNA") :part (g / gene :name (n4 / name :op1 "BRAF") :ARG2-of (m2 / mutate-01))))) :mod (a2 / all) :ARG1-of (t3 / test-01) :mod (d / disease :wiki "Cancer" :name (n7 / name :op1 "cancer"))) :ARG1-of (s2 / show-01 :ARG0 (f / figure :mod "5A"))) # ::id bio.bmtr_0003.5 ::date 2015-01-25T14:19:38 ::annotator SDL-AMR-09 ::preferred # ::snt Similar results were found following treatment with the MEK inhibitor AZD6244 (not shown). # ::save-date Sat Jan 16, 2016 ::file bio_bmtr_0003_5.txt (f / find-01 :ARG1 (t / thing :ARG2-of (r / result-01) :ARG1-of (r2 / resemble-01)) :ARG1-of (f2 / follow-01 :ARG2 (t2 / treat-04 :ARG2 (s / small-molecule :name (n / name :op1 "AZD6244") :ARG0-of (i / inhibit-01 :ARG1 (p / protein-family :name (n2 / name :op1 "MEK"))) :ARG1-of (s2 / show-01 :polarity -))))) # ::id bio.bmtr_0003.6 ::date 2015-01-25T14:28:31 ::annotator SDL-AMR-09 ::preferred # ::snt The effects of the MEK inhibitor on total HER2, HER3 protein and on pHER3 were dose dependent, and inversely associated with the degree of inhibition of pERK (Fig. 5B). # ::save-date Sat Jan 16, 2016 ::file bio_bmtr_0003_6.txt (a / and :op1 (d / depend-01 :ARG0 (a2 / affect-01 :ARG0 (m / molecular-physical-entity :ARG0-of (i / inhibit-01 :ARG1 (p2 / protein-family :name (n / name :op1 "MEK")))) :ARG1 (a3 / and :op1 (e2 / enzyme :name (n2 / name :op1 "HER2") :mod (t / total)) :op2 (e3 / enzyme :name (n3 / name :op1 "HER3")) :op3 (e4 / enzyme :name (n4 / name :op1 "HER3") :ARG3-of (p / phosphorylate-01)))) :ARG1 (d2 / dose-01)) :op2 (a4 / associate-01 :ARG1 a2 :ARG2 (t2 / thing :degree-of (i2 / inhibit-01 :ARG1 (e5 / enzyme :name (n5 / name :op1 "ERK") :ARG1-of p))) :mod (i3 / inverse)) :ARG1-of (d3 / describe-01 :ARG0 (f / figure :mod "5B"))) # ::id bio.bmtr_0003.7 ::date 2015-01-25T14:48:37 ::annotator SDL-AMR-09 ::preferred # ::snt RAF or MEK inhibitors induced luciferase activity of a HER3 promoter construct spanning ~ 1 kb upstream of the transcriptional start site in 8505C cells. # ::save-date Sun Jan 17, 2016 ::file bio_bmtr_0003_7.txt (i / induce-01 :ARG0 (o / or :op1 (m / molecular-physical-entity :ARG0-of (i2 / inhibit-01 :ARG1 (p2 / protein-family :name (n / name :op1 "RAF")))) :op2 (m2 / molecular-physical-entity :ARG0-of (i3 / inhibit-01 :ARG1 (p3 / protein-family :name (n2 / name :op1 "MEK"))))) :ARG2 (a / activity-06 :ARG0 (c / construct-01 :ARG0-of (p / promote-01 :ARG1 (e3 / enzyme :name (n3 / name :op1 "HER3"))) :ARG1-of (s / span-01 :location (r / relative-position :op1 (s2 / site :location-of (s3 / start-01 :ARG1 (t / transcribe-01))) :direction (u / upstream)) :quant (a2 / approximately :op1 (d / distance-quantity :quant 1 :unit (k / kilo-base-pair))) :location (c2 / cell-line :name (n5 / name :op1 "8505C")))) :ARG1 (l / luciferase))) # ::id bio.bmtr_0003.8 ::date 2015-01-25T15:10:43 ::annotator SDL-AMR-09 ::preferred # ::snt Serial deletions identified a minimal HER3 promoter retaining transcriptional response to vemurafenib and AZD6244, which was located between -401 and -42 bp (Fig. 5C). # ::save-date Thu Jun 4, 2015 ::file bio_bmtr_0003_8.txt (i / identify-01 :ARG0 (d / delete-01 :manner (s / serial)) :ARG1 (m / molecular-physical-entity :ARG0-of (p / promote-01 :ARG1 (e / enzyme :name (n / name :op1 "HER3"))) :ARG1-of (m2 / minimal-02) :ARG0-of (r / retain-01 :ARG1 (t / thing :ARG2-of (r2 / respond-01 :ARG1 (a / and :op1 (s2 / small-molecule :name (n2 / name :op1 "vemurafenib")) :op2 (s3 / small-molecule :name (n3 / name :op1 "AZD6244")))) :mod (t2 / transcribe-01))) :location (b / between :op1 (d2 / distance-quantity :quant "-401" :unit (b2 / base-pair)) :op2 (d3 / distance-quantity :quant "-42" :unit (b3 / base-pair)))) :ARG1-of (d4 / describe-01 :ARG0 (f / figure :mod "5C"))) # ::id bio.bmtr_0003.9 ::date 2015-01-25T15:28:42 ::annotator SDL-AMR-09 ::preferred # ::snt This region does not contain any predicted FoxO binding sites. # ::save-date Wed Feb 4, 2015 ::file bio_bmtr_0003_9.txt (c / contain-01 :polarity - :ARG0 (r / region :mod (t / this)) :ARG1 (p3 / protein-segment :part-of (p / protein :name (n / name :op1 "FoxO")) :ARG1-of (b / bind-01) :ARG1-of (p2 / predict-01) :mod (a / any))) # ::id bio.bmtr_0003.10 ::date 2015-01-25T15:36:32 ::annotator SDL-AMR-09 ::preferred # ::snt Moreover, PLX4032 led to an increase in phosphorylation of FoxO1/3A between 4–10h after addition of compound (not shown), which is known to promote its dissociation from DNA, and likely discards involvement of these factors as transcriptional regulators of HER3 in response to MAPK pathway inhibition. # ::save-date Wed Jun 24, 2015 ::file bio_bmtr_0003_10.txt (a / and :op2 (l / lead-03 :ARG0 (s / small-molecule :name (n / name :op1 "PLX4032")) :ARG1 (i / increase-01 :ARG1 (p / phosphorylate-01 :ARG1 (p2 / protein :name (n2 / name :op1 "FoxO1/3A"))) :time (a2 / after :op1 (a3 / add-02 :ARG1 (c / compound)) :quant (b / between :op1 (t / temporal-quantity :quant 4 :unit (h / hour)) :op2 (t2 / temporal-quantity :quant 10 :unit (h2 / hour)))) :ARG1-of (s2 / show-01 :polarity -) :ARG0-of (p3 / promote-01 :ARG1 (d / dissociate-01 :ARG1 p2 :ARG2 (n5 / nucleic-acid :wiki "DNA" :name (n6 / name :op1 "DNA"))) :ARG1-of (k / know-01)) :ARG0-of (d3 / discard-01 :ARG1 (i2 / involve-01 :ARG1 (f / factor :mod (t3 / this)) :mod (m / molecular-physical-entity :ARG0-of (r / regulate-01 :ARG1 (e / enzyme :name (n3 / name :op1 "HER3"))) :ARG0-of (t4 / transcribe-01))) :ARG1-of (l2 / likely-01) :ARG2-of (r2 / respond-01 :ARG1 (i3 / inhibit-01 :ARG1 (p4 / pathway :name (n4 / name :op1 "MAPK")))))))) # ::id bio.bmtr_0003.11 ::date 2015-01-25T15:59:16 ::annotator SDL-AMR-09 ::preferred # ::snt The minimal HER3 promoter region regulated by MAPK inhibitors overlaps with sequences previously described to be immunoprecipitated using antibodies against the ZFN217 transcription factor and CtBP1/CtBP2 corepressors (28–30). # ::save-date Mon Jan 4, 2016 ::file bio_bmtr_0003_11.txt (o / overlap-01 :ARG0 (r / region :mod (m2 / molecular-physical-entity :ARG0-of (p / promote-01 :ARG1 (e / enzyme :name (n / name :op1 "HER3"))) :ARG1-of (m / minimal-02)) :ARG1-of (r2 / regulate-01 :ARG0 (m3 / molecular-physical-entity :ARG0-of (i / inhibit-01 :ARG1 (p2 / pathway :name (n2 / name :op1 "MAPK")))))) :ARG1 (s / sequence :ARG1-of (i2 / immunoprecipitate-01 :ARG2-of (u / use-01 :ARG1 (a / antibody :ARG0-of (o2 / oppose-01 :ARG1 (a2 / and :op1 (f / factor :ARG0-of (t / transcribe-01 :ARG1 (e2 / enzyme :name (n3 / name :op1 "ZFN217")))) :op2 (m4 / molecular-physical-entity :ARG0-of (r3 / repress-01 :ARG1 (o3 / or :op1 (p5 / protein :name (n4 / name :op1 "CtBP1")) :op2 (p6 / protein :name (n5 / name :op1 "CtBP2"))))))))) :ARG1-of (d / describe-01 :time (p4 / previous)))) :ARG1-of (d2 / describe-01 :ARG0 (p3 / publication :ARG1-of (c3 / cite-01 :ARG2 (v / value-interval :op1 28 :op2 30))))) # ::id bio.bmtr_0003.12 ::date 2015-01-25T16:16:54 ::annotator SDL-AMR-09 ::preferred # ::snt CtBPs have also been described to negatively regulate transcriptional activity of the HER3 promoter in breast carcinoma cell lines (30). # ::save-date Fri Feb 5, 2016 ::file bio_bmtr_0003_12.txt (d / describe-01 :ARG1 (p / protein :name (n / name :op1 "CtBP")) :ARG2 (d3 / downregulate-01 :ARG0 p :ARG1 (a2 / activity-06 :ARG0 (m / molecular-physical-entity :ARG0-of (p2 / promote-01 :ARG1 (e / enzyme :name (n2 / name :op1 "HER3")))) :ARG1 (t / transcribe-01)) :location (c / cell-line :mod (m2 / medical-condition :name (n4 / name :op1 "carcinoma") :mod (b / breast)))) :mod (a / also) :ARG1-of (d2 / describe-01 :ARG0 (p3 / publication :ARG1-of (c3 / cite-01 :ARG2 30)))) # ::id bio.bmtr_0003.13 ::date 2015-01-25T16:25:03 ::annotator SDL-AMR-09 ::preferred # ::snt Silencing of CtBP1, and to a lesser extent CtBP2, increased basal HER3 in 8505C cells, and markedly potentiated the effects of PLX4032 (Fig. 5D and 5E). # ::save-date Sun Jan 17, 2016 ::file bio_bmtr_0003_13.txt (a / and :op1 (i / increase-01 :ARG0 (s / silence-01 :ARG1 (a2 / and :op1 (p / protein :name (n / name :op1 "CtBP1")) :op2 (p2 / protein :name (n2 / name :op1 "CtBP2") :degree (l / less :degree (m / more))))) :ARG1 (e / enzyme :name (n3 / name :op1 "HER3") :mod (b / basal)) :location (c / cell-line :name (n4 / name :op1 "8505C"))) :op2 (p3 / potentiate-01 :ARG1 (a3 / affect-01 :ARG0 (s2 / small-molecule :name (n5 / name :op1 "PLX4032"))) :ARG2 s :ARG3 (m2 / marked)) :ARG1-of (d / describe-01 :ARG0 (a4 / and :op1 (f / figure :mod "5D") :op2 (f2 / figure :mod "5E")))) # ::id bio.bmtr_0003.14 ::date 2015-01-25T16:32:44 ::annotator SDL-AMR-09 ::preferred # ::snt Knockdown of these factors modestly increased basal and PLX4032-induced HER2 levels, which likely contributes to the remarkable increase in pHER3 we observed (Fig. 5D and 5E). # ::save-date Fri Jul 24, 2015 ::file bio_bmtr_0003_14.txt (i / increase-01 :ARG0 (k / knock-down-02 :ARG1 (f / factor :mod (t / this))) :ARG1 (a / and :op1 (l2 / level :mod (e / enzyme :name (n / name :op1 "HER2") :mod (b / basal))) :op2 (l3 / level :mod (e2 / enzyme :name (n2 / name :op1 "HER2") :ARG2-of (i2 / induce-01 :ARG0 (s / small-molecule :name (n3 / name :op1 "PLX4032")))))) :degree (m / modest) :ARG0-of (c / contribute-01 :ARG1 (i3 / increase-01 :ARG1 (e3 / enzyme :name (n4 / name :op1 "HER3") :ARG3-of (p / phosphorylate-01)) :ARG1-of (r / remarkable-02) :ARG1-of (o / observe-01 :ARG0 (w / we))) :ARG1-of (l / likely-01)) :ARG1-of (d / describe-01 :ARG0 (a2 / and :op1 (f2 / figure :mod "5D") :op2 (f3 / figure :mod "5E")))) # ::id bio.bmtr_0003.15 ::date 2015-01-25T16:39:57 ::annotator SDL-AMR-09 ::preferred # ::snt Finally, CtBP1 and CtBP2 chromatin immunoprecipitation assays showed decreased binding to the HER3 promoter after treatment with PLX4032 (Fig. 5F). # ::save-date Fri Oct 23, 2015 ::file bio_bmtr_0003_15.txt (s / show-01 :li "-1" :ARG0 (a / assay-01 :ARG1 (i / immunoprecipitate-01 :ARG1 (a2 / and :op1 (p / protein :name (n / name :op1 "CtBP1")) :op2 (p2 / protein :name (n2 / name :op1 "CtBP2"))) :mod (c / chromatin))) :ARG1 (b / bind-01 :ARG2 (m / molecular-physical-entity :ARG0-of (p3 / promote-01 :ARG1 (e / enzyme :name (n3 / name :op1 "HER3")))) :ARG1-of (d / decrease-01 :time (a3 / after :op1 (t / treat-04 :ARG2 (s2 / small-molecule :name (n4 / name :op1 "PLX4032")))))) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure :mod "5F"))) # ::id bio.bmtr_0003.16 ::date 2015-01-25T16:48:03 ::annotator SDL-AMR-09 ::preferred # ::snt These findings were confirmed in a second cell line (Supplementary Fig. S5A). # ::save-date Sun Jan 25, 2015 ::file bio_bmtr_0003_16.txt (c / confirm-01 :ARG0 (t / thing :ARG1-of (f / find-01) :mod (t2 / this)) :location (c2 / cell-line :ord (o / ordinal-entity :value 2)) :ARG1-of (d / describe-01 :ARG0 (f2 / figure :mod "S5A" :ARG2-of (s / supplement-01)))) # ::id bio.bmtr_0003.17 ::date 2015-01-25T16:51:39 ::annotator SDL-AMR-09 ::preferred # ::snt The increase in expression of HER3 after MAPK inhibition is due to activation of gene transcription, which was associated with a reduction of binding of the transcriptional repressors CTBP1 and CTBP2 to the HER3 gene promoter. # ::save-date Wed Feb 4, 2015 ::file bio_bmtr_0003_17.txt (c / cause-01 :ARG0 (a2 / activate-01 :ARG1 (t / transcribe-01 :ARG1 (g / gene)) :ARG1-of (a3 / associate-01 :ARG2 (r / reduce-01 :ARG1 (b / bind-01 :ARG1 (a4 / and :op1 (p3 / protein :name (n3 / name :op1 "CTBP1") :ARG0-of (r2 / repress-01)) :op2 (p4 / protein :name (n4 / name :op1 "CTBP2") :ARG0-of r2) :ARG0-of (t2 / transcribe-01)) :ARG2 (m / molecular-physical-entity :ARG0-of (p2 / promote-01 :ARG1 (g2 / gene :ARG0-of (e3 / encode-01 :ARG1 e2)))))))) :ARG1 (i / increase-01 :ARG1 (e / express-03 :ARG1 (e2 / enzyme :name (n / name :op1 "HER3"))) :time (a / after :op1 (i2 / inhibit-01 :ARG1 (p / pathway :name (n2 / name :op1 "MAPK")))))) # ::id bio.bmtr_0003.18 ::date 2015-01-25T17:00:21 ::annotator SDL-AMR-09 ::preferred # ::snt These corepressors have been previously linked to inhibition of HER3 transcription through promoter regions that show overlapping occupancy with ZNF217, a transcription factor also involved in HER3 regulation (30). # ::save-date Fri Jun 19, 2015 ::file bio_bmtr_0003_18.txt (l / link-01 :ARG1 (c / corepressor :mod (t / this)) :ARG2 (i / inhibit-01 :ARG1 (t2 / transcribe-01 :ARG1 (e / enzyme :name (n / name :op1 "HER3")))) :ARG3 (r / region :ARG0-of (p2 / promote-01) :ARG0-of (s / show-01 :ARG1 (o / occupy-01 :ARG0 (p3 / protein :name (n2 / name :op1 "ZNF217") :mod (f / factor :ARG0-of (t3 / transcribe-01) :ARG1-of (i2 / involve-01 :ARG2 (r2 / regulate-01 :ARG1 e) :mod (a2 / also)))) :ARG1 r :ARG0-of (o2 / overlap-01)))) :time (p / previous) :ARG1-of (d / describe-01 :ARG0 (p4 / publication :ARG1-of (c2 / cite-01 :ARG2 30)))) # ::id bio.bmtr_0003.19 ::date 2015-01-25T17:07:41 ::annotator SDL-AMR-09 ::preferred # ::snt Accordingly, knockdown of CTBPs acutely induced HER3 expression and phosphorylation in thyroid cancer cells. # ::save-date Wed Dec 9, 2015 ::file bio_bmtr_0003_19.txt (i / induce-01 :ARG0 (k / knock-down-02 :ARG1 (p / protein :name (n / name :op1 "CTBP"))) :ARG2 (a2 / and :op1 (e / express-03 :ARG1 (e2 / enzyme :name (n2 / name :op1 "HER3"))) :op2 (p2 / phosphorylate-01 :ARG1 e2) :location (c / cell :source (t / thyroid) :mod (d / disease :wiki "Thyroid_cancer" :name (n3 / name :op1 "thyroid" :op2 "cancer")))) :manner (a / acute) :manner (a3 / accordingly)) # ::id bio.bmtr_0003.20 ::date 2015-01-25T17:14:26 ::annotator SDL-AMR-09 ::preferred # ::snt MAPK inhibition may dictate a chromatin redistribution of these repressors, and thus activate HER3 transcription. # ::save-date Sun Jan 17, 2016 ::file bio_bmtr_0003_20.txt (p / possible-01 :ARG1 (d / dictate-01 :ARG0 (i / inhibit-01 :ARG1 (e2 / enzyme :name (n / name :op1 "MAPK"))) :ARG1 (r / redistribute-01 :ARG1 (m / molecular-physical-entity :mod (t / this) :ARG0-of (r2 / repress-01)) :mod (c / chromatin))) :ARG0-of (c2 / cause-01 :ARG1 (a2 / activate-01 :ARG0 i :ARG1 (t2 / transcribe-01 :ARG1 (e / enzyme :name (n2 / name :op1 "HER3")))))) # ::id bio.bmtr_0003.21 ::date 2015-01-25T17:19:05 ::annotator SDL-AMR-09 ::preferred # ::snt The biochemical mechanisms involved in delocalization of CtBPs by MAPK inhibition have not been explored, but posttranslational modifications are known to regulate the repressive activity of CtBPs either by translocation to the cytoplasm or by targeting them for degradation (36, 37). # ::save-date Sun Jan 17, 2016 ::file bio_bmtr_0003_21.txt (c / contrast-01 :ARG1 (e / explore-01 :polarity - :ARG1 (m / mechanism :mod (b / biochemical) :ARG1-of (i / involve-01 :ARG2 (d / delocalize-01 :ARG0 (i2 / inhibit-01 :ARG1 (e2 / enzyme :name (n / name :op1 "MAPK"))) :ARG1 (p2 / protein :name (n2 / name :op1 "CtBP")))))) :ARG2 (k / know-01 :ARG1 (r / regulate-01 :ARG0 (m2 / modify-01 :time (a3 / after :op1 (t3 / translate-02))) :ARG1 (a / activity-06 :ARG0 p2 :ARG1 (r2 / repress-01)) :manner (o / or :op1 (t / translocate-01 :ARG1 p2 :ARG2 (c2 / cytoplasm)) :op2 (t2 / target-01 :ARG1 p2 :purpose (d2 / degrade-01 :ARG1 p2))))) :ARG1-of (d3 / describe-01 :ARG0 (p4 / publication :ARG1-of (c3 / cite-01 :ARG2 (a2 / and :op1 36 :op2 37))))) # ::id bio.bmtr_0004.1 ::date 2015-01-06T01:27:24 ::annotator SDL-AMR-09 ::preferred # ::snt Site-Specific Monoubiquitination Activates Ras by Impeding GTPase Activating Protein (PMC3537887) # ::save-date Fri Jul 24, 2015 ::file bio_bmtr_0004_1.txt (p / publication-91 :ARG1 (a / activate-01 :ARG0 (u / ubiquitinate-01 :quant 1 :ARG1-of (s / specific-02 :ARG2 (p3 / protein-segment))) :ARG1 (e / enzyme :name (n / name :op1 "Ras")) :manner (i / impede-01 :ARG0 u :ARG1 (p2 / protein :name (n2 / name :op1 "GTPase" :op2 "Activating" :op3 "Protein")))) :ARG8 "PMC3537887") # ::id bio.bmtr_0004.2 ::date 2015-01-06T08:06:39 ::annotator SDL-AMR-09 ::preferred # ::snt Passage 1-1 (Results) # ::save-date Fri Jan 1, 2016 ::file bio_bmtr_0004_2.txt (p / passage :mod "1-1" :part-of (t / thing :ARG2-of (r / result-01))) # ::id bio.bmtr_0004.3 ::date 2015-01-06T08:58:49 ::annotator SDL-AMR-09 ::preferred # ::snt We next considered the effect of Ras monoubiquitination on GAP-mediated hydrolysis. # ::save-date Wed Jan 7, 2015 ::file bio_bmtr_0004_3.txt (c / consider-02 :ARG0 (w / we) :ARG1 (a / affect-01 :ARG0 (u / ubiquitinate-01 :quant 1 :ARG1 (e / enzyme :name (n / name :op1 "Ras"))) :ARG1 (h / hydrolyze-01 :ARG1-of (m / mediate-01 :ARG0 (p / protein :name (n2 / name :op1 "GAP"))))) :time (n3 / next)) # ::id bio.bmtr_0004.4 ::date 2015-01-06T09:08:59 ::annotator SDL-AMR-09 ::preferred # ::snt To this end we compared the rate of GTP hydrolysis for Ras and mUbRas in the presence of the catalytic domains of two GAPs, NF1 (NF1-333) and p120GAP(GAP-334). # ::save-date Mon Jan 4, 2016 ::file bio_bmtr_0004_4.txt (c / compare-01 :ARG0 (w / we) :ARG1 (r / rate :degree-of (h / hydrolyze-01 :ARG1 (s / small-molecule :name (n / name :op1 "GTP") :ARG1-of (b / bind-01 :ARG2 (e / enzyme :name (n2 / name :op1 "Ras")))) :condition (p / present-02 :ARG1 (a / and :op1 (d2 / domain :name (n10 / name :op1 "NF1-333") :part-of (p4 / protein :name (n12 / name :op1 "NF1") :ARG1-of (i / include-91 :ARG2 (p6 / protein :name (n13 / name :op1 "GAP"))))) :op2 (d3 / domain :name (n11 / name :op1 "GAP-334") :part-of (p7 / protein :name (n14 / name :op1 "p120GAP") :ARG1-of (i2 / include-91 :ARG2 p6))) :ARG0-of (c2 / catalyze-01))))) :ARG2 (r2 / rate :degree-of (h2 / hydrolyze-01 :ARG1 (s2 / small-molecule :name (n9 / name :op1 "GTP") :ARG1-of (b2 / bind-01 :ARG2 (e2 / enzyme :name (n3 / name :op1 "Ras") :ARG3-of (u / ubiquitinate-01 :quant 1))))) :condition p) :purpose (t / this)) # ::id bio.bmtr_0004.5 ::date 2015-01-06T10:21:04 ::annotator SDL-AMR-09 ::preferred # ::snt At a GAP-to-Ras ratio of 1:500, we observed an order of magnitude increase in the rate of GTP hydrolysis for unmodified Ras relative to the intrinsic rate of GTP hydrolysis. # ::save-date Wed Jan 7, 2015 ::file bio_bmtr_0004_5.txt (o / observe-01 :ARG0 (w / we) :ARG1 (i / increase-01 :ARG1 (r / rate :degree-of (h / hydrolyze-01 :ARG1 (s / small-molecule :name (n / name :op1 "GTP") :ARG1-of (b / bind-01 :ARG2 (e / enzyme :name (n2 / name :op1 "Ras") :ARG1-of (m2 / modify-01 :polarity -)))))) :ARG4 (p2 / product-of :op1 (a / about :op1 10) :op2 (r3 / rate :mod (i2 / intrinsic) :degree-of (h2 / hydrolyze-01 :ARG1 (s2 / small-molecule :name (n5 / name :op1 "GTP"))))) :condition (e3 / equal-01 :ARG1 (r4 / ratio-of :op1 (p / protein :name (n3 / name :op1 "GAP")) :op2 (e2 / enzyme :name (n4 / name :op1 "Ras"))) :ARG2 "1/500"))) # ::id bio.bmtr_0004.6 ::date 2015-01-06T10:36:40 ::annotator SDL-AMR-09 ::preferred # ::snt No increase in the rate of GTP hydrolysis was observed for mUbRas in the presence of the same GAP-to Ras ratio (Fig. 5b). # ::save-date Mon Jan 4, 2016 ::file bio_bmtr_0004_6.txt (o / observe-01 :ARG1 (i / increase-01 :polarity - :ARG1 (r / rate :degree-of (h / hydrolyze-01 :ARG1 (s / small-molecule :name (n / name :op1 "GTP") :ARG1-of (b / bind-01 :ARG2 (e / enzyme :name (n4 / name :op1 "Ras") :ARG3-of (u / ubiquitinate-01 :quant 1)))))) :condition (p / present-02 :ARG1 (r2 / ratio-of :op1 (p2 / protein :name (n2 / name :op1 "GAP")) :op2 (e2 / enzyme :name (n3 / name :op1 "Ras")) :ARG1-of (s2 / same-01)))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "5b"))) # ::id bio.bmtr_0004.7 ::date 2015-01-06T10:42:11 ::annotator SDL-AMR-09 ::preferred # ::snt Therefore, mUbRas is insensitive to GAP-mediated regulation, similar to an oncogenic Ras-G12V mutation. # ::save-date Wed Dec 9, 2015 ::file bio_bmtr_0004_7.txt (c / cause-01 :ARG1 (s / sensitive-03 :polarity - :ARG0 (e / enzyme :name (n / name :op1 "Ras") :ARG3-of (u / ubiquitinate-01 :quant 1)) :ARG1 (r / regulate-01 :ARG1 e :ARG1-of (m / mediate-01 :ARG0 (p / protein :name (n2 / name :op1 "GAP")))) :ARG1-of (r2 / resemble-01 :ARG2 (m2 / mutate-01 :value "G12V" :ARG2 (e2 / enzyme :name (n3 / name :op1 "Ras")) :ARG0-of (c2 / cause-01 :ARG1 (d / disease :wiki "Cancer" :name (n4 / name :op1 "cancer"))))))) # ::id bio.bmtr_0004.8 ::date 2015-01-06T11:02:39 ::annotator SDL-AMR-09 ::preferred # ::snt We obtained similar results using K-Ras (Supplementary Figure 6), indicating that the effects of monoubiquitination on Ras are not isoform-specific. # ::save-date Fri Jul 24, 2015 ::file bio_bmtr_0004_8.txt (o / obtain-01 :ARG0 (w / we) :ARG1 (t / thing :ARG2-of (r / result-01) :ARG1-of (r2 / resemble-01) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod 6 :ARG2-of (s / supplement-01))) :ARG0-of (i / indicate-01 :ARG1 (s2 / specific-02 :polarity - :ARG1 (a / affect-01 :ARG0 (u2 / ubiquitinate-01 :quant 1) :ARG1 (e2 / enzyme :name (n2 / name :op1 "Ras"))) :ARG2 (i2 / isoform)))) :manner (u / use-01 :ARG0 w :ARG1 (e / enzyme :name (n / name :op1 "K-Ras")))) # ::id bio.bmtr_0004.9 ::date 2015-01-06T11:13:11 ::annotator SDL-AMR-09 ::preferred # ::snt To verify that the differences between the enzymatic and chemical ubiquitination linkers (seven bonds and five bonds, respectively) do not alter GAP-responsiveness, we placed an additional cysteine at the c-terminus of Ubiquitin (Ubiquitin-C77), thereby creating a linker one bond longer than the native linker. # ::save-date Wed Jun 3, 2015 ::file bio_bmtr_0004_9.txt (p / place-01 :ARG0 (w / we) :ARG1 (a / amino-acid :name (n / name :op1 "cysteine") :mod (a2 / additional)) :ARG2 (p2 / protein-segment :name (n2 / name :op1 "C-terminus") :part-of (p3 / protein :name (n3 / name :op1 "ubiquitin"))) :manner-of (b4 / become-01 :ARG1 a :ARG2 (a5 / amino-acid :mod 77 :name (n4 / name :op1 "cysteine") :part-of p3)) :ARG0-of (c / create-01 :ARG1 (p6 / protein-segment :ARG1-of (l / long-03 :ARG2 (b / bond :quant 1) :degree (m2 / more) :compared-to (p7 / protein-segment :mod (n7 / native) :ARG0-of (l3 / link-01))) :ARG0-of (l2 / link-01))) :purpose (v / verify-01 :ARG0 w :ARG1 (a4 / alter-01 :polarity - :ARG0 (d / differ-02 :ARG1 (p8 / protein-segment :consist-of (b2 / bond :quant 7) :ARG0-of (l4 / link-01) :location-of (u2 / ubiquitinate-01 :mod (e / enzyme))) :ARG2 (p9 / protein-segment :location-of (u / ubiquitinate-01 :mod (c2 / chemical)) :consist-of (b3 / bond :quant 5) :ARG0-of (l5 / link-01))) :ARG1 (r / respond-01 :ARG0 (p5 / protein :name (n5 / name :op1 "GAP")))))) # ::id bio.bmtr_0004.10 ::date 2015-01-06T11:14:24 ::annotator SDL-AMR-09 ::preferred # ::snt We measured the rate of GAP-mediated GTP hydrolysis and observed that the response of Ras ligated to Ubiquitin-C77 was identical to Ras ligated to Ubiquitin-G76C (Fig. 5b). # ::save-date Thu Jan 8, 2015 ::file bio_bmtr_0004_10.txt (a / and :op1 (m / measure-01 :ARG0 (w / we) :ARG1 (r / rate :degree-of (h / hydrolyze-01 :ARG1 (s / small-molecule :name (n / name :op1 "GTP")) :ARG1-of (m2 / mediate-01 :ARG0 (p / protein :name (n2 / name :op1 "GAP")))))) :op2 (o / observe-01 :ARG0 w :ARG1 (i / identical-01 :ARG1 (t / thing :ARG2-of (r2 / respond-01 :ARG0 (e / enzyme :name (n5 / name :op1 "Ras") :ARG1-of (l / ligate-01 :ARG3 (a2 / amino-acid :mod 77 :name (n7 / name :op1 "cysteine") :part-of (p4 / protein :name (n8 / name :op1 "ubiquitin"))))))) :ARG2 (t2 / thing :ARG2-of (r3 / respond-01 :ARG0 (e2 / enzyme :name (n4 / name :op1 "Ras") :ARG1-of (l2 / ligate-01 :ARG3 (a3 / amino-acid :mod 76 :name (n3 / name :op1 "cysteine") :part-of (p2 / protein :name (n9 / name :op1 "ubiquitin") :ARG3-of (m3 / mutate-01 :value "G76C"))))))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "5b"))))) # ::id bio.bmtr_0004.11 ::date 2015-01-06T12:31:02 ::annotator SDL-AMR-09 ::preferred # ::snt These results indicate that variations in the linker length on this scale (1-2 bonds) do not influence the sensitivity of mUbRas to GAP downregulation. # ::save-date Thu Jan 8, 2015 ::file bio_bmtr_0004_11.txt (i / indicate-01 :ARG0 (t / thing :ARG2-of (r / result-01) :mod (t2 / this)) :ARG1 (i2 / influence-01 :polarity - :ARG0 (v2 / vary-01 :ARG1 (p2 / protein-segment :ARG0-of (l2 / link-01)) :ARG2 (o / or :op1 (b / bond :quant 1) :op2 (b2 / bond :quant 2)) :ARG5 (l / length)) :ARG1 (s / sensitive-03 :ARG0 (e / enzyme :name (n / name :op1 "Ras") :ARG3-of (u / ubiquitinate-01 :quant 1)) :ARG1 (d / downregulate-01 :ARG1 e :ARG2 (p / protein :name (n2 / name :op1 "GAP")))))) # ::id bio.bmtr_0004.12 ::date 2015-01-06T12:43:54 ::annotator SDL-AMR-09 ::preferred # ::snt To validate the use of an in vitro system to dissect the mechanism of Ras regulation, we measured the sensitivity of mUbRas to GAP-mediated hydrolysis in a cellular reconstitution system. # ::save-date Mon Jan 4, 2016 ::file bio_bmtr_0004_12.txt (m / measure-01 :ARG0 (w / we) :ARG1 (s / sensitive-03 :ARG0 (e / enzyme :name (n / name :op1 "Ras") :ARG3-of (u / ubiquitinate-01 :quant 1)) :ARG1 (h / hydrolyze-01 :ARG1-of (m2 / mediate-01 :ARG0 (p / protein :name (n2 / name :op1 "GAP")))) :location (s2 / system :ARG0-of (r / reconstitute-01 :ARG1 (c / cell)))) :purpose (v / validate-01 :ARG0 w :ARG1 (u2 / use-01 :ARG0 w :ARG1 (s3 / system :mod (i / in-vitro)) :ARG2 (d / dissect-01 :ARG0 w :ARG1 (m3 / mechanism :instrument-of (r2 / regulate-01 :ARG1 (e2 / enzyme :name (n3 / name :op1 "Ras")))))))) # ::id bio.bmtr_0004.13 ::date 2015-01-06T12:53:31 ::annotator SDL-AMR-09 ::preferred # ::snt We immunoprecipitated Ras from HEK293T cells and compared the sensitivity of the monoubiquitinated and unmodified fractions of Ras to regulation by GAP. # ::save-date Thu Jan 8, 2015 ::file bio_bmtr_0004_13.txt (a / and :op1 (i / immunoprecipitate-01 :ARG0 (w / we) :ARG1 (e / enzyme :name (n / name :op1 "Ras")) :ARG2 (c / cell-line :name (n2 / name :op1 "HEK293T"))) :op2 (c2 / compare-01 :ARG0 w :ARG1 (s / sensitive-03 :ARG0 (f / fraction :part-of e :ARG1-of (u / ubiquitinate-01 :quant 1)) :ARG1 (r / regulate-01 :ARG0 (p / protein :name (n3 / name :op1 "GAP")) :ARG1 f)) :ARG2 (s2 / sensitive-03 :ARG0 (f2 / fraction :part-of e :ARG1-of (m / modify-01 :polarity -)) :ARG1 (r2 / regulate-01 :ARG0 p :ARG1 f2)))) # ::id bio.bmtr_0004.14 ::date 2015-01-06T13:00:57 ::annotator SDL-AMR-09 ::preferred # ::snt As seen in Figure 5c, monoubiquitinated K-Ras is less sensitive than the unmodified protein to GAP-mediated GTP hydrolysis. # ::save-date Thu Jan 8, 2015 ::file bio_bmtr_0004_14.txt (s / sensitive-03 :ARG0 (e / enzyme :name (n / name :op1 "K-Ras") :ARG1-of (u / ubiquitinate-01 :quant 1)) :ARG1 (h / hydrolyze-01 :ARG1 (s2 / small-molecule :name (n2 / name :op1 "GTP")) :ARG1-of (m2 / mediate-01 :ARG0 (p2 / protein :name (n3 / name :op1 "GAP")))) :degree (l / less) :compared-to (e2 / enzyme :name (n4 / name :op1 "K-Ras") :ARG1-of (m / modify-01 :polarity -)) :ARG1-of (s3 / see-01 :medium (f / figure :mod "5c"))) # ::id bio.bmtr_0004.15 ::date 2015-01-06T13:05:57 ::annotator SDL-AMR-09 ::preferred # ::snt These data support our in vitro findings that monoubiquitination increases the population of active, GTP-bound Ras through a defect in sensitivity to GAP-mediated regulation. # ::save-date Mon Jul 20, 2015 ::file bio_bmtr_0004_15.txt (s / support-01 :ARG0 (d / data :mod (t / this)) :ARG1 (f / find-01 :ARG0 (w / we) :ARG1 (i / increase-01 :ARG0 (u / ubiquitinate-01 :quant 1) :ARG1 (p / population :consist-of (e / enzyme :name (n / name :op1 "Ras") :ARG0-of (a / activity-06) :ARG2-of (b / bind-01 :ARG1 (s2 / small-molecule :name (n2 / name :op1 "GTP"))))) :manner (d2 / defect :topic (s3 / sensitive-03 :ARG1 (r / regulate-01 :ARG1-of (m / mediate-01 :ARG0 (p2 / protein :name (n3 / name :op1 "GAP"))))))) :manner (i2 / in-vitro))) # ::id bio.bmtr_0004.16 ::date 2015-01-06T13:16:30 ::annotator SDL-AMR-09 ::preferred # ::snt Passage 1-2 (Discussion/Conclusion) # ::save-date Fri Jan 1, 2016 ::file bio_bmtr_0004_16.txt (p / passage :mod "1-2" :part-of (s / slash :op1 (t / thing :ARG1-of (d / discuss-01)) :op2 (t2 / thing :ARG1-of (c / conclude-01)))) # ::id bio.bmtr_0004.17 ::date 2015-01-06T13:19:56 ::annotator SDL-AMR-09 ::preferred # ::snt It was established recently that monoubiquitination increases the proportion of Ras that is in the activated (GTP-bound) state, that monoubiquitination enhances association with the downstream effectors Raf and PI3-Kinase, and that mutation of the primary site of monoubiquitination impairs oncogenic Ras-mediated tumorigenesis. # ::save-date Fri Jan 1, 2016 ::file bio_bmtr_0004_17.txt (e / establish-01 :ARG1 (a / and :op1 (i / increase-01 :ARG0 (u / ubiquitinate-01 :quant 1) :ARG1 (p / proportion :quant-of (e2 / enzyme :name (n / name :op1 "Ras")) :ARG1-of (a2 / activate-01) :ARG1-of (b / bind-01 :ARG2 (s / small-molecule :name (n2 / name :op1 "GTP"))))) :op2 (e3 / enhance-01 :ARG0 u :ARG1 (a3 / associate-01 :ARG2 (a4 / and :op1 (e4 / effector :mod (d / downstream) :mod (e7 / enzyme :name (n3 / name :op1 "Raf"))) :op2 (e5 / effector :mod (e8 / enzyme :name (n4 / name :op1 "PI3-Kinase")))))) :op3 (i2 / impair-01 :ARG0 (m2 / mutate-01 :ARG1 (p3 / protein-segment :mod (p2 / primary) :part-of u)) :ARG1 (c3 / create-01 :ARG1 (t / tumor) :ARG1-of (m3 / mediate-01 :ARG0 (e6 / enzyme :name (n5 / name :op1 "Ras") :ARG0-of (c / cause-01 :ARG1 (d2 / disease :wiki "Cancer" :name (n6 / name :op1 "cancer")))))))) :time (r / recent)) # ::id bio.bmtr_0004.18 ::date 2015-01-06T13:33:35 ::annotator SDL-AMR-09 ::preferred # ::snt Here we show that monoubiquitination decreases the sensitivity of Ras to GAP-mediated hydrolysis. # ::save-date Tue Jan 6, 2015 ::file bio_bmtr_0004_18.txt (s / show-01 :ARG0 (w / we) :ARG1 (d / decrease-01 :ARG0 (u / ubiquitinate-01 :quant 1) :ARG1 (s2 / sensitive-03 :ARG0 (e / enzyme :name (n / name :op1 "Ras")) :ARG1 (h / hydrolyze-01 :ARG1-of (m / mediate-01 :ARG0 (p / protein :name (n2 / name :op1 "GAP")))))) :location (h2 / here)) # ::id bio.bmtr_0004.19 ::date 2015-01-06T13:36:10 ::annotator SDL-AMR-09 ::preferred # ::snt A major advance was our ability to easily generate mUbRas, modified at a single site, in a form suitable for detailed biophysical studies. # ::save-date Fri Jan 1, 2016 ::file bio_bmtr_0004_19.txt (a / advance-01 :ARG1 (c / capable-01 :ARG1 (w / we) :ARG2 (g / generate-01 :ARG0 w :ARG1 (e / enzyme :name (n / name :op1 "Ras") :ARG3-of (u / ubiquitinate-01 :quant 1) :ARG1-of (m2 / modify-01 :location (p / protein-segment :ARG1-of (s2 / single-02)))) :ARG4 (f / form :ARG1-of (s / suitable-04 :ARG2 (s4 / study-01 :ARG1 (b / biophysical) :ARG1-of (d / detail-01))))) :ARG1-of (e2 / easy-05)) :ARG2 (m / major-02)) # ::id bio.bmtr_0004.20 ::date 2015-01-06T13:41:51 ::annotator SDL-AMR-09 ::preferred # ::snt This chemical ligation strategy will likely be useful for the study of other monoubiquitinated proteins. # ::save-date Mon Jul 6, 2015 ::file bio_bmtr_0004_20.txt (l / likely-01 :ARG1 (u / useful-05 :ARG1 (s / strategy :mod (l2 / ligate-01 :mod (c / chemical)) :mod (t / this)) :ARG2 (s2 / study-01 :ARG1 (p / protein :ARG1-of (u2 / ubiquitinate-01 :quant 1) :mod (o / other))))) # ::id bio.bmtr_0004.21 ::date 2015-01-06T02:02:31 ::annotator SDL-AMR-09 ::preferred # ::snt Surprisingly, monoubiquitination did not alter the intrinsic activity of Ras, despite the size of the modification. # ::save-date Mon Jul 6, 2015 ::file bio_bmtr_0004_21.txt (s / surprise-01 :ARG0 (a / alter-01 :polarity - :ARG0 (u / ubiquitinate-01 :quant 1) :ARG1 (a2 / activity-06 :ARG0 (e / enzyme :name (n / name :op1 "Ras")) :mod (i / intrinsic))) :concession (t / thing :ARG2-of (s2 / size-01 :ARG1 (m / modify-01)))) # ::id bio.bmtr_0004.22 ::date 2015-01-06T02:13:25 ::annotator SDL-AMR-09 ::preferred # ::snt Our modeling and NMR analyses indicated that Ubiquitin dynamically samples a broad surface area of Ras that alters switch region dynamics. # ::save-date Wed Oct 28, 2015 ::file bio_bmtr_0004_22.txt (i / indicate-01 :ARG0 (a / and :op1 (m / model-01 :ARG0 (w / we)) :op2 (a2 / analyze-01 :ARG0 w :manner (r2 / resonate-01 :ARG1 (n / nucleus) :mod (m2 / magnet)))) :ARG1 (s / sample-01 :ARG0 (p / protein :name (n2 / name :op1 "ubiquitin")) :ARG1 (a3 / area :mod (s2 / surface :ARG1-of (b / broad-02)) :part-of (e / enzyme :name (n3 / name :op1 "Ras"))) :manner (d / dynamic) :ARG0-of (a4 / alter-01 :ARG1 (d2 / dynamic :location (r / region :mod (s3 / switch-01)))))) # ::id bio.bmtr_0004.23 ::date 2015-01-06T02:48:52 ::annotator SDL-AMR-09 ::preferred # ::snt These results led us to examine the effect of monoubiquitination on the interaction of Ras with its cognate GEF and GAPs, which also target the switch domains. # ::save-date Thu Jan 8, 2015 ::file bio_bmtr_0004_23.txt (l / lead-03 :ARG0 (t / thing :ARG2-of (r / result-01) :mod (t2 / this)) :ARG1 (w / we) :ARG2 (e / examine-01 :ARG0 w :ARG1 (a / affect-01 :ARG0 (u / ubiquitinate-01 :quant 1) :ARG1 (i / interact-01 :ARG0 (e2 / enzyme :name (n / name :op1 "Ras")) :ARG1 (a2 / and :op1 (p / protein :name (n2 / name :op1 "GEF")) :op2 (p2 / protein :name (n3 / name :op1 "GAP")) :mod (c / cognate :prep-with e2) :ARG0-of (t3 / target-01 :ARG1 (d / domain :mod (s / switch-01)) :mod (a3 / also))))))) # ::id bio.bmtr_0004.24 ::date 2015-01-06T03:38:45 ::annotator SDL-AMR-09 ::preferred # ::snt The analysis revealed that monoubiquitination abrogates GAP-mediated GTP hydrolysis. # ::save-date Tue Jan 6, 2015 ::file bio_bmtr_0004_24.txt (r / reveal-01 :ARG0 (a / analyze-01) :ARG1 (a2 / abrogate-01 :ARG0 (u / ubiquitinate-01 :quant 1) :ARG1 (h / hydrolyze-01 :ARG1 (s / small-molecule :name (n / name :op1 "GTP")) :ARG1-of (m / mediate-01 :ARG0 (p / protein :name (n2 / name :op1 "GAP")))))) # ::id bio.bmtr_0004.25 ::date 2015-01-06T03:44:41 ::annotator SDL-AMR-09 ::preferred # ::snt All other activities, including the ability to bind regulators, were largely preserved and our kinetic modeling suggests that the GAP defect will dominate. # ::save-date Thu Jan 8, 2015 ::file bio_bmtr_0004_25.txt (a3 / and :op1 (p / preserve-01 :ARG1 (a / act-02 :mod (a2 / all) :mod (o / other) :ARG2-of (i / include-01 :ARG1 (p2 / possible-01 :ARG1 (b / bind-01 :ARG1 (m2 / molecular-physical-entity :ARG0-of (r / regulate-01)))))) :mod (l / large)) :op2 (s / suggest-01 :ARG0 (m / model-01 :ARG0 (w / we) :mod (k / kinetic)) :ARG1 (d / dominate-01 :ARG1 (d2 / defect :mod (p3 / protein :name (n / name :op1 "GAP")))))) # ::id bio.bmtr_0004.26 ::date 2015-01-06T06:25:29 ::annotator SDL-AMR-09 ::preferred # ::snt Furthermore, this outcome was specific to monoubiquitination at position 147. # ::save-date Fri Jul 24, 2015 ::file bio_bmtr_0004_26.txt (a / and :op2 (s / specific-02 :ARG1 (o / outcome :mod (t / this)) :ARG2 (u / ubiquitinate-01 :quant 1 :ARG1 (a2 / amino-acid :mod 147)))) # ::id bio.bmtr_0004.27 ::date 2015-01-06T07:18:02 ::annotator SDL-AMR-09 ::preferred # ::snt Thus our work establishes an entirely new mode of Ras activation in which signaling is sustained even in the absence of hormone stimulus or oncogene mutation. # ::save-date Fri Jan 1, 2016 ::file bio_bmtr_0004_27.txt (e / establish-01 :ARG0 (w / work-01 :ARG0 (w2 / we)) :ARG1 (m / mode :ARG1-of (n / new-01 :degree (e2 / entire)) :mod (a / activate-01 :ARG1 (e3 / enzyme :name (n2 / name :op1 "Ras"))) :ARG0-of (s / sustain-01 :ARG1 (s2 / signal-07) :concession (a2 / absent-01 :ARG1 (o / or :op1 (s3 / stimulus :mod (h / hormone)) :op2 (m2 / mutate-01 :ARG0-of (c / cause-01 :ARG1 (d / disease :wiki "Cancer" :name (n3 / name :op1 "cancer"))))))))) # ::id bio.bmtr_0005.1 ::date 2015-01-06T07:32:43 ::annotator SDL-AMR-09 ::preferred # ::snt Phosphorylation of ASPP2 by RAS/MAPK Pathway Is Critical for Its Full Pro-Apoptotic Function (PMC3847091) # ::save-date Wed Jun 24, 2015 ::file bio_bmtr_0005_1.txt (p5 / publication-91 :ARG1 (c / critical-02 :ARG1 (p / phosphorylate-01 :ARG1 (p2 / protein :name (n / name :op1 "ASPP2")) :ARG2 (p3 / pathway :name (n2 / name :op1 "RAS/MAPK"))) :ARG2 (f / function-01 :ARG0 p2 :ARG1 (a / apoptosis :ARG1-of (f3 / favor-01)) :mod (f2 / full))) :ARG8 "PMC3847091") # ::id bio.bmtr_0005.2 ::date 2015-01-06T07:47:04 ::annotator SDL-AMR-09 ::preferred # ::snt Passage 1-1 (Results) # ::save-date Fri Jan 1, 2016 ::file bio_bmtr_0005_2.txt (p / passage :mod "1-1" :part-of (t / thing :ARG2-of (r / result-01))) # ::id bio.bmtr_0005.3 ::date 2015-01-06T07:52:16 ::annotator SDL-AMR-09 ::preferred # ::snt It has recently been shown that oncogenic RAS can enhance the apoptotic function of p53 via ASPP1 and ASPP2. # ::save-date Wed Dec 9, 2015 ::file bio_bmtr_0005_3.txt (s / show-01 :ARG1 (p / possible-01 :ARG1 (e / enhance-01 :ARG0 (e2 / enzyme :name (n / name :op1 "Ras") :ARG0-of (c / cause-01 :ARG1 (d / disease :wiki "Cancer" :name (n5 / name :op1 "cancer")))) :ARG1 (f / function-01 :ARG0 (p2 / protein :name (n2 / name :op1 "p53")) :ARG1 (a / apoptosis)) :instrument (a2 / and :op1 (p3 / protein :name (n3 / name :op1 "ASPP1")) :op2 (p4 / protein :name (n4 / name :op1 "ASPP2"))))) :time (r / recent)) # ::id bio.bmtr_0005.4 ::date 2015-01-06T08:05:46 ::annotator SDL-AMR-09 ::preferred # ::snt Mechanistically ASPP1 and ASPP2 bind RAS-GTP and potentiates RAS signalling to enhance p53 mediated apoptosis [2]. # ::save-date Thu Feb 4, 2016 ::file bio_bmtr_0005_4.txt (b / bind-01 :ARG1 (a2 / and :op1 (p / protein :name (n / name :op1 "ASPP1")) :op2 (p2 / protein :name (n2 / name :op1 "ASPP2"))) :ARG2 (m3 / macro-molecular-complex :part (e / enzyme :name (n3 / name :op1 "Ras")) :part (s / small-molecule :name (n4 / name :op1 "GTP"))) :manner (m / mechanistic) :ARG2-of (p3 / potentiate-01 :ARG1 (s2 / signal-07 :ARG0 e) :purpose (e2 / enhance-01 :ARG0 b :ARG1 (a / apoptosis :ARG1-of (m2 / mediate-01 :ARG0 (p4 / protein :name (n5 / name :op1 "p53")))))) :ARG1-of (d / describe-01 :ARG0 (p5 / publication :ARG1-of (c / cite-01 :ARG2 2)))) # ::id bio.bmtr_0005.5 ::date 2015-01-07T00:52:41 ::annotator SDL-AMR-09 ::preferred # ::snt As RAS is upstream of several signalling cascades [13], we queried whether the activity of ASPP2 is regulated by the activation of a RAS-mediated signalling pathway. # ::save-date Sat Jan 16, 2016 ::file bio_bmtr_0005_5.txt (q / query-01 :ARG0 (w / we) :ARG2 (r / regulate-01 :ARG0 (a / activate-01 :ARG0 (p / pathway :ARG0-of (s / signal-07 :ARG1-of (m / mediate-01 :ARG0 e)))) :ARG1 (a2 / activity-06 :ARG0 (p2 / protein :name (n2 / name :op1 "ASPP2")))) :ARG1-of (c / cause-01 :ARG0 (b / be-located-at-91 :ARG1 (e / enzyme :name (n / name :op1 "RAS")) :ARG2 (r2 / relative-position :op1 (c2 / cascade :subevent (s2 / signal-07) :quant (s3 / several)) :direction (u / upstream)) :ARG1-of (d / describe-01 :ARG0 (p3 / publication :ARG0-of (c3 / cite-01 :ARG2 13)))))) # ::id bio.bmtr_0005.6 ::date 2015-01-07T01:51:47 ::annotator SDL-AMR-09 ::preferred # ::snt One of the most studied downstream pathways of RAS signalling is the Raf-MAPK pathway. # ::save-date Wed Jan 7, 2015 ::file bio_bmtr_0005_6.txt (i / include-91 :ARG1 (p / pathway :name (n / name :op1 "Raf-MAPK")) :ARG2 (p2 / pathway :ARG1-of (s / study-01 :degree (m / most)) :mod (d / downstream) :location-of (s2 / signal-07 :ARG0 (e / enzyme :name (n2 / name :op1 "Ras"))))) # ::id bio.bmtr_0005.7 ::date 2015-01-07T02:19:05 ::annotator SDL-AMR-09 ::preferred # ::snt Interestingly, we observed two conserved putative MAPK phosphorylation sites in ASPP1 and ASPP2. # ::save-date Sun Dec 13, 2015 ::file bio_bmtr_0005_7.txt (o / observe-01 :ARG0 (w2 / we) :ARG1 (a / and :op1 (p3 / protein-segment :quant 2 :ARG1-of (c / conserve-01) :ARG1-of (p2 / phosphorylate-01 :ARG2 (e / enzyme :name (n / name :op1 "MAPK")) :ARG2-of (t / think-01)) :part-of (a2 / and :op1 (p5 / protein :name (n2 / name :op1 "ASPP1")) :op2 (p6 / protein :name (n3 / name :op1 "ASPP2"))))) :ARG2-of (i / interest-01 :ARG1 w2)) # ::id bio.bmtr_0005.8 ::date 2015-01-07T02:54:52 ::annotator SDL-AMR-09 ::preferred # ::snt The ASPP1 sites are at residues 671 and 746, and the ASPP2 sites are at residues 698 and 827 (Figure 1A). # ::save-date Thu Jan 8, 2015 ::file bio_bmtr_0005_8.txt (a4 / and :op1 (b / be-located-at-91 :ARG1 (p / protein-segment :part-of (p2 / protein :name (n / name :op1 "ASPP1"))) :ARG2 (a2 / and :op1 (r / residue :mod (a / amino-acid :mod 671)) :op2 (r2 / residue :mod (a3 / amino-acid :mod 746)))) :op2 (b2 / be-located-at-91 :ARG1 (p3 / protein-segment :part-of (p4 / protein :name (n2 / name :op1 "ASPP2"))) :ARG2 (a5 / and :op1 (r3 / residue :mod (a6 / amino-acid :mod 698)) :op2 (r4 / residue :mod (a7 / amino-acid :mod 827)))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "1A"))) # ::id bio.bmtr_0005.9 ::date 2015-01-07T01:10:14 ::annotator SDL-AMR-09 ::preferred # ::snt We thus tested whether RAS activation may regulate ASPP2 phosphorylation. # ::save-date Wed Jan 7, 2015 ::file bio_bmtr_0005_9.txt (c / cause-01 :ARG1 (t / test-01 :ARG0 (w / we) :ARG1 (p / possible-01 :mode interrogative :ARG1 (r / regulate-01 :ARG0 (a / activate-01 :ARG1 (e / enzyme :name (n / name :op1 "RAS"))) :ARG1 (p2 / phosphorylate-01 :ARG1 (p3 / protein :name (n2 / name :op1 "ASPP2"))))))) # ::id bio.bmtr_0005.10 ::date 2015-01-07T01:19:03 ::annotator SDL-AMR-09 ::preferred # ::snt An in vitro phophorylation assay was performed with a purified C-terminus fragment of ASPP2 (693-1128) containing both MAPK putative phosphorylation sites. # ::save-date Thu Jan 8, 2015 ::file bio_bmtr_0005_10.txt (a / assay-01 :ARG1 (p / phosphorylate-01 :ARG1 (p2 / protein-segment :part-of (p3 / protein-segment :name (n / name :op1 "C-terminus") :part-of (p4 / protein :name (n2 / name :op1 "ASPP2"))) :ARG1-of (p5 / purify-01) :mod (b / between :op1 (a2 / amino-acid :mod 693) :op2 (a3 / amino-acid :mod 1128)) :ARG0-of (c / contain-01 :ARG1 (p6 / protein-segment :ARG1-of (p7 / phosphorylate-01 :ARG2 (e / enzyme :name (n4 / name :op1 "MAPK")) :ARG1-of (t / think-01)) :mod (b2 / both)))) :manner (i / in-vitro))) # ::id bio.bmtr_0005.11 ::date 2015-01-07T01:50:22 ::annotator SDL-AMR-09 ::preferred # ::snt When compared to p38 SAPK, MAPK1 was clearly able to phosphorylate the ASPP2 fragment in vitro (Figure 1B, left and middle panels). # ::save-date Sat Jan 30, 2016 ::file bio_bmtr_0005_11.txt (p / possible-01 :ARG1 (p2 / phosphorylate-01 :ARG1 (p3 / protein-segment :part-of (p4 / protein :name (n2 / name :op1 "ASPP2"))) :ARG2 (e / enzyme :name (n / name :op1 "MAPK1")) :manner (i / in-vitro)) :ARG1-of (c / clear-06) :compared-to (p5 / possible-01 :ARG1 (p6 / phosphorylate-01 :ARG1 p3 :ARG2 (e2 / enzyme :name (n3 / name :op1 "p38" :op2 "SAPK")))) :ARG1-of (d / describe-01 :ARG0 (a / and :op1 (p7 / panel :ARG1-of (l / left-20)) :op2 (p8 / panel :location (m / middle)) :part-of (f / figure :mod "1B")))) # ::id bio.bmtr_0005.12 ::date 2015-01-07T02:20:07 ::annotator SDL-AMR-09 ::preferred # ::snt As shown in Figure S1, histone 2B phosphorylated by p38 SAPK had high levels of incorporated 32P, suggesting that p38 SAPK was active; while under the same conditions, ASPP2 (693-1128) fragment phosphorylated by p38 SAPK had very low levels of incorporated 32P, indicating that p38 SAPK is not an efficient kinase for ASPP2 phosphorylation. # ::save-date Sun Jul 26, 2015 ::file bio_bmtr_0005_12.txt (s / show-01 :ARG0 (f / figure :mod "S1") :ARG1 (c / contrast-01 :ARG1 (h / have-part-91 :ARG1 (p8 / protein :name (n / name :op1 "Histone" :op2 "2B") :ARG3-of (p2 / phosphorylate-01 :ARG2 (e / enzyme :name (n2 / name :op1 "p38" :op2 "SAPK")))) :ARG2 (p / phosphorus :mod (m / molecular-mass :value 32) :quant (l / level :ARG1-of (h2 / high-02)) :ARG1-of (i / incorporate-02 :ARG2 p8)) :ARG0-of (s2 / suggest-01 :ARG1 (a / activity-06 :ARG0 e))) :ARG2 (h4 / have-part-91 :ARG1 (p3 / protein-segment :mod (b / between :op1 (a2 / amino-acid :mod 693) :op2 (a3 / amino-acid :mod 1128)) :part (p5 / protein :name (n3 / name :op1 "ASPP2")) :ARG3-of (p6 / phosphorylate-01 :ARG2 e)) :ARG2 (p4 / phosphorus :mod (m2 / molecular-mass :value 32) :quant (l2 / level :ARG1-of (l3 / low-04 :degree (v / very))) :ARG1-of (i2 / incorporate-02 :ARG2 p3)) :ARG0-of (i3 / indicate-01 :ARG1 (e2 / efficient-01 :polarity - :ARG1 e :ARG2 (p7 / phosphorylate-01 :ARG1 p5 :ARG2 e))) :condition (t / thing :ARG1-of (s3 / same-01 :ARG2 (t2 / thing :condition-of h)))))) # ::id bio.bmtr_0005.13 ::date 2015-01-07T02:45:06 ::annotator SDL-AMR-09 ::preferred # ::snt The phosphorylated ASPP2 fragment by MAPK1 was digested by trypsin and fractioned on a high performance liquid chromatography (HPLC). # ::save-date Tue Jul 28, 2015 ::file bio_bmtr_0005_13.txt (a / and :op1 (d / digest-01 :ARG0 (e / enzyme :name (n / name :op1 "trypsin")) :ARG1 (p / protein-segment :part-of (p2 / protein :name (n2 / name :op1 "ASPP2")) :ARG3-of (p3 / phosphorylate-01 :ARG2 (e2 / enzyme :name (n3 / name :op1 "MAPK1"))))) :op2 (f / fraction-01 :ARG1 p :manner (c / chromatography :mod (l / liquid :ARG0-of (p4 / perform-02 :ARG1-of (h / high-02)))))) # ::id bio.bmtr_0005.14 ::date 2015-01-07T02:59:19 ::annotator SDL-AMR-09 ::preferred # ::snt Each eluted fraction was measured for its radioactivity content (Figure 1B, right panel). # ::save-date Fri Dec 18, 2015 ::file bio_bmtr_0005_14.txt (m / measure-01 :ARG1 (f / fraction :ARG1-of (e / elute-01) :mod (e2 / each)) :purpose (t / thing :mod (r2 / radioactive) :ARG1-of (c / contain-01 :ARG0 f)) :ARG1-of (d / describe-01 :ARG0 (p / panel :ARG1-of (r / right-04) :part-of (f2 / figure :mod "1B")))) # ::id bio.bmtr_0005.15 ::date 2015-01-07T03:12:21 ::annotator SDL-AMR-09 ::preferred # ::snt The fractions representing these radioactive peaks were analysed by mass spectrometry. # ::save-date Wed Jan 7, 2015 ::file bio_bmtr_0005_15.txt (a / analyze-01 :ARG1 (f / fraction :ARG0-of (r / represent-01 :ARG1 (p / peak :mod (r2 / radioactive) :mod (t / this)))) :manner (s / spectrometry :mod (m / mass))) # ::id bio.bmtr_0005.16 ::date 2015-01-07T03:17:37 ::annotator SDL-AMR-09 ::preferred # ::snt Of the two radioactive peaks, one represented the linker region between the GST and our ASPP2 fragment and the other corresponded to a fragment of the same mass as that containing the second putative phosphorylation site, serine 827. # ::save-date Mon Jan 4, 2016 ::file bio_bmtr_0005_16.txt (a / and :op1 (r / represent-01 :ARG0 (p / peak :ARG1-of (i / include-91 :ARG2 (p2 / peak :quant 2 :mod (r2 / radioactive)))) :ARG1 (r4 / region :ARG3-of (l / link-01 :ARG1 (e / enzyme :name (n / name :op1 "GST")) :ARG2 (p3 / protein-segment :part-of (p4 / protein :name (n2 / name :op1 "ASPP2")) :poss (w / we))))) :op2 (c / correspond-02 :ARG1 (p5 / peak :mod (o / other) :ARG1-of (i2 / include-91 :ARG2 p2)) :ARG2 (p6 / protein-segment :ARG0-of (h / have-03 :ARG1 (m / mass :ARG1-of (s / same-01 :ARG2 (m2 / mass :poss (p7 / protein-segment :ARG1-of (p8 / phosphorylate-01) :ord (o2 / ordinal-entity :value 2) :ARG1-of (e2 / equal-01 :ARG2 (a3 / amino-acid :mod 827 :name (n3 / name :op1 "serine")) :ARG1-of (t / think-01)))))))))) # ::id bio.bmtr_0005.17 ::date 2015-01-07T04:57:02 ::annotator SDL-AMR-09 ::preferred # ::snt Hence ASPP2 can be phosphorylated at serine 827 by MAPK1 in vitro. # ::save-date Wed Jan 7, 2015 ::file bio_bmtr_0005_17.txt (c / cause-01 :ARG1 (p / possible-01 :ARG1 (p2 / phosphorylate-01 :ARG1 (a / amino-acid :name (n / name :op1 "serine") :mod 827 :part-of (p3 / protein :name (n2 / name :op1 "ASPP2"))) :ARG2 (e / enzyme :name (n3 / name :op1 "MAPK1")) :manner (i / in-vitro)))) # ::id bio.bmtr_0005.18 ::date 2015-01-07T05:01:25 ::annotator SDL-AMR-09 ::preferred # ::snt Passage 1-2 (Discussion/Conclusion) # ::save-date Fri Jan 1, 2016 ::file bio_bmtr_0005_18.txt (p / passage :mod "1-2" :part-of (s / slash :op1 (t2 / thing :ARG1-of (d / discuss-01)) :op2 (t / thing :ARG1-of (c / conclude-01)))) # ::id bio.bmtr_0005.19 ::date 2015-01-07T05:12:17 ::annotator SDL-AMR-09 ::preferred # ::snt We and others have recently shown that ASPP2 can potentiate RAS signaling by binding directly via the ASPP2 N-terminus [2,6]. # ::save-date Fri Jan 1, 2016 ::file bio_bmtr_0005_19.txt (s / show-01 :ARG0 (a / and :op1 (w / we) :op2 (p / person :mod (o / other))) :ARG1 (p2 / possible-01 :ARG1 (p3 / potentiate-01 :ARG1 (s2 / signal-07 :ARG0 (e / enzyme :name (n2 / name :op1 "RAS"))) :ARG2 (p4 / protein :name (n / name :op1 "ASPP2")) :manner (b / bind-01 :ARG1 e :ARG2 (p5 / protein-segment :name (n3 / name :op1 "N-terminus") :part-of p4) :ARG1-of (d / direct-02)))) :time (r / recent) :ARG1-of (d2 / describe-01 :ARG0 (p6 / publication :ARG1-of (c / cite-01 :ARG2 (a2 / and :op1 2 :op2 6))))) # ::id bio.bmtr_0005.20 ::date 2015-01-07T05:23:11 ::annotator SDL-AMR-09 ::preferred # ::snt Moreover, the RAS-ASPP interaction enhances the transcription function of p53 in cancer cells [2]. # ::save-date Wed Dec 9, 2015 ::file bio_bmtr_0005_20.txt (a / and :op2 (e / enhance-01 :ARG0 (i / interact-01 :ARG0 (a2 / and :op1 (e2 / enzyme :name (n / name :op1 "RAS")) :op2 (p / protein :name (n2 / name :op1 "ASPP")))) :ARG1 (f / function-01 :ARG0 (p2 / protein :name (n3 / name :op1 "p53")) :ARG1 (t / transcribe-01) :location (c2 / cell :mod (d2 / disease :wiki "Cancer" :name (n4 / name :op1 "cancer")))) :ARG1-of (d / describe-01 :ARG0 (p3 / publication :ARG1-of (c4 / cite-01 :ARG2 2))))) # ::id bio.bmtr_0005.21 ::date 2015-01-07T05:39:33 ::annotator SDL-AMR-09 ::preferred # ::snt Until now, it has been unclear how RAS could affect ASPP2 to enhance p53 function. # ::save-date Fri May 29, 2015 ::file bio_bmtr_0005_21.txt (c / clear-06 :polarity - :ARG1 (t / thing :manner-of (p / possible-01 :ARG1 (a / affect-01 :ARG0 (e / enzyme :name (n / name :op1 "RAS")) :ARG1 (p2 / protein :name (n3 / name :op1 "ASPP2")) :ARG2 (e2 / enhance-01 :ARG1 (f / function-01 :ARG0 (p3 / protein :name (n4 / name :op1 "p53"))))))) :time (u / until :op1 (n2 / now))) # ::id bio.bmtr_0005.22 ::date 2015-01-07T05:10:22 ::annotator SDL-AMR-09 ::preferred # ::snt We show here that ASPP2 is phosphorylated by the RAS/Raf/MAPK pathway and that this phosphorylation leads to its increased translocation to the cytosol/nucleus and increased binding to p53, providing an explanation of how RAS can activate p53 pro-apoptotic functions (Figure 5). # ::save-date Thu Jan 8, 2015 ::file bio_bmtr_0005_22.txt (s / show-01 :ARG0 (w / we) :ARG1 (p / phosphorylate-01 :ARG1 (p3 / protein :name (n2 / name :op1 "ASPP2")) :ARG2 (p2 / pathway :name (n / name :op1 "RAS/Raf/MAPK")) :ARG0-of (l / lead-03 :ARG2 (a / and :op1 (i / increase-01 :ARG1 (t / translocate-01 :ARG1 p3 :ARG2 (s2 / slash :op1 (c / cytosol) :op2 (n3 / nucleus)))) :op2 (i2 / increase-01 :ARG1 (b / bind-01 :ARG1 p3 :ARG2 (p4 / protein :name (n4 / name :op1 "p53")))))) :ARG0-of (e2 / explain-01 :ARG1 (p5 / possible-01 :ARG1 (a2 / activate-01 :ARG0 (e / enzyme :name (n5 / name :op1 "RAS")) :ARG1 (f / function-01 :ARG0 p4 :ARG1 (a3 / apoptosis :ARG1-of (f2 / favor-01)))))) :ARG1-of (d / describe-01 :ARG0 (f3 / figure :mod 5))) :location (h / here)) # ::id bio.bmtr_0005.23 ::date 2015-01-07T05:40:37 ::annotator SDL-AMR-09 ::preferred # ::snt Additionally, RAS/Raf/MAPK pathway activation stabilizes ASPP2 protein, although the underlying mechanism remains to be investigated. # ::save-date Thu Jan 8, 2015 ::file bio_bmtr_0005_23.txt (a / and :op2 (s / stabilize-01 :ARG0 (a2 / activate-01 :ARG1 (p / pathway :name (n / name :op1 "RAS/Raf/MAPK"))) :ARG1 (p2 / protein :name (n2 / name :op1 "ASPP2")) :concession (r / remain-01 :ARG1 (m / mechanism :ARG0-of (u / underlie-01 :ARG1 s)) :ARG3 (i / investigate-01 :ARG1 m)))) # ::id bio.chicago_2015.17089 ::date 2015-10-25T12:26:35 ::annotator SDL-AMR-09 ::preferred # ::snt The analogous result for PKC interaction with Par6 in the lower panel shows that, similarly to p62, Par6b binds to PKC only when the PKC OPCA motif is not mutated and the back of Par6b has the wild-type Lys 20. # ::save-date Sun Jan 17, 2016 ::file bio_chicago_2015_17089.txt (s / show-01 :ARG0 (t / thing :ARG2-of (r / result-01) :mod (a / analogous) :topic (i / interact-01 :ARG0 (e / enzyme :name (n / name :op1 "PKC")) :ARG1 (p2 / protein :name (n2 / name :op1 "Par6b"))) :location (p3 / panel :ARG1-of (l / low-04 :degree (m / more)))) :ARG1 (b / bind-01 :ARG0 p2 :ARG1 e :condition (a2 / and :op1 (m2 / mutate-01 :polarity - :ARG1 (m3 / motif :mod (p4 / protein-segment :name (n3 / name :op1 "OPCA") :part-of e))) :op2 (h / have-03 :ARG0 (b2 / back :poss p2) :ARG1 (a3 / amino-acid :mod 20 :name (n7 / name :op1 "lysine") :mod (w / wild-type)))) :mod (o / only) :ARG1-of (r2 / resemble-01 :ARG2 (p6 / protein :name (n6 / name :op1 "p62"))))) # ::id bio.chicago_2015.17091 ::date 2015-10-25T12:49:36 ::annotator SDL-AMR-09 ::preferred # ::snt A model is proposed in which endosomal Sca and Gp150 promote Notch activation in response to Delta, by regulating acquisition of insensitivity to Delta in a subset of cells. # ::save-date Sun Jan 17, 2016 ::file bio_chicago_2015_17091.txt (p / propose-01 :ARG1 (m / model :topic (p2 / promote-02 :ARG0 (a / and :op1 (p3 / protein :name (n / name :op1 "Sca")) :op2 (p4 / protein :name (n2 / name :op1 "Gp150")) :mod (e / endosomal)) :ARG1 (a2 / activate-01 :ARG1 (p5 / protein :name (n3 / name :op1 "Notch")) :ARG2-of (r / respond-01 :ARG1 (p6 / protein :name (n4 / name :op1 "Delta")))) :manner (r2 / regulate-01 :ARG1 (a3 / acquire-01 :ARG1 (s / sensitive-03 :polarity - :ARG0 p5 :ARG1 p6)) :location (s2 / subset :consist-of (c / cell)))))) # ::id bio.chicago_2015.17114 ::date 2015-10-25T12:59:51 ::annotator SDL-AMR-09 ::preferred # ::snt Because PLD activates PKC through the formation of diacylglycerol in VSMCs,47 PLD also may contribute to this suppression. # ::save-date Sun Jan 17, 2016 ::file bio_chicago_2015_17114.txt (c / cause-01 :ARG0 (a / activate-01 :ARG0 (e3 / enzyme :name (n / name :op1 "PLD")) :ARG1 (e2 / enzyme :name (n2 / name :op1 "PKC")) :manner (f / form-01 :ARG1 (e / enzyme :name (n3 / name :op1 "diacylglycerol")) :location (c2 / cell :name (n4 / name :op1 "VSMC"))) :ARG1-of (d2 / describe-01 :ARG0 (p4 / publication :ARG1-of (c4 / cite-01 :ARG2 47)))) :ARG1 (p3 / possible-01 :ARG1 (c3 / contribute-01 :ARG0 e3 :ARG1 (s / suppress-01 :mod (t / this))) :mod (a2 / also))) # ::id bio.chicago_2015.17152 ::date 2015-10-25T13:07:12 ::annotator SDL-AMR-09 ::preferred # ::snt Whether PKC regulation of DAT and other neurotransmitter transporters is due to direct phosphorylation of the transporter remains unclear. # ::save-date Sun Jan 17, 2016 ::file bio_chicago_2015_17152.txt (r / remain-01 :ARG1 (c2 / cause-01 :mode interrogative :ARG0 (p / phosphorylate-01 :ARG1 (m / molecular-physical-entity :ARG0-of (t2 / transport-01)) :ARG1-of (d / direct-02)) :ARG1 (r2 / regulate-01 :ARG0 (e / enzyme :name (n / name :op1 "PKC")) :ARG1 (a / and :op1 (p3 / protein :name (n2 / name :op1 "DAT")) :op2 (p4 / protein-family :name (n3 / name :op1 "neurotransmitter" :op2 "transporter") :mod (o / other))))) :ARG3 (c / clear-06 :polarity - :ARG1 c2)) # ::id bio.chicago_2015.17165 ::date 2015-10-25T13:24:48 ::annotator SDL-AMR-09 ::preferred # ::snt Venable et al. ( 66) also described an inhibition by ceramide of PLD stimulation by PKC, but ascribed this to an upstream effect on PKC rather than a decrease in the translocation to membranes. # ::save-date Sun Jan 17, 2016 ::file bio_chicago_2015_17165.txt (c2 / contrast-01 :ARG1 (d / describe-01 :ARG0 (p / publication-91 :ARG0 (a / and :op1 (p2 / person :name (n / name :op1 "Venable")) :op1 (p3 / person :mod (o / other))) :ARG1-of (c / cite-01 :ARG2 66)) :ARG1 (i / inhibit-01 :ARG0 (s2 / small-molecule :name (n2 / name :op1 "ceramide")) :ARG1 (s / stimulate-01 :ARG0 (e / enzyme :name (n4 / name :op1 "PKC")) :ARG1 (e2 / enzyme :name (n3 / name :op1 "PLD")))) :mod (a4 / also)) :ARG2 (a2 / ascribe-01 :ARG0 p :ARG1 i :ARG2 (a3 / affect-01 :ARG1 e :mod (u / upstream) :ARG1-of (i2 / instead-of-91 :ARG2 (d2 / decrease-01 :ARG1 (t2 / translocate-01 :ARG2 (m / membrane))))))) # ::id bio.chicago_2015.17176 ::date 2015-10-27T05:34:49 ::annotator SDL-AMR-09 ::preferred # ::snt dSir2 Interacts Genetically with Hairy Embryos derived from mothers transheterozygous for hairy and dSir2 mated to wild-type males exhibit moderate # ::save-date Sat Nov 14, 2015 ::file bio_chicago_2015_17176.txt (i / interact-01 :ARG0 (p / protein :name (n / name :op1 "dSir2")) :ARG1 (e / embryo :mod (p3 / protein :name (n2 / name :op1 "hairy")) :ARG1-of (d / derive-01 :ARG2 (p2 / person :ARG0-of (h2 / have-rel-role-91 :ARG2 (m / mother)) :mod (t / transheterozygous :topic (a / and :op1 p3 :op2 p)) :ARG1-of (m2 / mate-02 :ARG2 (m3 / male :mod (w / wild-type))) :ARG0-of (e2 / exhibit-01 :ARG1 (t2 / thing :ARG1-of (m4 / moderate-01)))))) :manner (g / genetic)) # ::id bio.chicago_2015.17177 ::date 2015-10-27T05:36:13 ::annotator SDL-AMR-09 ::preferred # ::snt We now report that, although PS1 mutations augment gamma-secretase cleavage at residue 42, they in fact suppress both S3-cleavage of Notch and epsilon-cleavage of APP near residue 50. # ::save-date Sun Jan 17, 2016 ::file bio_chicago_2015_17177.txt (r3 / report-01 :ARG0 (w / we) :ARG1 (s / suppress-01 :ARG0 m :ARG1 (a / and :op1 (c / cleave-01 :ARG1 (p3 / protein-segment :name (n / name :op1 "S3") :part-of (p / protein :name (n2 / name :op1 "Notch")) :ARG1-of (n5 / near-02 :ARG2 (r / residue :mod (a2 / amino-acid :mod 50))))) :op2 (c2 / cleave-01 :ARG1 (p4 / protein-segment :name (n4 / name :op1 "epsilon") :part-of (p2 / protein :name (n3 / name :op1 "APP")) :ARG1-of n5))) :mod (i / in-fact) :concession (a3 / augment-01 :ARG0 (m / mutate-01 :ARG1 (p5 / protein :name (n6 / name :op1 "PS1"))) :ARG1 (c3 / cleave-01 :ARG1 (r2 / residue :mod (a4 / amino-acid :mod 42 :part-of (e3 / enzyme :name (n7 / name :op1 "gamma-secretase"))))))) :time (n8 / now)) # ::id bio.chicago_2015.17180 ::date 2015-10-27T07:35:52 ::annotator SDL-AMR-09 ::preferred # ::snt At the nucleus, PKC betaII mediates direct phosphorylation of the nuclear envelope polypeptide lamin B on sites involved in mitotic nuclear lamina disassembly ( 12, 13, 15). # ::save-date Sat Nov 14, 2015 ::file bio_chicago_2015_17180.txt (m / mediate-01 :ARG0 (e / enzyme :name (n / name :op1 "PKC" :op2 "betaII")) :ARG1 (p2 / phosphorylate-01 :ARG1 (p3 / protein-segment :name (n2 / name :op1 "lamin" :op2 "B") :part-of (e2 / envelope :part-of n3)) :ARG1-of (d / direct-02) :location (s / site :ARG1-of (i / involve-01 :ARG2 (a / assemble-01 :polarity - :ARG1 (l / lamina :mod (m2 / mitosis) :part-of n3))))) :location (n3 / nucleus) :ARG1-of (d2 / describe-01 :ARG0 (p4 / publication :ARG1-of (c / cite-01 :ARG2 (a2 / and :op1 12 :op2 13 :op3 15))))) # ::id bio.chicago_2015.17227 ::date 2015-10-27T08:07:18 ::annotator SDL-AMR-09 ::preferred # ::snt At the nucleus, PKC betaII directly phosphorylates the nuclear envelope polypeptide lamin B at sites involved in mitotic nuclear lamina disassembly ( 8-10). # ::save-date Tue Oct 27, 2015 ::file bio_chicago_2015_17227.txt (p / phosphorylate-01 :ARG1 (p2 / protein-segment :name (n3 / name :op1 "lamin" :op2 "B") :part-of (e2 / envelope :part-of n2)) :ARG2 (e / enzyme :name (n / name :op1 "PKC" :op2 "betaII")) :manner (d / direct) :location (n2 / nucleus) :location (s / site :ARG1-of (i / involve-01 :ARG2 (a / assemble-01 :polarity - :ARG1 (l / lamina :part-of n2 :mod (m / mitosis))))) :ARG1-of (d2 / describe-01 :ARG0 (p3 / publication :ARG1-of (c / cite-01 :ARG2 (v / value-interval :op1 8 :op2 10))))) # ::id bio.chicago_2015.17275 ::date 2015-10-27T08:19:07 ::annotator SDL-AMR-09 ::preferred # ::snt To determine whether in vitro phosphorylation of fascin with PKC occurs at the same sites as observed in vivo, two-dimensional phosphopeptide mapping was performed. # ::save-date Sat Feb 13, 2016 ::file bio_chicago_2015_17275.txt (p2 / perform-02 :ARG1 (m / map-02 :ARG1 (s4 / small-molecule :name (n / name :op1 "phosphopeptide")) :manner (d / dimension :quant 2)) :purpose (d2 / determine-01 :ARG1 (p4 / phosphorylate-01 :mode interrogative :ARG1 (p5 / protein :name (n2 / name :op1 "fascin")) :ARG2 (e / enzyme :name (n3 / name :op1 "PKC")) :manner (i / in-vitro) :location (s / site :ARG1-of (s2 / same-01 :ARG2 (s3 / site :location-of p4 :ARG1-of (o2 / observe-01 :manner (i2 / in-vivo)))))))) # ::id bio.chicago_2015.17347 ::date 2015-10-27T08:45:34 ::annotator SDL-AMR-09 ::preferred # ::snt Dl then activates Notch (N) in the R4 precursor ( Cooper and Bray, 1999; Fanto and Mlodzik, 1999; Tomlinson and Struhl, 1999). # ::save-date Sat Nov 14, 2015 ::file bio_chicago_2015_17347.txt (a / activate-01 :ARG0 (p11 / protein :name (n9 / name :op1 "Dl")) :ARG1 (p / protein :name (n / name :op1 "Notch")) :location (c / cell :name (n2 / name :op1 "R4" :op2 "precursor")) :ARG1-of (d3 / describe-01 :ARG0 (a2 / and :op1 (p2 / publication-91 :ARG0 (a3 / and :op1 (p3 / person :name (n3 / name :op1 "Cooper")) :op2 (p4 / person :name (n4 / name :op1 "Bray"))) :time (d4 / date-entity :year 1999)) :op2 (p5 / publication-91 :ARG0 (a4 / and :op1 (p7 / person :name (n6 / name :op1 "Fanto")) :op2 (p6 / person :name (n5 / name :op1 "Mlodzik"))) :time d4) :op3 (p8 / publication-91 :ARG0 (a5 / and :op1 (p9 / person :name (n7 / name :op1 "Tomlinson")) :op2 (p10 / person :name (n8 / name :op1 "Struhl"))) :time d4))) :time (t / then)) # ::id bio.chicago_2015.17446 ::date 2015-10-27T09:03:36 ::annotator SDL-AMR-09 ::preferred # ::snt to prevent the additional stabilization of U2AF65 binding conferred by the interaction between U2AF35 and the AG dinucleotide. # ::save-date Thu Nov 12, 2015 ::file bio_chicago_2015_17446.txt (h / have-purpose-91 :ARG2 (p / prevent-01 :ARG1 (s / stabilize-01 :ARG1 (b / bind-01 :ARG1 (p2 / protein :name (n / name :op1 "U2AF65")) :ARG1-of (c / confer-02 :ARG0 (i / interact-01 :ARG0 (p3 / protein :name (n2 / name :op1 "U2AF35")) :ARG1 (d / dinucleotide :name (n3 / name :op1 "AG"))))) :mod (a / additional)))) # ::id bio.chicago_2015.17480 ::date 2015-10-27T09:19:04 ::annotator SDL-AMR-09 ::preferred # ::snt Axin mutants with C-terminal truncations lacked the ability to inhibit Lef-1 reporter activity, even though they bound GSK-3beta and beta-catenin. # ::save-date Sat Nov 14, 2015 ::file bio_chicago_2015_17480.txt (l / lack-01 :ARG0 (p2 / protein :name (n / name :op1 "Axin") :ARG2-of (m / mutate-01) :ARG0-of (h / have-03 :ARG1 (t / truncate-01 :ARG1 (p3 / protein-segment :name (n2 / name :op1 "C-terminus"))))) :ARG1 (c / capable-01 :ARG1 p2 :ARG2 (i / inhibit-01 :ARG0 p2 :ARG1 (a / activity-06 :ARG0 (m2 / molecular-physical-entity :ARG0-of (r2 / report-01 :ARG1 (p / protein :name (n3 / name :op1 "Lef-1"))))))) :concession (b / bind-01 :ARG1 p2 :ARG2 (a2 / and :op1 (e / enzyme :name (n4 / name :op1 "GSK-3beta")) :op2 (p4 / protein :name (n5 / name :op1 "beta-catenin"))))) # ::id bio.chicago_2015.17550 ::date 2015-10-27T14:46:47 ::annotator SDL-AMR-09 ::preferred # ::snt In vivo binding of GSK-3beta with Axin or beta-catenin. # ::save-date Tue Oct 27, 2015 ::file bio_chicago_2015_17550.txt (b / bind-01 :ARG1 (e / enzyme :name (n / name :op1 "GSK-3beta")) :ARG2 (o / or :op1 (p / protein :name (n2 / name :op1 "Axin")) :op2 (p2 / protein :name (n3 / name :op1 "beta-catenin"))) :manner (i / in-vivo)) # ::id bio.chicago_2015.17615 ::date 2015-10-27T14:48:22 ::annotator SDL-AMR-09 ::preferred # ::snt For some of these transcription factors, the domain that interacts with Groucho is mapped to a short peptide motif. # ::save-date Sat Nov 14, 2015 ::file bio_chicago_2015_17615.txt (m / map-02 :ARG1 (d / domain :ARG0-of (i / interact-01 :ARG1 (p / protein :name (n / name :op1 "Groucho"))) :part-of f) :ARG2 (m2 / motif :part-of (p2 / peptide :ARG1-of (s / short-07))) :beneficiary (f / factor :ARG0-of (t / transcribe-01) :quant (s2 / some) :mod (t2 / this))) # ::id bio.chicago_2015.17655 ::date 2015-10-27T15:27:57 ::annotator SDL-AMR-09 ::preferred # ::snt We may conclude that GAGA factor binds to ( CT) n repeats independently of TBP binding and facilitates binding of the latter directly or indirectly. # ::save-date Sat Nov 14, 2015 ::file bio_chicago_2015_17655.txt (p / possible-01 :ARG1 (c / conclude-01 :ARG0 (w / we) :ARG1 (a / and :op1 (b / bind-01 :ARG1 (p2 / protein :name (n / name :op1 "GAGA" :op2 "factor")) :ARG2 (p3 / protein :name (n2 / name :op1 "(CT)n" :op2 "repeat")) :ARG0-of (d / depend-01 :polarity - :ARG1 (b2 / bind-01 :ARG1 (p4 / protein :name (n3 / name :op1 "TBP"))))) :op2 (f / facilitate-01 :ARG0 p2 :ARG1 (b3 / bind-01 :ARG1 p4 :ARG1-of (d2 / direct-02) :ARG1-of (d3 / direct-02 :polarity -)))))) # ::id bio.chicago_2015.17666 ::date 2015-10-27T15:29:09 ::annotator SDL-AMR-09 ::preferred # ::snt As - catenin interacts with transcription factors of the LEF/ TCF family to regulate target gene expression, this raises the possibility that nuclear events of Wnt/ - catenin signaling are involved in regulating convergent extension. # ::save-date Fri Feb 5, 2016 ::file bio_chicago_2015_17666.txt (i / interact-01 :ARG0 (p / protein :name (n / name :op1 "beta-catenin")) :ARG1 (f / factor :ARG0-of (t / transcribe-01) :part-of (p2 / protein-family :name (n2 / name :op1 "LEF" :op2 "TCF"))) :ARG2 (r / regulate-01 :ARG0 p :ARG1 (e / express-03 :ARG1 (g / gene :ARG1-of (t2 / target-01)))) :ARG0-of (r2 / raise-01 :ARG1 (p3 / possible-01 :ARG1 (i2 / involve-01 :ARG1 (e2 / event :location (n3 / nucleus) :ARG1-of (c / cause-01 :ARG0 (s / signal-07 :ARG0 (p4 / pathway :name (n4 / name :op1 "Wnt/beta-catenin"))))) :ARG2 (r3 / regulate-01 :ARG0 e2 :ARG1 (e3 / extend-01 :ARG0-of (c2 / converge-01))))))) # ::id bio.chicago_2015.17703 ::date 2015-10-27T15:29:27 ::annotator SDL-AMR-09 ::preferred # ::snt We believe that it represents an unlikely scenario as we have shown that a PS1 allele defective in beta-catenin binding, while retaining full Notch processing activity, cannot suppress the elevated beta-catenin signaling caused by PS1 deficiency (Fig. 4). # ::save-date Sun Jan 17, 2016 ::file bio_chicago_2015_17703.txt (b / believe-01 :ARG0 (w2 / we) :ARG1 (r / represent-01 :ARG1 (i / it) :ARG2 (s / scenario :ARG1-of (l / likely-01 :polarity -))) :ARG1-of (c / cause-01 :ARG0 (s2 / show-01 :ARG0 w2 :ARG1 (p / possible-01 :polarity - :ARG1 (s3 / suppress-01 :ARG0 (p5 / protein :name (n / name :op1 "PS1") :mod (d / defective) :ARG1-of (b2 / bind-01 :ARG2 (p2 / protein :name (n2 / name :op1 "beta-catenin"))) :ARG2-of (m / mutate-01)) :ARG1 (s4 / signal-07 :ARG0 p2 :ARG1-of (e / elevate-01) :ARG1-of (c2 / cause-01 :ARG0 (l2 / lack-01 :ARG1 p5))) :concession (r2 / retain-01 :ARG0 p5 :ARG1 (a2 / activity-06 :ARG1 (p3 / process-01 :ARG0 p5 :ARG1 (p4 / protein :name (n3 / name :op1 "Notch"))) :mod (f / full))))))) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure :mod 4))) # ::id bio.chicago_2015.17707 ::date 2015-10-27T15:29:36 ::annotator SDL-AMR-09 ::preferred # ::snt CKI did not phosphorylate GSK3beta, B56alpha, or beta-TrCP. # ::save-date Wed Oct 28, 2015 ::file bio_chicago_2015_17707.txt (p / phosphorylate-01 :polarity - :ARG1 (o / or :op1 (e2 / enzyme :name (n2 / name :op1 "GSK3beta")) :op2 (e3 / enzyme :name (n3 / name :op1 "B56alpha")) :op2 (p2 / protein :name (n4 / name :op1 "beta-TrCP"))) :ARG2 (e / enzyme :name (n / name :op1 "CKI"))) # ::id bio.chicago_2015.17718 ::date 2015-10-28T00:35:29 ::annotator SDL-AMR-09 ::preferred # ::snt Because the mutations in PS1 apparently inhibit transcriptional activity of beta-catenin downstream of GSK 3beta, we hypothesized that PS1 may be interacting with the binding partner of beta-catenin, namely hTcf-4. # ::save-date Sat Nov 14, 2015 ::file bio_chicago_2015_17718.txt (h / hypothesize-01 :ARG0 (w / we) :ARG1 (p / possible-01 :ARG1 (i / interact-01 :ARG0 (p4 / protein :name (n / name :op1 "PS1")) :ARG1 (p2 / partner :ARG1-of (b / bind-01 :ARG2 (p3 / protein :name (n2 / name :op1 "beta-catenin"))) :ARG1-of (m / mean-01 :ARG2 (p5 / protein :name (n3 / name :op1 "hTcf-4")))))) :ARG1-of (c / cause-01 :ARG0 (i2 / inhibit-01 :ARG0 (m2 / mutate-01 :ARG1 p4) :ARG1 (a3 / activity-06 :ARG0 p3 :ARG1 (t2 / transcribe-01) :location (r / relative-position :op1 (e / enzyme :name (n5 / name :op1 "GSK3" :op2 "beta")) :direction (d2 / downstream))) :ARG1-of (a / appear-02)))) # ::id bio.chicago_2015.17743 ::date 2015-10-28T00:41:06 ::annotator SDL-AMR-09 ::preferred # ::snt Currently, a link between MAPK activation and the phosphorylation and activation of transcription factors involved in proliferation and cell growth is established by the finding that MAPK activates p90 ribosomal S6 kinase (p90RSK; De Cesare et al., 1998 ; Frodin and Gammeltoft, 1999 ; Smith et al. 1999 ). # ::save-date Sun Jan 17, 2016 ::file bio_chicago_2015_17743.txt (e / establish-01 :ARG0 (f / find-01 :ARG1 (a / activate-01 :ARG0 (e2 / enzyme :name (n2 / name :op1 "MAPK")) :ARG1 (e3 / enzyme :name (n3 / name :op1 "p90" :op2 "ribosomal" :op3 "S6" :op4 "kinase")))) :ARG1 (l / link-01 :ARG1 (a2 / activate-01 :ARG0 e2) :ARG2 (a3 / and :op1 (p3 / phosphorylate-01 :ARG1 (f2 / factor :ARG0-of (t / transcribe-01) :ARG1-of (i / involve-01 :ARG2 (a5 / and :op1 (p4 / proliferate-01) :op2 (g / grow-01 :ARG1 (c / cell)))))) :op2 (a4 / activate-01 :ARG1 f2))) :ARG1-of (d3 / describe-01 :ARG0 (a6 / and :op1 (p5 / publication-91 :ARG0 (a7 / and :op1 (p6 / person :name (n4 / name :op1 "De" :op2 "Cesare")) :op2 (p7 / person :mod (o / other))) :time (d4 / date-entity :year 1998)) :op2 (p8 / publication-91 :ARG0 (a8 / and :op1 (p9 / person :name (n5 / name :op1 "Frodin")) :op2 (p10 / person :name (n6 / name :op1 "Gammeltoft"))) :time (d5 / date-entity :year 1999)) :op3 (p11 / publication-91 :ARG0 (a9 / and :op1 (p12 / person :name (n7 / name :op1 "Smith")) :op2 (p13 / person :mod (o2 / other))) :time d5))) :time (c2 / current)) # ::id bio.chicago_2015.17757 ::date 2015-10-28T01:04:42 ::annotator SDL-AMR-09 ::preferred # ::snt These results suggest that CBP can bind to various transcription factors of the ATF/ CREB family through the b-ZIP domain. # ::save-date Thu Nov 12, 2015 ::file bio_chicago_2015_17757.txt (s / suggest-01 :ARG0 (t / thing :ARG2-of (r / result-01) :mod (t3 / this)) :ARG1 (p / possible-01 :ARG1 (b / bind-01 :ARG1 (p2 / protein :name (n / name :op1 "CBP")) :ARG2 (f / factor :ARG0-of (t2 / transcribe-01) :part-of (p3 / protein-family :name (n2 / name :op1 "ATF" :op2 "CREB")) :mod (v / various)) :instrument (p4 / protein-segment :name (n3 / name :op1 "b-ZIP"))))) # ::id bio.chicago_2015.17801 ::date 2015-10-28T01:30:03 ::annotator SDL-AMR-09 ::preferred # ::snt GSK-3beta, glycogen synthase kinase 3beta; EC, embryonal carcinoma; RA, retinoic acid; DMEM, Dulbecco's modified Eagle's medium; FBS, fetal bovine serum; CM, conditioned medium; PBS, phosphate-buffered saline; RT, reverse transcriptase; PMSF, phenylmethylsulfonyl fluoride; MAP2, microtubule-associated protein 2; GFP, green fluorescence protein; EGFP, enhanced GFP; CMV, cytomegalovirus; Dox, doxycycline; Tcf/ LEF, T cell factor/ lymphoid enhancer factor; CKI, casein kinase I; dpc, days post-coitum; rtTA, reverse tetracycline controlled transactivator; ICAT, inhibitor of beta-catenin and Tcf-4. # ::save-date Sat Feb 13, 2016 ::file bio_chicago_2015_17801.txt (a / and :op1 (n19 / name :op1 "GSK-3beta" :ARG2-of (l / label-01 :ARG1 (e / enzyme :name (n / name :op1 "glycogen" :op2 "synthase" :op3 "kinase3" :op4 "beta")))) :op2 (n20 / name :op1 "EC" :ARG2-of (l2 / label-01 :ARG1 (m / medical-condition :name (n2 / name :op1 "carcinoma") :location (e4 / embryo)))) :op3 (n21 / name :op1 "RA" :ARG2-of (l3 / label-01 :ARG1 (p / protein :name (n17 / name :op1 "retinoic" :op2 "acid")))) :op4 (n22 / name :op1 "DMEM" :ARG2-of (l4 / label-01 :ARG1 (m21 / medium :poss (p3 / person :name (n3 / name :op1 "Eagle")) :ARG1-of (m22 / modify-01) :poss (p4 / person :name (n4 / name :op1 "Dulbecco"))))) :op5 (n23 / name :op1 "FBS" :ARG2-of (l5 / label-01 :ARG1 (s / serum :source (f2 / fetus :mod (b2 / bovine))))) :op6 (n24 / name :op1 "CM" :ARG2-of (l6 / label-01 :ARG1 (m23 / medium :ARG1-of (c4 / condition-01)))) :op7 (n25 / name :op1 "PBS" :ARG2-of (l7 / label-01 :ARG1 (s2 / saline :ARG1-of (b / buffer-01 :ARG0 (p5 / phosphate))))) :op8 (n26 / name :op1 "RT" :ARG2-of (l8 / label-01 :ARG1 (e5 / enzyme :name (n6 / name :op1 "reverse" :op2 "transcriptase")))) :op9 (n27 / name :op1 "PMSF" :ARG2-of (l9 / label-01 :ARG1 (s4 / small-molecule :name (n7 / name :op1 "phenylmethylsulfonyl" :op2 "fluoride")))) :op10 (n28 / name :op1 "MAP2" :ARG2-of (l10 / label-01 :ARG1 (p6 / protein :name (n8 / name :op1 "microtubule-associated" :op2 "protein" :op3 "2")))) :op11 (n29 / name :op1 "GFP" :ARG2-of (l11 / label-01 :ARG1 (p7 / protein :name (n9 / name :op1 "green" :op2 "fluorescence" :op3 "protein")))) :op12 (n30 / name :op1 "EGFP" :ARG2-of (l12 / label-01 :ARG1 (p8 / protein :name (n10 / name :op1 "GFP") :ARG1-of (e7 / enhance-01)))) :op13 (n31 / name :op1 "CMV" :ARG2-of (l13 / label-01 :ARG1 (c / cytomegalovirus))) :op14 (n32 / name :op1 "Dox" :ARG2-of (l14 / label-01 :ARG1 (s3 / small-molecule :name (n14 / name :op1 "doxycycline")))) :op15 (n33 / name :op1 "TcfLEF" :ARG2-of (l15 / label-01 :ARG1 (p9 / protein-family :name (n12 / name :op1 "T" :op2 "cell" :op3 "factor/" :op4 "lymphoid" :op5 "enhancer" :op6 "factor")))) :op16 (n34 / name :op1 "CKI" :ARG2-of (l16 / label-01 :ARG1 (e6 / enzyme :name (n13 / name :op1 "casein" :op2 "kinase" :op3 "I")))) :op17 (n35 / name :op1 "dpc" :ARG2-of (l17 / label-01 :ARG1 (m2 / multiple :op1 (t / temporal-quantity :quant 1 :unit (d / day)) :time (a3 / after :op1 (c5 / coitus))))) :op18 (n18 / name :op1 "rtTA" :ARG2-of (l18 / label-01 :ARG1 (p11 / protein :name (n15 / name :op1 "reverse" :op2 "tetracycline" :op3 "controlled" :op4 "transactivator")))) :op19 (n11 / name :op1 "ICAT" :ARG2-of (l19 / label-01 :ARG1 (m26 / molecular-physical-entity :ARG0-of (i / inhibit-01 :ARG1 (a2 / and :op1 (p12 / protein :name (n5 / name :op1 "beta-catenin")) :op2 (p13 / protein :name (n16 / name :op1 "Tcf-4")))))))) # ::id bio.chicago_2015.17831 ::date 2015-10-28T02:37:03 ::annotator SDL-AMR-09 ::preferred # ::snt The ability to form H-DNA cannot substitute for GAGA factor binding to the ( CT)n sequence. # ::save-date Thu Nov 12, 2015 ::file bio_chicago_2015_17831.txt (p / possible-01 :polarity - :ARG1 (s / substitute-01 :ARG1 (c / capable-01 :ARG2 (f / form-01 :ARG1 (n / nucleic-acid :name (n2 / name :op1 "H-DNA")))) :ARG2 (b / bind-01 :ARG1 (p2 / protein :name (n3 / name :op1 "GAGA" :op2 "factor")) :ARG2 (p3 / protein-segment :name (n4 / name :op1 "(CT)n" :op2 "sequence"))))) # ::id bio.chicago_2015.17892 ::date 2015-10-28T02:49:19 ::annotator SDL-AMR-09 ::preferred # ::snt Identification of the pathway directing TCF-1 import will be an important step in determining whether different mechanisms of LEF-1 and TCF-1 nuclear transport promote different LEF-1, TCF-1, and beta-catenin function. # ::save-date Thu Nov 12, 2015 ::file bio_chicago_2015_17892.txt (s / step-01 :ARG1 (i2 / identify-01 :ARG1 (p / pathway :ARG0-of (d4 / direct-01 :ARG1 (i3 / import-01 :ARG1 (p2 / protein :name (n / name :op1 "TCF-1")))))) :ARG2 (d / determine-01 :ARG1 (p3 / promote-01 :mode interrogative :ARG0 (m / mechanism :ARG1-of (d2 / differ-02) :instrument-of (t / transport-01 :ARG1 (a / and :op1 (p4 / protein :name (n3 / name :op1 "LEF-1")) :op2 p2) :ARG4 (n2 / nucleus))) :ARG1 (f / function-01 :ARG0 (a2 / and :op1 p4 :op2 p2 :op3 (p5 / protein :name (n4 / name :op1 "beta-catenin"))) :ARG1-of d2))) :mod (i / important)) # ::id bio.chicago_2015.17923 ::date 2015-10-28T03:02:13 ::annotator SDL-AMR-09 ::preferred # ::snt The role of other transcription factors that are regulated by PKA and that bind to the CRE of the fibronectin promoter, such as ATF-1 and ATF-2, may also be relevant to TGF-beta stimulation of fibronectin gene transcription. # ::save-date Sun Jan 17, 2016 ::file bio_chicago_2015_17923.txt (p / possible-01 :ARG1 (r / relevant-01 :ARG1 (r2 / role :poss (f / factor :ARG0-of (t / transcribe-01) :ARG1-of (r3 / regulate-01 :ARG0 (e / enzyme :name (n / name :op1 "PKA"))) :ARG1-of (b / bind-01 :ARG2 (e3 / enzyme :name (n2 / name :op1 "CRE") :part-of (m / molecular-physical-entity :ARG0-of (p2 / promote-01 :ARG1 (p3 / protein :name (n3 / name :op1 "fibronectin"))) :example (a / and :op1 (p4 / protein :name (n4 / name :op1 "ATF-1")) :op2 (p5 / protein :name (n5 / name :op1 "ATF-2")))))) :mod (o / other))) :ARG2 (s / stimulate-01 :ARG0 (p6 / protein :name (n6 / name :op1 "TGF-beta")) :ARG1 (t2 / transcribe-01 :ARG1 (g / gene :ARG0-of (e2 / encode-01 :ARG1 p3)))) :mod (a2 / also))) # ::id bio.chicago_2015.18003 ::date 2015-10-28T03:20:35 ::annotator SDL-AMR-09 ::preferred # ::snt LiCl Activates a Prosurvival Pathway through GSK-3beta Inhibition and Activation of beta-Catenincf-mediated Transcription-- To determine whether LiCl had an effect on GSK-3-mediated beta-catenin signaling, we used the pTopflash or pFopflash luciferase reporter plasmids. # ::save-date Sat Feb 13, 2016 ::file bio_chicago_2015_18003.txt (m / multi-sentence :snt1 (a / activate-01 :ARG0 (s3 / small-molecule :name (n / name :op1 "LiCl")) :ARG1 (p2 / pathway :ARG0-of (f / favor-01 :ARG1 (s2 / survive-01))) :manner (a2 / and :op1 (i / inhibit-01 :ARG1 (e / enzyme :name (n3 / name :op1 "GSK-3beta"))) :op2 (a3 / activate-01 :ARG1 (t / transcribe-01 :ARG1-of (m3 / mediate-01 :ARG0 (p3 / protein-family :name (n4 / name :op1 "beta-catenin/Tcf"))))))) :snt2 (u / use-01 :ARG0 (w / we) :ARG1 (o / or :op1 (d / dna-sequence :name (n5 / name :op1 "pTopflash" :op2 "plasmid") :ARG0-of (r2 / report-01 :ARG1 (e2 / enzyme :name (n7 / name :op1 "luciferase")))) :op2 (d2 / dna-sequence :name (n6 / name :op1 "pFopflash" :op2 "plasmid") :ARG0-of r2)) :purpose (d3 / determine-01 :mode interrogative :ARG0 w :ARG1 (s4 / small-molecule :name (n8 / name :op1 "LiCl") :ARG0-of (a4 / affect-01 :ARG1 (s / signal-07 :ARG0 (p4 / protein :name (n9 / name :op1 "beta-catenin")) :ARG1-of (m5 / mediate-01 :ARG0 (e3 / enzyme :name (n10 / name :op1 "GSK-3"))))))))) # ::id bio.chicago_2015.18005 ::date 2015-10-28T03:44:52 ::annotator SDL-AMR-09 ::preferred # ::snt ILK also appears to regulate muscle differentiation by activating Erk, which suppresses transcription factors required for myogenic differentiation ( Huang et al., 2000). # ::save-date Sat Jan 16, 2016 ::file bio_chicago_2015_18005.txt (a / appear-02 :ARG1 (r / regulate-01 :ARG0 (p2 / protein :name (n2 / name :op1 "ILK")) :ARG1 (d2 / differentiate-01 :ARG1 (m / muscle)) :manner (a2 / activate-01 :ARG0 p2 :ARG1 (e / enzyme :name (n4 / name :op1 "Erk") :ARG0-of (s / suppress-01 :ARG1 (f / factor :ARG0-of (t / transcribe-01) :ARG1-of (r2 / require-01 :ARG0 (d3 / differentiate-01 :mod (m2 / myogenic)))))))) :ARG1-of (d4 / describe-01 :ARG0 (p3 / publication-91 :ARG0 (a3 / and :op1 (p4 / person :name (n3 / name :op1 "Huang")) :op2 (p5 / person :mod (o / other))) :time (d5 / date-entity :year 2000))) :mod (a4 / also)) # ::id bio.chicago_2015.18031 ::date 2015-10-28T03:57:48 ::annotator SDL-AMR-09 ::preferred # ::snt This observation suggested that the 60-residue linker region may assist Ldb binding by LIM B in the 1m construct. # ::save-date Thu Nov 26, 2015 ::file bio_chicago_2015_18031.txt (s / suggest-01 :ARG0 (o / observe-01 :mod (t / this)) :ARG1 (p / possible-01 :ARG1 (a / assist-01 :ARG0 (r / region :ARG3-of (l / link-01 :ARG1 (r2 / residue :mod 60))) :ARG1 (b / bind-01 :ARG1 (p3 / protein :name (n2 / name :op1 "LIM" :op2 "B")) :ARG2 (p2 / protein :name (n / name :op1 "Ldb")) :location (c / construct :ARG1-of (l2 / label-01 :ARG2 (n3 / name :op1 "1m"))))))) # ::id bio.chicago_2015.18065 ::date 2015-10-28T04:11:05 ::annotator SDL-AMR-09 ::preferred # ::snt Again, Ser 5 phosphorylation of the CTD is seen at the promoter (Fig. 3, CTD-S5-P), whereas phosphorylation at Ser 2 increases as Pol II passes through the coding region (Fig. 3, CTD-S2-P). As seen with the ADH1 gene, levels of Ser 2 phosphorylation in coding regions increased in the fcp1 mutants. # ::save-date Thu Nov 26, 2015 ::file bio_chicago_2015_18065.txt (m / multi-sentence :snt1 (c / contrast-01 :ARG1 (s / see-01 :ARG1 (p2 / phosphorylate-01 :ARG1 (a / amino-acid :mod 5 :name (n / name :op1 "serine") :part-of (p3 / protein-segment :name (n2 / name :op1 "CTD"))) :ARG1-of (l2 / label-01 :ARG2 (n8 / name :op1 "CTD-S5-P"))) :location (m3 / molecular-physical-entity :ARG0-of (p4 / promote-01)) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod 3))) :ARG2 (i / increase-01 :ARG1 (p5 / phosphorylate-01 :ARG1 (a3 / amino-acid :mod 2 :name (n3 / name :op1 "serine")) :ARG1-of (l3 / label-01 :ARG2 (n9 / name :op1 "CTD-S2-P"))) :time (p6 / pass-08 :ARG0 (e / enzyme :name (n4 / name :op1 "Pol" :op2 "II")) :ARG1 (r / region :location-of (c3 / code-01))) :ARG1-of (d2 / describe-01 :ARG0 f)) :mod (a6 / again)) :snt2 (i2 / increase-01 :ARG1 (l / level :degree-of (p7 / phosphorylate-01 :ARG1 (a5 / amino-acid :mod 2 :name (n5 / name :op1 "serine")) :location (r2 / region :location-of (c5 / code-01)))) :location (g / gene :name (n6 / name :op1 "fcp1") :ARG2-of (m2 / mutate-01)) :ARG1-of (s2 / see-01 :topic (g2 / gene :name (n7 / name :op1 "ADH1"))))) # ::id bio.chicago_2015.18079 ::date 2015-10-28T04:55:26 ::annotator SDL-AMR-09 ::preferred # ::snt Thus, these results suggest that endogenous bHLH proteins bind to the E1 E-box and consequently activate GAP-43 promoter activity, an activity that is affected by the action of Id2. # ::save-date Thu Nov 12, 2015 ::file bio_chicago_2015_18079.txt (i / infer-01 :ARG1 (s / suggest-01 :ARG0 (t / thing :ARG2-of (r / result-01) :mod (t2 / this)) :ARG1 (a / and :op1 (b / bind-01 :ARG1 (p / protein :name (n / name :op1 "bHLH") :mod (e / endogenous)) :ARG2 (d / dna-sequence :name (n2 / name :op1 "E1" :op2 "E-box"))) :op2 (a2 / activate-01 :ARG0 p :ARG1 (a3 / activity-06 :ARG0 (m / molecular-physical-entity :ARG0-of (p2 / promote-01 :ARG1 (p3 / protein :name (n3 / name :op1 "GAP-43")))) :ARG1-of (a4 / affect-01 :ARG0 (a5 / act-02 :ARG0 (p4 / protein :name (n4 / name :op1 "Id2"))))))))) # ::id bio.chicago_2015.18091 ::date 2015-10-28T05:17:13 ::annotator SDL-AMR-09 ::preferred # ::snt Inhibition of GSK-3beta-dependent phosphorylation of Axin by Dvl. # ::save-date Wed Oct 28, 2015 ::file bio_chicago_2015_18091.txt (i / inhibit-01 :ARG1 (p2 / phosphorylate-01 :ARG1 (p / protein :name (n2 / name :op1 "Axin")) :ARG2 (p3 / protein :name (n3 / name :op1 "Dvl")) :ARG0-of (d / depend-01 :ARG1 (e / enzyme :name (n / name :op1 "GSK-3beta"))))) # ::id bio.chicago_2015.18127 ::date 2015-10-28T05:25:16 ::annotator SDL-AMR-09 ::preferred # ::snt Axin also blocks beta-catenin-mediated transcription in colon cancer cells that have a mutation in the adenomatous polyposis coli gene. # ::save-date Wed Dec 9, 2015 ::file bio_chicago_2015_18127.txt (b / block-01 :ARG0 (p / protein :name (n / name :op1 "Axin")) :ARG1 (t / transcribe-01 :ARG1-of (m2 / mediate-01 :ARG0 (p2 / protein :name (n2 / name :op1 "beta-catenin")))) :location (c / cell :poss-of (t2 / thing) :source (d / disease :wiki "Colorectal_cancer" :name (n4 / name :op1 "colon" :op2 "cancer")) :ARG2-of (m / mutate-01 :location (g / gene :name (n3 / name :op1 "adenomatous" :op2 "polyposis" :op3 "coli")))) :mod (a / also)) # ::id bio.chicago_2015.18130 ::date 2015-10-20T03:27:20 ::annotator SDL-AMR-09 ::preferred # ::snt Hemin treatment caused no reduction in cellular glutathione concentrations, indicating that the increased TRX expression was not due to oxidative stress. # ::save-date Thu Oct 29, 2015 ::file bio_chicago_2015_18130.txt (c / cause-01 :polarity - :ARG0 (t / treat-04 :ARG2 (s2 / small-molecule :name (n / name :op1 "hemin"))) :ARG1 (r / reduce-01 :ARG1 (c2 / concentrate-02 :ARG1 (e / enzyme :name (n2 / name :op1 "glutathione")) :mod (c3 / cell))) :ARG0-of (i / indicate-01 :ARG1 (c4 / cause-01 :polarity - :ARG0 (s / stress :mod (o / oxidative)) :ARG1 (e2 / express-03 :ARG1 (p / protein :name (n3 / name :op1 "TRX")) :ARG1-of (i2 / increase-01))))) # ::id bio.chicago_2015.18156 ::date 2015-10-20T09:26:53 ::annotator SDL-AMR-09 ::preferred # ::snt Upon CTD phosphorylation by TFIIH, RNA pol II dissociates from the initiation complex and leaves the promoter. # ::save-date Thu Oct 29, 2015 ::file bio_chicago_2015_18156.txt (a / and :op1 (d / dissociate-01 :ARG1 (e / enzyme :name (n / name :op1 "RNA" :op2 "pol" :op3 "II")) :ARG2 (c / complex :mod (i / initiate-01))) :op2 (l / leave-05 :ARG0 e :ARG1 (m / molecular-physical-entity :ARG0-of (p2 / promote-01))) :condition (p / phosphorylate-01 :ARG1 (p4 / protein-segment :name (n3 / name :op1 "C-terminus")) :ARG2 (p3 / protein :name (n2 / name :op1 "TFIIH")))) # ::id bio.chicago_2015.18159 ::date 2015-10-20T09:28:01 ::annotator SDL-AMR-09 ::preferred # ::snt This is supported by the in vitro observations that Dvl inhibits GSK-3beta-dependent phosphorylation of Axin, APC, and beta-catenin in the Axin complex, although the bindings of GSK-3beta, beta-catenin, and APC to Axin are not changed, and that Dvl does not affect GSK-3beta activity to phosphorylate the peptide substrate ( 22, 26). # ::save-date Fri Nov 27, 2015 ::file bio_chicago_2015_18159.txt (s / support-01 :ARG0 (o / observe-01 :ARG1 (a / and :op1 (h / have-concession-91 :ARG1 (i / inhibit-01 :ARG0 (p2 / protein :name (n / name :op1 "Dvl")) :ARG1 (p / phosphorylate-01 :ARG1 (a2 / and :op1 (p3 / protein :name (n2 / name :op1 "Axin")) :op2 (p4 / protein :name (n4 / name :op1 "APC")) :op3 (p5 / protein :name (n5 / name :op1 "beta-catenin")) :location (c2 / complex :mod p3)) :ARG0-of (d / depend-01 :ARG1 (e / enzyme :name (n3 / name :op1 "GSK-3beta"))))) :ARG2 (c / change-01 :polarity - :ARG1 (b / bind-01 :ARG1 (a3 / and :op1 e :op2 p5 :op3 p4) :ARG2 p3))) :op2 (a4 / affect-01 :polarity - :ARG0 p2 :ARG1 (a5 / activity-06 :ARG0 e :ARG1 (p6 / phosphorylate-01 :ARG1 (s2 / substrate :mod (p7 / peptide)) :ARG2 e)))) :manner (i2 / in-vitro)) :ARG1 (t / this) :ARG1-of (d2 / describe-01 :ARG0 (p8 / publication :ARG1-of (c3 / cite-01 :ARG2 (a6 / and :op1 22 :op2 26))))) # ::id bio.chicago_2015.18163 ::date 2015-10-21T09:20:17 ::annotator SDL-AMR-09 ::preferred # ::snt As demonstrated in Figure 5, B and C, in the absence of neurotrophins, DRG neurons derived from NF1-deficient embryos exhibit elevated erk phosphorylation levels that are comparable to wild-type neurons in the presence of NGF. # ::save-date Sat Jan 16, 2016 ::file bio_chicago_2015_18163.txt (e / exhibit-01 :ARG0 (n8 / neuron :ARG1-of (d / derive-01 :ARG2 (e2 / embryo :ARG0-of (l / lack-01 :ARG1 (p3 / protein :name (n3 / name :op1 "NF1"))))) :source (g / ganglion :mod (r / root) :mod (d3 / dorsal))) :ARG1 (l2 / level :degree-of (p4 / phosphorylate-01 :ARG1 (e4 / enzyme :name (n / name :op1 "ERK"))) :ARG1-of (e3 / elevate-01) :ARG1-of (c / comparable-03 :ARG2 (n4 / neuron :mod (w / wild-type) :condition (p5 / present-02 :ARG1 (p6 / protein :name (n5 / name :op1 "NGF")))))) :condition (a / absent-01 :ARG1 (e5 / enzyme :name (n6 / name :op1 "neurotrophin"))) :ARG1-of (d2 / demonstrate-01 :ARG0 (a2 / and :op1 (f / figure :mod "B") :op2 (f2 / figure :mod "C") :part-of (f3 / figure :mod 5)))) # ::id bio.chicago_2015.18186 ::date 2015-10-21T09:35:41 ::annotator SDL-AMR-09 ::preferred # ::snt This result suggests that Axin binding to both GSK-3beta and beta-catenin is necessary for inhibition of Lef-1 reporter gene transcription. # ::save-date Thu Oct 22, 2015 ::file bio_chicago_2015_18186.txt (s / suggest-01 :ARG0 (t / thing :ARG2-of (r2 / result-01) :mod (t2 / this)) :ARG1 (n2 / need-01 :ARG0 (i / inhibit-01 :ARG1 (t3 / transcribe-01 :ARG1 (g / gene :name (n / name :op1 "Lef-1") :ARG0-of (r / report-01)))) :ARG1 (b / bind-01 :ARG1 (p2 / protein :name (n3 / name :op1 "Axin")) :ARG2 (a / and :op1 (e / enzyme :name (n4 / name :op1 "GSK-3beta")) :op2 (p4 / protein :name (n5 / name :op1 "beta-catenin")))))) # ::id bio.chicago_2015.18196 ::date 2015-10-21T09:43:28 ::annotator SDL-AMR-09 ::preferred # ::snt The major region of phosphorylation of beta-catenin by CK2 is the central armadillo repeat domain, where carrier proteins like axin and the adenomatous polyposis coli gene product APC interact with beta-catenin. # ::save-date Fri Nov 27, 2015 ::file bio_chicago_2015_18196.txt (r2 / region :ARG1-of (m / major-02) :location-of (p / phosphorylate-01 :ARG1 (p2 / protein :name (n / name :op1 "beta-catenin")) :ARG2 (e / enzyme :name (n2 / name :op1 "CK2"))) :domain (p6 / protein-segment :name (n5 / name :op1 "central" :op2 "armadillo" :op3 "repeat") :location-of (i / interact-01 :ARG0 (p3 / protein :example (a2 / and :op1 (p4 / protein :name (n3 / name :op1 "axin")) :op2 (p5 / protein :name (n6 / name :op1 "APC") :ARG1-of (e2 / encode-01 :ARG0 (g / gene :name (n4 / name :op1 "adenomatous" :op2 "polyposis" :op3 "coli"))))) :mod (c / carrier)) :ARG1 p2))) # ::id bio.chicago_2015.18258 ::date 2015-10-21T09:55:48 ::annotator SDL-AMR-09 ::preferred # ::snt In contrast, the ATP binding-deficient, dominant-negative HA-MEKK1-K1255M reduced Axin activation of JNK by 3-fold, suggesting that MEKK1 acts in the same signaling pathway in Axin-mediated activation of JNK. # ::save-date Fri Feb 5, 2016 ::file bio_chicago_2015_18258.txt (c / contrast-01 :ARG2 (r / reduce-01 :ARG0 (e / enzyme :name (n / name :op1 "HA-MEKK1-K1255M") :ARG2-of (m2 / mutate-01 :mod "-/-" :ARG0-of (d / dominate-01)) :ARG0-of (l / lack-01 :ARG1 (b / bind-01 :ARG1 e :ARG2 (s / small-molecule :name (n5 / name :op1 "ATP"))))) :ARG1 (a / activate-01 :ARG0 (p / protein :name (n2 / name :op1 "Axin")) :ARG1 (e3 / enzyme :name (n3 / name :op1 "JNK"))) :ARG2 (p2 / product-of :op1 3) :ARG0-of (s4 / suggest-01 :ARG1 (a2 / act-02 :ARG0 (e2 / enzyme :name (n6 / name :op1 "MEKK1")) :location (p3 / pathway :ARG0-of (s2 / signal-07) :ARG1-of (s3 / same-01)) :topic (a3 / activate-01 :ARG1 e3 :ARG1-of (m / mediate-01 :ARG0 p)))))) # ::id bio.chicago_2015.18265 ::date 2015-10-21T10:13:09 ::annotator SDL-AMR-09 ::preferred # ::snt First, PR facilitates binding of NF1 by an ATP-dependent process that results in marked reduction of the linking number of chromosomal DNA. # ::save-date Sun Jan 17, 2016 ::file bio_chicago_2015_18265.txt (f / facilitate-01 :ARG0 (e / enzyme :name (n / name :op1 "PR")) :ARG1 (b / bind-01 :ARG0 (p3 / process-02 :ARG0-of (d / depend-01 :ARG1 (s / small-molecule :name (n3 / name :op1 "ATP"))) :ARG1-of (r / result-01 :ARG2 (r2 / reduce-01 :ARG1 (n4 / number :mod (l / link-01) :quant-of (n5 / nucleic-acid :name (n6 / name :op1 "DNA") :mod (c / chromosome))) :ARG2 (m / mark-01)))) :ARG1 (p2 / protein :name (n2 / name :op1 "NF1"))) :time (f2 / first)) # ::id bio.chicago_2015.18319 ::date 2015-10-21T10:22:56 ::annotator SDL-AMR-09 ::preferred # ::snt Axin is also phosphorylated by GSK-3beta and stabilized by its phosphorylation in contrast to beta-catenin ( 22), and the phosphorylation increases the binding of Axin to beta-catenin ( 23, 24). # ::save-date Thu Oct 29, 2015 ::file bio_chicago_2015_18319.txt (a / and :op1 (a2 / and :op1 (p2 / phosphorylate-01 :ARG1 (p3 / protein :name (n / name :op1 "Axin")) :ARG2 (e / enzyme :name (n2 / name :op1 "GSK-3beta"))) :op2 (s / stabilize-01 :ARG0 (p / phosphorylate-01 :ARG1 p3) :ARG1 p3) :mod (a3 / also) :ARG1-of (c / contrast-01 :ARG2 (p4 / protein :name (n3 / name :op1 "beta-catenin")) :ARG1-of (d / describe-01 :ARG0 (p5 / publication :ARG1-of (c2 / cite-01 :ARG2 22))))) :op2 (i / increase-01 :ARG0 p2 :ARG1 (b / bind-01 :ARG1 p3 :ARG2 p4) :ARG1-of (d2 / describe-01 :ARG0 (p7 / publication :ARG1-of (c3 / cite-01 :ARG2 (a4 / and :op1 23 :op2 24)))))) # ::id bio.chicago_2015.18396 ::date 2015-10-21T10:35:19 ::annotator SDL-AMR-09 ::preferred # ::snt Axin enhances the phosphorylation of beta-catenin by GSK-3beta by positioning GSK-3beta close to beta-catenin, resulting in the inhibition of the Wnt signaling pathway ( 32). # ::save-date Wed Oct 21, 2015 ::file bio_chicago_2015_18396.txt (e / enhance-01 :ARG0 (p2 / protein :name (n / name :op1 "Axin")) :ARG1 (p3 / phosphorylate-01 :ARG1 (p4 / protein :name (n2 / name :op1 "beta-catenin")) :ARG2 (e2 / enzyme :name (n3 / name :op1 "GSK-3beta"))) :manner (p5 / position-01 :ARG0 p2 :ARG1 e2 :ARG2 (c / close-10 :ARG1 e2 :ARG2 n2)) :ARG1-of (r / result-01 :ARG2 (i / inhibit-01 :ARG1 (p / pathway :name (n4 / name :op1 "Wnt") :ARG0-of (s / signal-07))) :ARG1-of (d / describe-01 :ARG0 (p6 / publication :ARG1-of (c2 / cite-01 :ARG2 32))))) # ::id bio.chicago_2015.18464 ::date 2015-10-21T10:41:59 ::annotator SDL-AMR-09 ::preferred # ::snt ( c) Axin inhibits secondary axis formation induced by CKI . # ::save-date Sun Jan 17, 2016 ::file bio_chicago_2015_18464.txt (i / inhibit-01 :li "c" :ARG0 (p / protein :name (n / name :op1 "Axin")) :ARG1 (f / form-01 :ARG1 (a / axis :mod (s / secondary)) :ARG2-of (i2 / induce-01 :ARG0 (e / enzyme :name (n2 / name :op1 "CKI"))))) # ::id bio.chicago_2015.18510 ::date 2015-10-21T10:44:36 ::annotator SDL-AMR-09 ::preferred # ::snt Full-length Axin did not activate TCF-dependent transcription, but unexpectedly, the introduction of L521P into full-length Myc- or Flag-tagged murine Axin [mFlagAx-(1-956)] transformed it into a transcriptional activator (Figure 5D). # ::save-date Fri Jan 15, 2016 ::file bio_chicago_2015_18510.txt (c / contrast-01 :ARG1 (a2 / activate-01 :polarity - :ARG0 (p / protein :name (n / name :op1 "Axin") :ARG1-of (l / long-03 :ARG1-of (f / full-09))) :ARG1 (t2 / transcribe-01 :ARG0-of (d / depend-01 :ARG1 (p2 / protein :name (n2 / name :op1 "TCF"))))) :ARG2 (t3 / transform-01 :ARG0 (i / introduce-02 :ARG1 (m / mutate-01 :ARG1 p :ARG2 (p3 / protein :name (n3 / name :op1 "L521P"))) :ARG2 (o / or :op1 (p4 / protein :name (n4 / name :op1 "Axin") :mod (m2 / murine) :ARG1-of (t4 / tag-01 :ARG0 (p7 / protein :name (n6 / name :op1 "Myc"))) :ARG1-of l) :op2 (p5 / protein :name (n5 / name :op1 "Axin") :ARG1-of (t5 / tag-01 :ARG0 (p6 / protein-segment :name (n7 / name :op1 "Flag"))) :mod m2 :ARG1-of l))) :ARG1 p :ARG2 (m3 / molecular-physical-entity :ARG0-of (a5 / activate-01 :ARG1 (t7 / transcribe-01))) :ARG1-of (e / expect-01 :polarity -)) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure :mod "5D"))) # ::id bio.chicago_2015.18552 ::date 2015-10-21T12:34:15 ::annotator SDL-AMR-09 ::preferred # ::snt These interactions are specific, because an E1A polypeptide that binds to the ASH1 binding region in dCBP blocks the GST-ASH1(47-456)- dCBP interaction more efficiently than an E1A-RG2 polypeptide that carries a mutation that reduces E1A binding to dCBP (Fig. 7E). # ::save-date Sun Jan 17, 2016 ::file bio_chicago_2015_18552.txt (s / specific-02 :ARG1 (i / interact-01 :mod (t / this)) :ARG1-of (c / cause-01 :ARG0 (b2 / block-01 :ARG0 (p / polypeptide :mod (p2 / protein :name (n / name :op1 "E1A")) :ARG1-of (b3 / bind-01 :ARG2 (r / region :location-of (b4 / bind-01 :ARG1 (e / enzyme :name (n2 / name :op1 "ASH1"))) :location (p3 / protein :name (n3 / name :op1 "dCBP"))))) :ARG1 (i2 / interact-01 :ARG0 (e2 / enzyme :name (n4 / name :op1 "GST")) :ARG1 (a / and :op1 (a2 / amino-acid :mod (v2 / value-interval :op1 47 :op2 456) :part-of e) :op2 p3)) :ARG1-of (e3 / efficient-01 :degree (m / more) :compared-to (p5 / polypeptide :mod (p6 / protein :name (n6 / name :op1 "E1A-RG2")) :ARG0-of (c2 / carry-01 :ARG1 (m2 / mutate-01 :ARG0-of (r2 / reduce-01 :ARG1 (b5 / bind-01 :ARG1 p2 :ARG2 p3)))))))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "7E"))) # ::id bio.chicago_2015.18587 ::date 2015-10-21T12:48:06 ::annotator SDL-AMR-09 ::preferred # ::snt The copurification suggested that BMP-1 and BMP-2 might physically interact, leading to the idea that Tolloid might increase DPP activity by proteolytically processing DPP precursors (Shimell et al., 1991 ; Childs and O'Connor, 1994 ; Finelli et al., 1994 ). # ::save-date Sun Nov 1, 2015 ::file bio_chicago_2015_18587.txt (s / suggest-01 :ARG0 (c / copurify-00) :ARG1 (p2 / possible-01 :ARG1 (i / interact-01 :ARG0 (p3 / protein :name (n / name :op1 "BMP-1")) :ARG1 (p4 / protein :name (n2 / name :op1 "BMP-2")) :manner (p5 / physical))) :ARG0-of (l / lead-03 :ARG2 (i2 / idea :topic (p6 / possible-01 :ARG1 (i3 / increase-01 :ARG0 (p7 / protein :name (n3 / name :op1 "Tolloid")) :ARG1 (a / activity-06 :ARG0 (p19 / protein :name (n4 / name :op1 "DPP"))) :manner (p8 / process-01 :ARG1 (p10 / precursor :mod p19) :manner (p9 / proteolytical)))))) :ARG1-of (d3 / describe-01 :ARG0 (a2 / and :op1 (p11 / publication-91 :ARG0 (a3 / and :op1 (p12 / person :name (n5 / name :op1 "Shimell")) :op2 (p13 / person :mod (o / other))) :time (d / date-entity :year 1991)) :op2 (p14 / publication-91 :ARG0 (a4 / and :op1 (p15 / person :name (n6 / name :op1 "Childs")) :op2 (p16 / person :name (n7 / name :op1 "O'Connor"))) :time (d2 / date-entity :year 1994)) :op3 (p / publication-91 :ARG0 (a5 / and :op1 (p17 / person :name (n8 / name :op1 "Finelli")) :op2 (p18 / person :mod (o2 / other))) :time d2)))) # ::id bio.chicago_2015.18599 ::date 2015-10-21T13:03:50 ::annotator SDL-AMR-09 ::preferred # ::snt Moreover ectopic expression of cyclin E does not activate E2F in the absence of cdk4 and cdk6 activity (Lukas et al., 1997 ). # ::save-date Sun Nov 1, 2015 ::file bio_chicago_2015_18599.txt (a2 / and :op2 (a / activate-01 :polarity - :ARG0 (e / express-03 :ARG2 (p / protein :name (n / name :op1 "cyclin" :op2 "E")) :mod (e2 / ectopic)) :ARG1 (p5 / protein :name (n2 / name :op1 "E2F")) :condition (a3 / absent-01 :ARG1 (a4 / activity-06 :ARG0 (a5 / and :op1 (e3 / enzyme :name (n3 / name :op1 "cdk4")) :op2 (e4 / enzyme :name (n4 / name :op1 "cdk6")))))) :ARG1-of (d2 / describe-01 :ARG0 (p2 / publication-91 :ARG0 (a6 / and :op1 (p3 / person :name (n5 / name :op1 "Lukas")) :op1 (p4 / person :mod (o / other))) :time (d / date-entity :year 1997)))) # ::id bio.chicago_2015.18617 ::date 2015-10-21T13:09:51 ::annotator SDL-AMR-09 ::preferred # ::snt DLT Interacts with CRB and NRX IV # ::save-date Sun Nov 1, 2015 ::file bio_chicago_2015_18617.txt (i / interact-01 :ARG0 (p / protein :name (n / name :op1 "DLT")) :ARG1 (a / and :op1 (p2 / protein :name (n2 / name :op1 "CRB")) :op2 (p3 / protein :name (n3 / name :op1 "NRX" :op2 "IV")))) # ::id bio.chicago_2015.18666 ::date 2015-10-20T09:27:46 ::annotator SDL-AMR-09 ::preferred # ::snt The negative regulation of brinker expression by Dpp signaling illustrates a significant element of regulatory versatility afforded by the use of a Type II, as compared with a Type I, switch mechanism. # ::save-date Sun Jan 17, 2016 ::file bio_chicago_2015_18666.txt (i / illustrate-01 :ARG0 (d / downregulate-01 :ARG1 (e / express-03 :ARG2 (p2 / protein :name (n3 / name :op1 "brinker"))) :ARG2 (s / signal-07 :ARG0 (p / pathway :name (n2 / name :op1 "Dpp")))) :ARG1 (e2 / element :ARG1-of (s2 / significant-02) :part-of (v / versatility :ARG0-of (r2 / regulate-01) :ARG1-of (a / afford-02 :ARG0 (u / use-01 :ARG1 (m / mechanism :mod (s3 / switch-01) :ARG1-of (t / type-03 :ARG2 (s4 / string-entity :value "II")) :compared-to (m2 / mechanism :mod s3 :ARG1-of (t2 / type-03 :ARG2 (s5 / string-entity :value "I"))))))))) # ::id bio.chicago_2015.18675 ::date 2015-10-21T13:22:15 ::annotator SDL-AMR-09 ::preferred # ::snt Unlike known E2Fs, these E2F-like proteins efficiently bind E2F sites in the monomeric form but not as a heterodimer with DP proteins and repress E2F-regulated promoters. # ::save-date Sun Nov 1, 2015 ::file bio_chicago_2015_18675.txt (a / and :op1 (b / bind-01 :ARG1 (p / protein :ARG1-of (r2 / resemble-01 :ARG2 (p4 / protein-family :name (n / name :op1 "E2F"))) :ARG1-of (r5 / resemble-01 :polarity - :ARG2 (p5 / protein-family :name (n3 / name :op1 "E2F") :ARG1-of (k / know-01))) :mod (t2 / this)) :ARG2 (s / site :mod p4) :ARG1-of (e / efficient-01) :condition (c / contrast-01 :ARG1 (f / form :mod (m / monomer)) :ARG2 (h / heterodimer :polarity - :prep-with (p2 / protein :name (n2 / name :op1 "DP"))))) :op2 (r3 / repress-01 :ARG0 p :ARG1 (m2 / molecular-physical-entity :ARG0-of (p3 / promote-01) :ARG1-of (r4 / regulate-01 :ARG0 p4)))) # ::id bio.chicago_2015.18689 ::date 2015-10-21T13:36:50 ::annotator SDL-AMR-09 ::preferred # ::snt By definition, PLD catalyzes the hydrolysis of PC to PA and choline. # ::save-date Thu Oct 29, 2015 ::file bio_chicago_2015_18689.txt (c / catalyze-01 :ARG0 (e / enzyme :name (n / name :op1 "PLD")) :ARG1 (h / hydrolyze-01 :ARG1 (s / small-molecule :name (n2 / name :op1 "PC")) :ARG3 (a / and :op1 (s2 / small-molecule :name (n3 / name :op1 "PA")) :op2 (s3 / small-molecule :name (n4 / name :op1 "choline")))) :ARG1-of (d / define-01)) # ::id bio.chicago_2015.18690 ::date 2015-10-21T13:45:39 ::annotator SDL-AMR-09 ::preferred # ::snt Dephosphorylation of cyclin E by Cdc14 reverses the effects of the mitotic kinases and promotes cyclin E - Cdk2 binding to chromatin. # ::save-date Sun Nov 1, 2015 ::file bio_chicago_2015_18690.txt (a2 / and :op1 (r / reverse-01 :ARG0 (d / dephosphorylate-01 :ARG1 (p2 / protein :name (n2 / name :op1 "cyclin" :op2 "E")) :ARG2 (p / protein :name (n / name :op1 "Cdc14"))) :ARG1 (a / affect-01 :ARG0 (k / kinase :mod (m / mitosis)))) :op2 (p3 / promote-01 :ARG0 d :ARG1 (b / bind-01 :ARG1 (m2 / macro-molecular-complex :part p2 :part (e / enzyme :name (n3 / name :op1 "Cdk2"))) :ARG2 (m3 / macro-molecular-complex :name (n4 / name :op1 "chromatin"))))) # ::id bio.chicago_2015.18717 ::date 2015-10-22T08:52:41 ::annotator SDL-AMR-09 ::preferred # ::snt Our results demonstrate that the chromosome condensation defect caused by perturbed ISWI function is mediated through the NURF complex. # ::save-date Thu Oct 22, 2015 ::file bio_chicago_2015_18717.txt (d / demonstrate-01 :ARG0 (t / thing :ARG2-of (r / result-01) :poss (w / we)) :ARG1 (m / mediate-01 :ARG0 (m2 / macro-molecular-complex :name (n2 / name :op1 "NURF")) :ARG1 (d2 / defect :mod (c / condense-01 :ARG1 (c2 / chromosome)) :ARG1-of (c3 / cause-01 :ARG0 (f / function-01 :ARG0 (p / protein :name (n / name :op1 "ISWI")) :ARG1-of (p2 / perturb-01)))))) # ::id bio.chicago_2015.18724 ::date 2015-10-22T09:11:09 ::annotator SDL-AMR-09 ::preferred # ::snt The Essential Activity of DSmurf Is Limited to the DPP Signaling Pathway # ::save-date Sun Nov 1, 2015 ::file bio_chicago_2015_18724.txt (l / limit-01 :ARG1 (a / activity-06 :ARG0 (e2 / enzyme :name (n / name :op1 "DSmurf")) :mod (e / essential)) :ARG2 (p / pathway :name (n2 / name :op1 "DPP") :ARG0-of (s / signal-07))) # ::id bio.chicago_2015.18744 ::date 2015-10-22T09:17:29 ::annotator SDL-AMR-09 ::preferred # ::snt Alternatively, auxilin might bind much more weakly to Hsc70 in ADP than ATP. # ::save-date Thu Oct 22, 2015 ::file bio_chicago_2015_18744.txt (p2 / possible-01 :ARG1 (b / bind-01 :ARG1 (e / enzyme :name (n / name :op1 "auxilin")) :ARG2 (p3 / protein :name (n2 / name :op1 "Hsc70")) :ARG1-of (w / weak-02 :degree (m / more :quant (m2 / much))) :location (s / small-molecule :name (n3 / name :op1 "ADP")) :compared-to (b2 / bind-01 :ARG1 e :ARG2 p3 :location (s2 / small-molecule :name (n4 / name :op1 "ATP")))) :manner (a / alternative)) # ::id bio.chicago_2015.18747 ::date 2015-10-22T09:22:43 ::annotator SDL-AMR-09 ::preferred # ::snt Regulation of Dpp Targets by brinker. # ::save-date Sun Nov 1, 2015 ::file bio_chicago_2015_18747.txt (r / regulate-01 :ARG0 (p2 / protein :name (n2 / name :op1 "brinker")) :ARG1 (m / molecular-physical-entity :ARG1-of (t / target-01 :ARG0 (p / protein :name (n / name :op1 "Dpp"))))) # ::id bio.chicago_2015.18750 ::date 2015-10-22T09:25:20 ::annotator SDL-AMR-09 ::preferred # ::snt The only other known zinc finger-homeodomain cooperation is in Drosophila, where it was recently shown that the orphan nuclear receptor alphaFtz-F1 is a cofactor for the homeodomain protein Ftz (Guichet et al., 1997; Yu et al., 1997); in this case, the physical association between alphaFtz-F1 and Ftz is thought to enhance the binding of the Ftz to its lower-affinity target sequences (Guichet et al., 1997; Yu et al., 1997), much in the same way that Extradenticle and Pbx modulate the DNA binding activity of Hox proteins (Phelan et al., 1995; Lu and Kamps, 1996 ; Peltenburg and Murre, 1997 ). # ::save-date Sat Jan 30, 2016 ::file bio_chicago_2015_18750.txt (m / multi-sentence :snt1 (o / organism :wiki "Drosophila" :name (n / name :op1 "Drosophila") :location-of (c / cooperate-01 :ARG0 (p / protein :name (n2 / name :op1 "zinc" :op2 "finger")) :ARG1 (p23 / protein :name (n3 / name :op1 "homeodomain")) :ARG1-of (k / know-01) :mod (o2 / other) :mod (o3 / only)) :location-of (s / show-01 :ARG1 (c2 / cofactor :domain (r / receptor :name (n4 / name :op1 "alphaFtz-F1") :mod (n5 / nucleus) :mod (o4 / orphan)) :beneficiary (p4 / protein :name (n6 / name :op1 "Ftz") :mod p23)) :time (r2 / recent) :ARG1-of (d2 / describe-01 :ARG0 (a4 / and :op1 (p2 / publication-91 :ARG0 (a2 / and :op1 (p5 / person :name (n7 / name :op1 "Guichet")) :op2 (p6 / person :mod (o5 / other))) :time (d / date-entity :year 1997)) :op2 (p7 / publication-91 :ARG0 (a3 / and :op1 (p8 / person :name (n8 / name :op1 "Yu")) :op2 (p9 / person :mod (o6 / other))) :time d))))) :snt2 (t / think-01 :ARG1 (e / enhance-01 :ARG0 (a5 / associate-01 :ARG1 (r4 / receptor :name (n17 / name :op1 "alphaFtz-F1")) :ARG2 (p3 / protein :name (n18 / name :op1 "Ftz")) :mod (p10 / physical)) :ARG1 (b / bind-01 :ARG1 p3 :ARG2 (s2 / sequence :ARG1-of (t2 / target-01) :mod (a6 / affinity :ARG1-of (l / low-04 :degree (m2 / more))) :poss p3)) :ARG1-of (r3 / resemble-01 :ARG2 (m4 / modulate-01 :ARG0 (a7 / and :op1 (p11 / protein :name (n9 / name :op1 "Extradenticle")) :op2 (p12 / protein :name (n10 / name :op1 "Pbx"))) :ARG1 (a8 / activity-06 :ARG0 (p13 / protein-family :name (n11 / name :op1 "Hox")) :ARG1 (b2 / bind-01 :ARG2 (n21 / nucleic-acid :name (n22 / name :op1 "DNA")))) :ARG1-of (d8 / describe-01 :ARG0 (a9 / and :op1 (p14 / publication-91 :ARG0 (a10 / and :op1 (p15 / person :name (n12 / name :op1 "Phelan")) :op2 (p16 / person :mod (o7 / other))) :time (d9 / date-entity :year 1995)) :op2 (p17 / publication-91 :ARG0 (a11 / and :op1 (p18 / person :name (n13 / name :op1 "Lu")) :op2 (p19 / person :name (n14 / name :op1 "Kamps"))) :time (d10 / date-entity :year 1996)) :op3 (p20 / publication-91 :ARG0 (a12 / and :op1 (p21 / person :name (n15 / name :op1 "Peltenburg")) :op2 (p22 / person :name (n16 / name :op1 "Murre"))) :time (d11 / date-entity :year 1997))))) :degree (m3 / much))) :ARG1-of (d4 / describe-01 :ARG0 (a / and :op1 (p24 / publication-91 :ARG0 (a13 / and :op1 (p26 / person :name (n19 / name :op1 "Guichet")) :op2 (p29 / person :mod (o8 / other))) :time d11) :op2 (p25 / publication-91 :ARG0 (a14 / and :op1 (p27 / person :name (n20 / name :op1 "Yu")) :op2 (p28 / person :mod (o9 / other))) :time d11))) :mod (c3 / case-04 :ARG1 (t3 / this)))) # ::id bio.chicago_2015.18761 ::date 2015-10-22T09:59:43 ::annotator SDL-AMR-09 ::preferred # ::snt During gastrulation, DLT may first form a complex with CRB to target it to the apical domain. # ::save-date Sun Nov 1, 2015 ::file bio_chicago_2015_18761.txt (p / possible-01 :ARG1 (f / form-01 :ARG0 (a2 / and :op1 (p2 / protein :name (n / name :op1 "DLT")) :op2 (p3 / protein :name (n2 / name :op1 "CRB"))) :ARG1 (m / macro-molecular-complex) :purpose (t / target-01 :ARG0 p2 :ARG1 (d2 / domain :mod (a / apical)) :ARG2 p3) :time (f2 / first)) :time (g / gastrulate-00)) # ::id bio.chicago_2015.18776 ::date 2015-10-22T10:03:55 ::annotator SDL-AMR-09 ::preferred # ::snt We compared cdc25A induction to that of cyclin E, which is regulated by E2F and Rb family members ( 4, 20, 45). # ::save-date Sun Jan 17, 2016 ::file bio_chicago_2015_18776.txt (c / compare-01 :ARG0 (w / we) :ARG1 (i / induce-01 :ARG2 (e / enzyme :name (n / name :op1 "cdc25A"))) :ARG2 (i2 / induce-01 :ARG2 (p2 / protein :name (n2 / name :op1 "cyclin" :op2 "E")) :ARG1-of (r / regulate-01 :ARG0 (a / and :op1 (m / member :part-of (p3 / protein-family :name (n3 / name :op1 "E2F"))) :op2 (m2 / member :part-of (p4 / protein-family :name (n4 / name :op1 "Rb")))))) :ARG1-of (d / describe-01 :ARG0 (p5 / publication :ARG1-of (c2 / cite-01 :ARG2 (a2 / and :op1 4 :op2 20 :op3 45))))) # ::id bio.chicago_2015.18798 ::date 2015-10-22T10:18:54 ::annotator SDL-AMR-09 ::preferred # ::snt Furthermore, during early gastrulation, DLT normally colocalizes with CRB. # ::save-date Tue Feb 2, 2016 ::file bio_chicago_2015_18798.txt (a / and :op2 (c / colocalize-01 :ARG1 (a2 / and :op1 (p / protein :name (n / name :op1 "DLT")) :op2 (p2 / protein :name (n2 / name :op1 "CRB"))) :ARG1-of (n3 / normal-02) :time (g / gastrulate-00 :mod (e / early)))) # ::id bio.chicago_2015.18911 ::date 2015-10-22T10:26:00 ::annotator SDL-AMR-09 ::preferred # ::snt However, caldesmon together with TM completely inhibits actin binding of human fascin. # ::save-date Sun Nov 1, 2015 ::file bio_chicago_2015_18911.txt (c / contrast-01 :ARG2 (i / inhibit-01 :ARG0 (a / and :op1 (p / protein :name (n / name :op1 "caldesmon")) :op2 (p2 / protein :name (n2 / name :op1 "TM"))) :ARG1 (b / bind-01 :ARG1 (p3 / protein :name (n3 / name :op1 "actin")) :ARG2 (p4 / protein :name (n4 / name :op1 "fascin") :mod (h / human))) :ARG1-of (c2 / complete-02))) # ::id bio.chicago_2015.18974 ::date 2015-10-22T11:18:19 ::annotator SDL-AMR-09 ::preferred # ::snt Binding of filamin to actin bundles was determined in the absence of another ABP (curve 1, A,B) or in the presence of saturating quantities of calponin (curve 2, A) or - actinin (curve 2, B). # ::save-date Sun Nov 1, 2015 ::file bio_chicago_2015_18974.txt (d / determine-01 :ARG1 (b / bind-01 :ARG1 (p / protein :name (n / name :op1 "filamin")) :ARG2 (b2 / bundle :mod (p2 / protein :name (n2 / name :op1 "actin")))) :condition (o / or :op1 (a / absent-01 :ARG1 (p3 / protein :name (n3 / name :op1 "ABP") :mod (a2 / another)) :ARG1-of (d2 / describe-01 :ARG0 (a3 / and :op1 (f / figure :mod "A") :op2 (f2 / figure :mod "B") :part-of (f3 / figure :mod (c / curve :mod 1))))) :op2 (p4 / present-02 :ARG1 (q / quantity :ARG0-of (s / saturate-01 :ARG2 (o2 / or :op1 (p5 / protein :name (n4 / name :op1 "calponin") :ARG1-of (d3 / describe-01 :ARG0 (f4 / figure :mod "A" :part-of (f5 / figure :mod (c2 / curve :mod 2))))) :op2 (p6 / protein :name (n5 / name :op1 "actinin") :ARG1-of (d4 / describe-01 :ARG0 (f6 / figure :mod "B" :part-of f5))))))))) # ::id bio.chicago_2015.18987 ::date 2015-10-22T11:30:05 ::annotator SDL-AMR-09 ::preferred # ::snt During cell morphogenesis and motility, cells undergo extensive remodeling of the actin cytoskeleton, a phenomenon that is mediated by various actin-binding proteins ( 1). # ::save-date Sun Nov 1, 2015 ::file bio_chicago_2015_18987.txt (u / undergo-28 :ARG1 (c / cell) :ARG2 (r / remodel-01 :ARG1 (c2 / cytoskeleton :mod (p / protein :name (n / name :op1 "actin"))) :ARG1-of (e / extensive-03)) :time (a / and :op1 (m / motility :mod (c3 / cell)) :op2 (m2 / morphogenesis :mod c3)) :ARG1-of (m3 / mediate-01 :ARG0 (p3 / protein :ARG0-of (b / bind-01 :ARG1 p) :mod (v / various))) :ARG1-of (d / describe-01 :ARG0 (p4 / publication :ARG1-of (c4 / cite-01 :ARG2 1)))) # ::id bio.chicago_2015.19008 ::date 2015-10-22T11:34:00 ::annotator SDL-AMR-09 ::preferred # ::snt For instance, the proposed role of Grb2 in clathrin-independent endocytosis of EGFR (Yamazaki et al., 2002 ) may be related to the ability of Grb2 to mediate EGFR signaling to actin cytoskeleton # ::save-date Thu Oct 29, 2015 ::file bio_chicago_2015_19008.txt (p / possible-01 :ARG1 (r / relate-01 :ARG1 (r2 / role :ARG1-of (p2 / propose-01 :ARG1-of (d4 / describe-01 :ARG0 (p5 / publication-91 :ARG0 (a / and :op1 (p6 / person :name (n5 / name :op1 "Yamazaki")) :op2 (p7 / person :mod (o / other))) :time (d5 / date-entity :year 2002)))) :mod (p3 / protein :name (n2 / name :op1 "Grb2")) :topic (e3 / endocytosis :ARG0-of (d3 / depend-01 :polarity - :ARG1 (p4 / protein :name (n3 / name :op1 "clathrin"))) :mod (e4 / enzyme :name (n4 / name :op1 "EGFR")))) :ARG2 (c / capable-01 :ARG1 p3 :ARG2 (m / mediate-01 :ARG0 p3 :ARG1 (s / signal-07 :ARG1 e4 :ARG2 (c2 / cytoskeleton :mod (p8 / protein :name (n / name :op1 "actin"))))))) :ARG0-of (e / exemplify-01)) # ::id bio.chicago_2015.19022 ::date 2015-10-22T11:45:49 ::annotator SDL-AMR-09 ::preferred # ::snt We found that the overexpression of SH3PX1 alone did not significantly affect the EGF receptor levels through a 60-min exposure to EGF (Fig. 6, lanes 9-12, upper panel). # ::save-date Sun Jan 17, 2016 ::file bio_chicago_2015_19022.txt (f / find-01 :ARG0 (w / we) :ARG1 (a / affect-01 :polarity - :ARG1 (o / overexpress-01 :ARG1 (g / gene :name (n / name :op1 "SH3PX1")) :mod (a2 / alone)) :ARG2 (l / level :quant-of (e2 / enzyme :name (n3 / name :op1 "EGF" :op2 "receptor"))) :ARG1-of (s / significant-02) :time (e / expose-01 :ARG2 (r / receptor) :duration (t / temporal-quantity :quant 60 :unit (m / minute)))) :ARG1-of (d / describe-01 :ARG0 (l2 / lane :value (v / value-interval :op1 9 :op2 12) :part-of (f2 / figure :mod 6) :location (p / panel :ARG1-of (u / up-02 :degree (m2 / more)))))) # ::id bio.chicago_2015.19058 ::date 2015-10-20T05:40:46 ::annotator SDL-AMR-09 ::preferred # ::snt Overexpression of cdc5delta N induces a disturbance in septin ring structures and Cdc5 interacts with two septins, Cdc11 and Cdc12, in a polo-box - dependent manner. # ::save-date Sun Nov 8, 2015 ::file bio_chicago_2015_19058.txt (a / and :op1 (i / induce-01 :ARG0 (o / overexpress-01 :ARG1 (p3 / protein :name (n6 / name :op1 "cdc5" :op2 "delta" :op3 "N"))) :ARG2 (d / disturb-01 :ARG1 (s / structure-01 :ARG1 (r / ring :mod (p / protein-family :name (n2 / name :op1 "septin")))))) :op2 (i2 / interact-01 :ARG0 (p4 / protein :name (n3 / name :op1 "Cdc5")) :ARG1 (a2 / and :op1 (s2 / septin :name (n4 / name :op1 "Cdc11")) :op2 (s3 / septin :name (n5 / name :op1 "Cdc12"))) :ARG0-of (d3 / depend-01 :ARG1 (p2 / polo-box)))) # ::id bio.chicago_2015.19083 ::date 2015-10-20T06:32:06 ::annotator SDL-AMR-09 ::preferred # ::snt How the interactions of filamin with actin and transmembrane proteins are regulated is largely unknown. # ::save-date Mon Oct 26, 2015 ::file bio_chicago_2015_19083.txt (k / know-01 :polarity - :ARG1 (t2 / thing :manner-of (r / regulate-01 :ARG1 (i / interact-01 :ARG0 (p / protein :name (n / name :op1 "filamin")) :ARG1 (a / and :op1 (p2 / protein :name (n2 / name :op1 "actin")) :op2 (p3 / protein :mod (t / transmembrane)))))) :degree (l / large)) # ::id bio.chicago_2015.19095 ::date 2015-10-20T11:08:30 ::annotator SDL-AMR-09 ::preferred # ::snt P-TEFb may alter the role of Spt proteins either by phosphorylation of Pol II or Spt5 (Ivanov et al. 2000 ). # ::save-date Tue Oct 20, 2015 ::file bio_chicago_2015_19095.txt (p / possible-01 :ARG1 (a / alter-01 :ARG0 (p2 / protein :name (n / name :op1 "P-TEFb")) :ARG1 (r / role :poss (p3 / protein :name (n2 / name :op1 "Spt"))) :manner (p4 / phosphorylate-01 :ARG1 (o / or :op1 (e / enzyme :name (n3 / name :op1 "Pol" :op2 "II")) :op2 (p5 / protein :name (n4 / name :op1 "SPT5"))))) :ARG1-of (d / describe-01 :ARG0 (p6 / publication-91 :ARG0 (a2 / and :op1 (p7 / person :name (n5 / name :op1 "Ivanov")) :op2 (p8 / person :mod (o2 / other))) :time (d2 / date-entity :year 2000)))) # ::id bio.chicago_2015.19112 ::date 2015-10-20T11:57:48 ::annotator SDL-AMR-09 ::preferred # ::snt Site II seems to be generally less well conserved (for example, Arp1 and beta- and gamma-tubulin), and this may explain why these target proteins bind less well to prefoldin than actin and alpha-tubulin (see Fig. 4; the fragments of Arp1 and beta- and gamma-tubulin also show binding to CCT, whereas actin and alpha-tubulin do not). # ::save-date Sun Jan 17, 2016 ::file bio_chicago_2015_19112.txt (a2 / and :op1 (s / seem-01 :ARG1 (c / conserve-01 :ARG1 (s2 / site :mod 2 :example (a4 / and :op1 (p / protein :name (n / name :op1 "Arp1")) :op2 (a5 / and :op1 (p7 / protein :name (n5 / name :op1 "beta-tubulin")) :op2 (p8 / protein-family :name (n6 / name :op1 "gamma-tubulin"))))) :mod (w / well :degree (l / less)) :ARG1-of (g / general-02))) :op2 (p2 / possible-01 :ARG1 (e / explain-01 :ARG0 s :ARG1 (t4 / thing :ARG0-of (c2 / cause-01 :ARG1 (b / bind-01 :ARG1 (p3 / protein :ARG0-of (t / target-01) :mod (t2 / this)) :ARG2 (p4 / protein-family :name (n2 / name :op1 "prefoldin")) :mod (w2 / well :degree (l2 / less) :compared-to (a3 / and :op1 (p5 / protein :name (n3 / name :op1 "actin")) :op2 (p6 / protein :name (n4 / name :op1 "alpha-tubulin"))))))))) :ARG1-of (d / describe-01 :ARG2 (f / figure :mod 4 :ARG0-of (e2 / explain-01 :ARG1 (s3 / show-01 :ARG0 (f2 / fragment :part-of (a6 / and :op1 p :op2 a5)) :ARG1 (b2 / bind-01 :ARG1 (a7 / and :op1 p :op2 a5) :ARG2 (p9 / protein :name (n7 / name :op1 "CCT"))) :ARG1-of (c3 / contrast-01 :ARG2 (s4 / show-01 :polarity - :ARG0 (a8 / and :op1 p5 :op2 p6) :ARG1 b2)) :mod (a / also))) :ARG1-of (s5 / see-01 :mode imperative :ARG0 (y / you))))) # ::id bio.chicago_2015.19139 ::date 2015-10-20T14:25:08 ::annotator SDL-AMR-09 ::preferred # ::snt These functions of cadherin require intracellular attachment of cadherin to the actin cytoskeleton that is dependent on binding of cadherin to catenins (Hirano et al., 1987 ; Nagafuchi and Takeichi, 1988 ; Ozawa et al., 1990 ); beta-catenin mediates the linkage of cadherins to alpha-catenin, which in turn interacts with the actin cytoskeleton (Aberle et al., 1994 ; Hulsken et al., 1994 ; Jou et al., 1995 ; Rimm et al., 1995 ). # ::save-date Sun Jan 17, 2016 ::file bio_chicago_2015_19139.txt (m / multi-sentence :snt1 (r / require-01 :ARG0 (f / function-01 :ARG0 (p / protein-family :name (n / name :op1 "cadherin")) :mod (t / this)) :ARG1 (a / attach-01 :ARG1 p :ARG2 (c / cytoskeleton :mod (p2 / protein :name (n2 / name :op1 "actin")) :ARG0-of (d / depend-01 :ARG1 (b / bind-01 :ARG1 p :ARG2 (p3 / protein-family :name (n3 / name :op1 "catenin"))))) :mod (i3 / intracellular)) :ARG1-of (d2 / describe-01 :ARG0 (a2 / and :op1 (p4 / publication-91 :ARG0 (a3 / and :op1 (p5 / person :name (n4 / name :op1 "Hirano")) :op2 (p6 / person :mod (o / other))) :time (d3 / date-entity :year 1987)) :op2 (p7 / publication-91 :ARG0 (a4 / and :op1 (p8 / person :name (n5 / name :op1 "Nagafuchi")) :op2 (p9 / person :name (n6 / name :op1 "Takeichi"))) :time (d4 / date-entity :year 1988)) :op3 (p10 / publication-91 :ARG0 (a5 / and :op1 (p11 / person :name (n7 / name :op1 "Ozawa")) :op2 (p12 / person :mod (o2 / other))) :time (d5 / date-entity :year 1990))))) :snt2 (m2 / mediate-01 :ARG0 (p13 / protein :name (n8 / name :op1 "beta-catenin")) :ARG1 (l / link-01 :ARG1 (p14 / protein-family :name (n9 / name :op1 "cadherin")) :ARG2 (p15 / protein :name (n10 / name :op1 "alpha-catenin") :ARG0-of (i / interact-01 :ARG1 c :mod (i2 / in-turn)))) :ARG1-of (d6 / describe-01 :ARG0 (a6 / and :op1 (p16 / publication-91 :ARG0 (a7 / and :op1 (p17 / person :name (n11 / name :op1 "Aberle")) :op2 (p18 / person :mod (o3 / other))) :time d7) :op2 (p19 / publication-91 :ARG0 (a8 / and :op1 (p20 / person :name (n12 / name :op1 "Hulsken")) :op2 (p21 / person :mod (o4 / other))) :time (d7 / date-entity :year 1994)) :op3 (p22 / publication-91 :ARG0 (a9 / and :op1 (p23 / person :name (n13 / name :op1 "Jou")) :op2 (p24 / person :mod (o5 / other))) :time (d8 / date-entity :year 1995)) :op4 (p25 / publication-91 :ARG0 (a10 / and :op1 (p26 / person :name (n14 / name :op1 "Rimm")) :op2 (p27 / person :mod (o6 / other))) :time d8))))) # ::id bio.chicago_2015.19160 ::date 2015-10-20T15:07:36 ::annotator SDL-AMR-09 ::preferred # ::snt Other possibilities would be that actin promotes interaction of the BR particle with a fibrous network in the nucleoplasm, allows binding to export receptors (cf. ref. 52), or is involved in the dramatic conformational change of the particle upon translocation through the nuclear pore. # ::save-date Sun Nov 8, 2015 ::file bio_chicago_2015_19160.txt (p / possible-01 :ARG1 (o2 / or :op1 (p2 / promote-02 :ARG0 (p3 / protein :name (n / name :op1 "actin")) :ARG1 (i / interact-01 :ARG0 (p4 / particle :name (n2 / name :op1 "BR")) :ARG1 (n3 / network :mod (f / fibrous)) :location (n4 / nucleoplasm))) :op2 (a2 / allow-01 :ARG0 p3 :ARG1 (b / bind-01 :ARG2 (r / receptor :ARG0-of (e / export-01))) :ARG1-of (c / compare-01 :ARG2 (p5 / publication :ARG1-of (c2 / cite-01 :ARG2 52)))) :op3 (i2 / involve-01 :ARG1 p3 :ARG2 (c3 / change-01 :ARG1 p4 :degree (d / dramatic) :mod (c4 / conformational) :condition (t / translocate-01 :ARG1 p4 :path (p6 / pore :mod (n5 / nucleus)))))) :mod (o / other)) # ::id bio.chicago_2015.19248 ::date 2015-10-21T00:52:45 ::annotator SDL-AMR-09 ::preferred # ::snt 1) the MLC-pep blocks an interaction between vMLC-1 and actin, which releases a tethering effect that leads to the inotropic effect; 2) the MLC-pep blocks a site on myosin to which the vMLC-1 binds that disrupts myosin binding to actin; and 3) the MLC-pep exerts a direct effect on the actin-myosin interaction or actin-actin interactions in the presence of regulatory proteins and Ca2+, such that it cooperatively stimulates the entire thin filament. # ::save-date Sat Feb 13, 2016 ::file bio_chicago_2015_19248.txt (a / and :op1 (b / block-01 :li 1 :ARG0 (s / small-molecule :name (n / name :op1 "MLC-pep")) :ARG1 (i / interact-01 :ARG0 (p / protein :name (n2 / name :op1 "vMLC-1")) :ARG1 (p2 / protein :name (n3 / name :op1 "actin"))) :ARG0-of (r / release-01 :ARG1 (a2 / affect-01 :ARG0-of (t / tether-01) :ARG0-of (l / lead-03 :ARG2 (a3 / affect-01 :mod (i2 / inotropic)))))) :op2 (b2 / block-01 :li 2 :ARG0 s :ARG1 (s2 / site :part-of (p3 / protein :name (n4 / name :op1 "myosin")) :ARG2-of (b3 / bind-01 :ARG1 p)) :ARG0-of (d / disrupt-01 :ARG1 (b4 / bind-01 :ARG1 p3 :ARG2 p2))) :op3 (e / exert-01 :li 3 :ARG0 s :ARG1 (a4 / affect-01 :ARG1-of (d2 / direct-02)) :ARG2 (o / or :op1 (i3 / interact-01 :ARG0 p2 :ARG1 p3) :op2 (i4 / interact-01 :ARG0 p2 :ARG1 p2)) :condition (p4 / present-02 :ARG1 (a5 / and :op1 (p5 / protein :ARG0-of (r2 / regulate-01)) :op2 (s3 / small-molecule :name (n5 / name :op1 "calcium") :ARG0-of r2 :ARG1-of (i5 / ionize-01 :value "2+")))) :ARG0-of (c2 / cause-01 :ARG1 (s4 / stimulate-01 :ARG0 s :ARG1 (f / filament :mod (e2 / entire) :ARG1-of (t2 / thin-03)) :ARG2-of (c / cooperate-01))))) # ::id bio.chicago_2015.19251 ::date 2015-10-21T01:50:29 ::annotator SDL-AMR-09 ::preferred # ::snt In addition, in co-transfection experiments, Rlf (Zwartkruis et al., 1998 ), but apparently not RalGDS (Urano et al., 1996 ), can mediate Rap1- and C3G-induced Ral activation. # ::save-date Thu Dec 17, 2015 ::file bio_chicago_2015_19251.txt (a / and :op2 (c / contrast-01 :ARG1 (p / possible-01 :ARG1 (m / mediate-01 :ARG0 (e / enzyme :name (n / name :op1 "Rlf") :ARG1-of (d / describe-01 :ARG0 (p2 / publication-91 :ARG0 (a2 / and :op1 (p3 / person :name (n2 / name :op1 "Zwartkruis")) :op2 (p4 / person :mod (o / other))) :time (d4 / date-entity :year 1998)))) :ARG1 (a3 / activate-01 :ARG1 (p5 / protein :name (n3 / name :op1 "Ral")) :ARG2-of (i / induce-01 :ARG0 (a4 / and :op1 (e2 / enzyme :name (n4 / name :op1 "Rap1")) :op2 (s / small-molecule :name (n5 / name :op1 "C3G")))))) :time (e3 / experiment-01 :ARG2 (c2 / cotransfect-01))) :ARG2 (p6 / possible-01 :polarity - :ARG1 (m2 / mediate-01 :ARG0 (p7 / protein :name (n6 / name :op1 "RalGDS") :ARG1-of (d2 / describe-01 :ARG0 (p8 / publication-91 :ARG0 (a5 / and :op1 (p9 / person :name (n7 / name :op1 "Urano")) :op2 (p10 / person :mod (o2 / other))) :time (d3 / date-entity :year 1996)))) :ARG1 a3 :time e3) :ARG1-of (a6 / appear-02)))) # ::id bio.chicago_2015.19256 ::date 2015-10-21T02:14:06 ::annotator SDL-AMR-09 ::preferred # ::snt Towards the center of the gradient, high levels of Dpp signaling strongly repress brk transcription. # ::save-date Sun Jan 17, 2016 ::file bio_chicago_2015_19256.txt (r / repress-01 :ARG0 (l / level :ARG1-of (h / high-02) :degree-of (s / signal-07 :ARG0 (p / pathway :name (n / name :op1 "Dpp")))) :ARG1 (t / transcribe-01 :ARG0 (p2 / protein :name (n2 / name :op1 "brk"))) :direction (c / center :part-of (g2 / gradient)) :ARG1-of (s2 / strong-02)) # ::id bio.chicago_2015.19269 ::date 2015-10-21T02:29:26 ::annotator SDL-AMR-09 ::preferred # ::snt high amounts of Dpp signaling abolish brk transcription completely, intermediate amounts of Dpp only partially repress brk transcription, while the absence of Dpp results in high levels of brk transcription. # ::save-date Sun Jan 17, 2016 ::file bio_chicago_2015_19269.txt (c / contrast-01 :ARG1 (a / and :op1 (a2 / abolish-01 :ARG0 (a3 / amount :degree-of (s / signal-07 :ARG0 (p / pathway :name (n / name :op1 "Dpp"))) :ARG1-of (h3 / high-02)) :ARG1 (t / transcribe-01 :ARG0 (p3 / protein :name (n2 / name :op1 "brk"))) :ARG1-of (c2 / complete-02)) :op2 (r / repress-01 :ARG0 (a4 / amount :degree (i / intermediate) :quant-of p) :ARG1 t :degree (p4 / part :mod (o / only)))) :ARG2 (r2 / result-01 :ARG1 (a5 / absent-01 :ARG1 p) :ARG2 (l / level :quant-of t :ARG1-of h3))) # ::id bio.chicago_2015.19306 ::date 2015-10-21T03:50:36 ::annotator SDL-AMR-09 ::preferred # ::snt Dissected wing imaginal discs stained with antibodies against the beta-galactosidase and Engrailed proteins showing the induction and suppression of induction of Engrailed expression; anterior upward, wing pouch to the left. # ::save-date Wed Mar 2, 2016 ::file bio_chicago_2015_19306.txt (d3 / disc :ARG1-of (s / stain-01 :ARG2 (a2 / antibody :ARG0-of (o / oppose-01 :ARG1 (a3 / and :op1 (e2 / enzyme :name (n2 / name :op1 "beta-galactosidase")) :op2 (p2 / protein :name (n3 / name :op1 "Engrailed")))))) :ARG0-of (s2 / show-01 :ARG1 (a4 / and :op1 (i / induce-01 :ARG2 (e / express-03 :ARG2 p2)) :op2 (s3 / suppress-01 :ARG1 i))) :ARG1-of (d2 / describe-01 :medium (p / pouch :ARG1-of (l / left-20) :mod (a5 / anterior :direction (u / upward)) :mod (w2 / wing))) :mod (w / wing) :ARG1-of (d / dissect-01) :mod (i2 / imaginal)) # ::id bio.chicago_2015.19311 ::date 2015-10-21T13:44:06 ::annotator SDL-AMR-09 ::preferred # ::snt To identify the site(s) on the cytoplasmic domain of the EGFR that mediates its recruitment of PI3K-C2beta, a panel of receptor point mutations was expressed in HEK293 cells. # ::save-date Sun Nov 8, 2015 ::file bio_chicago_2015_19311.txt (e / express-03 :ARG2 (p / panel :consist-of (m / mutate-01 :ARG1 (p2 / point :mod (r / receptor)))) :ARG3 (c / cell :name (n / name :op1 "HEK293")) :purpose (i / identify-01 :ARG1 (s / site :location (d / domain :mod (c2 / cytoplasm) :part-of (e2 / enzyme :name (n2 / name :op1 "EGFR") :ARG0-of (m2 / mediate-01 :ARG1 (r2 / recruit-01 :ARG0 e2 :ARG1 (e3 / enzyme :name (n3 / name :op1 "PI3K-C2beta"))))))))) # ::id bio.chicago_2015.19345 ::date 2015-10-21T14:06:37 ::annotator SDL-AMR-09 ::preferred # ::snt Formation of sharp borders of Iro-C gene expression in response to localized EGFR signaling The lateral border delimiting Iro-C expression in the wing disc is relatively straight and sharp (e.g. Fig. 1B, Fig. 4C), raising the question of how such a well-defined border can be established and maintained in response to EGFR signaling. # ::save-date Thu Feb 4, 2016 ::file bio_chicago_2015_19345.txt (m / multi-sentence :snt1 (f / form-01 :ARG1 (b / border :ARG1-of (s / sharp-02) :poss (e / express-03 :ARG1 (g / gene :name (n / name :op1 "Iro-C")))) :ARG2-of (r / respond-01 :ARG1 (s2 / signal-07 :ARG0 (e2 / enzyme :name (n2 / name :op1 "EGFR")) :ARG1-of (l / local-02)))) :snt2 (a / and :op1 (s3 / straight-04 :ARG1 (b2 / border :mod (l2 / lateral) :ARG1-of (d / delimit-01 :ARG2 (e4 / express-03 :ARG1 (g2 / gene :name (n3 / name :op1 "Iro-C"))) :location (d2 / disc :topic (w / wing)))) :ARG2-of (r2 / relative-05)) :op2 (s4 / sharp-02 :ARG1 b2 :degree r2) :ARG1-of (d3 / describe-01 :ARG0 (a2 / and :op1 (f2 / figure :mod "1B") :op2 (f3 / figure :mod "4C"))) :ARG0-of (r3 / raise-01 :ARG1 (q / question-01 :ARG1 (t / thing :manner-of (e3 / establish-01 :ARG1 (b3 / border :ARG1-of (d4 / define-01 :manner (w2 / well) :mod (s6 / such))) :ARG2-of (r4 / respond-01 :ARG1 (s5 / signal-07 :ARG0 (e5 / enzyme :name (n4 / name :op1 "EGFR")))) :ARG1-of (p / possible-01)) :ARG0-of (m2 / maintain-01 :ARG1 b3 :ARG2-of r4)))))) # ::id bio.chicago_2015.19362 ::date 2015-10-21T14:50:57 ::annotator SDL-AMR-09 ::preferred # ::snt Ectopic Gem or Rad expression inhibits ROK-dependent functions such as formation of stress fibers and focal adhesions, neurite retraction, and Rho-dependent transformation. # ::save-date Sun Nov 8, 2015 ::file bio_chicago_2015_19362.txt (i / inhibit-01 :ARG0 (e / express-03 :ARG2 (a / and :op1 (p / protein :name (n / name :op1 "Gem")) :op2 (p2 / protein :name (n2 / name :op1 "Rad")) :mod (e2 / ectopic))) :ARG1 (f / function-01 :ARG0-of (d / depend-01 :ARG1 (p3 / protein :name (n3 / name :op1 "ROK"))) :example (a2 / and :op1 (f2 / form-01 :ARG1 (a3 / and :op1 (f3 / fiber :mod (s / stress)) :op2 (a4 / adhere-01 :mod (f4 / focal)))) :op2 (r / retract-01 :ARG1 (c / cell :name (n4 / name :op1 "neurite"))) :op3 (t / transform-01 :ARG0-of (d2 / depend-01 :ARG1 (p4 / protein-family :name (n5 / name :op1 "Rho"))))))) # ::id bio.mskcc_0001.1 ::date 2014-11-03T12:55:43 ::annotator SDL-AMR-09 ::preferred # ::snt We identify four S/TP sites of B-Raf phosphorylated by activated ERK and find that feedback phosphorylation of B-Raf inhibits binding to activated Ras and disrupts heterodimerization with C-Raf, which is dependent on the B-Raf pS729/14-3-3 binding site. # ::save-date Wed Dec 10, 2014 ::file bio_mskcc_0001_1.txt (a / and :op1 (i / identify-01 :ARG0 (w / we) :ARG1 (p / protein-segment :quant 4 :part (a5 / amino-acid :ARG3-of (p2 / phosphorylate-01 :ARG2 (e / enzyme :name (n3 / name :op1 "ERK") :ARG1-of (a2 / activate-01)) :subevent-of (f2 / feedback)) :mod (o / or :op1 (a6 / amino-acid :name (n / name :op1 "serine")) :op2 (a7 / amino-acid :name (n9 / name :op1 "threonine")))) :part-of (e4 / enzyme :name (n2 / name :op1 "B-Raf")))) :op2 (f / find-01 :ARG0 w :ARG1 (a3 / and :op1 (i2 / inhibit-01 :ARG0 p2 :ARG1 (b / bind-01 :ARG1 e4 :ARG2 (e3 / enzyme :name (n4 / name :op1 "Ras") :ARG1-of (a4 / activate-01)))) :op2 (d / disrupt-01 :ARG0 p2 :ARG1 (h / heterodimerize-01 :ARG1 e4 :ARG2 (e2 / enzyme :name (n5 / name :op1 "C-Raf")) :ARG0-of (d2 / depend-01 :ARG1 (a8 / amino-acid :mod 729 :name (n10 / name :op1 "serine") :ARG3-of (p4 / phosphorylate-01) :ARG1-of (b2 / bind-01 :ARG2 (p3 / protein :name (n6 / name :op1 "14-3-3"))) :part-of e4))))))) # ::id bio.mskcc_0001.2 ::date 2014-11-03T19:18:55 ::annotator SDL-AMR-09 ::preferred # ::snt 14-3-3 dimers bind to phosphorylation sites present in both the N- and C-terminal regions and stabilize the autoinhibited state (22). # ::save-date Fri Jan 1, 2016 ::file bio_mskcc_0001_2.txt (a / and :op1 (b / bind-01 :ARG1 (d / dimer :part (p5 / protein :name (n / name :op1 "14-3-3"))) :ARG2 (p9 / protein-segment :ARG1-of (p / phosphorylate-01) :ARG1-of (p11 / present-02 :ARG2 (p2 / protein-segment :name (n2 / name :op1 "N-terminus"))))) :op2 (b2 / bind-01 :ARG1 d :ARG2 (p10 / protein-segment :ARG1-of (p3 / phosphorylate-01) :ARG1-of (p12 / present-02 :ARG2 (p4 / protein-segment :name (n3 / name :op1 "C-terminus"))))) :op3 (s3 / stabilize-01 :ARG0 d :ARG1 (i / inhibit-01 :ARG0 p5 :ARG1 p5)) :ARG1-of (d2 / describe-01 :ARG0 (p8 / publication :ARG1-of (c / cite-01 :ARG2 22)))) # ::id bio.mskcc_0001.3 ::date 2014-11-03T19:35:08 ::annotator SDL-AMR-09 ::preferred # ::snt To activate the Raf proteins, autoinhibition mediated by the N terminus must be relieved and the kinase domain must adopt the active catalytic conformation # ::save-date Fri Jan 1, 2016 ::file bio_mskcc_0001_3.txt (r / require-01 :ARG0 (a / activate-01 :ARG1 (p / protein-family :name (n / name :op1 "Raf"))) :ARG1 (a2 / and :op1 (o / obligate-01 :ARG2 (r2 / relieve-01 :ARG1 (i / inhibit-01 :ARG0 (p2 / protein-segment :part-of p) :ARG1 (p3 / protein-segment :part-of p) :ARG1-of (m / mediate-01 :ARG0 (p5 / protein-segment :name (n2 / name :op1 "N-terminus") :part-of p))))) :op2 (o2 / obligate-01 :ARG2 (a3 / activate-01 :ARG1 (d / domain :mod (k / kinase) :part-of p :ARG0-of (c / catalyze-01)))))) # ::id bio.mskcc_0001.4 ::date 2014-11-03T20:16:00 ::annotator SDL-AMR-09 ::preferred # ::snt Under normal signaling conditions, Ras activation helps mediate these events by recruiting the Raf proteins to the plasma membrane, which induces the release of 14-3-3 from the N-terminal binding site and facilitates phosphorylation of the Raf kinase domain (19). # ::save-date Fri Jul 24, 2015 ::file bio_mskcc_0001_4.txt (h / help-01 :ARG0 (a / activate-01 :ARG1 (e3 / enzyme :name (n / name :op1 "Ras"))) :ARG1 (m / mediate-01 :ARG0 a :ARG1 (e / event :mod (t / this))) :manner (r / recruit-01 :ARG0 a :ARG1 (e2 / enzyme :name (n6 / name :op1 "Raf")) :destination (m2 / membrane :mod (p2 / plasma)) :ARG0-of (i / induce-01 :ARG2 (r2 / release-01 :ARG1 (p3 / protein :name (n2 / name :op1 "14-3-3")) :ARG2 (p8 / protein-segment :part-of (p4 / protein-segment :name (n3 / name :op1 "N-terminus")) :ARG1-of (b / bind-01)))) :ARG0-of (f / facilitate-01 :ARG1 (p5 / phosphorylate-01 :ARG1 (d / domain :mod (k / kinase) :part-of e2)))) :condition (n4 / normal-02 :ARG1 (s2 / signal-07 :ARG0 e3)) :ARG1-of (d2 / describe-01 :ARG0 (p6 / publication :ARG1-of (c / cite-01 :ARG2 19)))) # ::id bio.mskcc_0001.5 ::date 2014-11-03T20:23:34 ::annotator SDL-AMR-09 ::preferred # ::snt Once activated, either by upstream signaling or by mutational events, all Raf proteins are capable of initiating the phosphorylation cascade that results in the sequential activation of MEK and ERK. # ::save-date Sun Jan 17, 2016 ::file bio_mskcc_0001_5.txt (c / capable-01 :ARG1 (p / protein-family :name (n / name :op1 "Raf") :mod (a / all)) :ARG2 (i / initiate-01 :ARG0 p :ARG1 (c2 / cascade :subevent (p3 / phosphorylate-01) :ARG1-of (r / result-01 :ARG2 (a3 / and :op1 (a2 / activate-01 :ARG1 (e / enzyme :name (n2 / name :op1 "MEK"))) :op2 (a4 / activate-01 :ARG1 (e2 / enzyme :name (n3 / name :op1 "ERK")) :ARG2-of (f / follow-01 :ARG1 a2)))))) :time (a6 / activate-01 :ARG0 (o / or :op1 (s / signal-07 :source (u / upstream)) :op2 (m / mutate-01)) :ARG1 p)) # ::id bio.mskcc_0001.6 ::date 2014-11-03T20:34:01 ::annotator SDL-AMR-09 ::preferred # ::snt Strikingly, the Raf proteins themselves are also substrates of activated ERK. # ::save-date Sun Jan 17, 2016 ::file bio_mskcc_0001_6.txt (c / catalyze-01 :ARG0 (e / enzyme :name (n / name :op1 "ERK") :ARG1-of (a / activate-01)) :ARG1 (p / protein-family :name (n2 / name :op1 "Raf") :mod (a2 / also)) :ARG1-of (s / strike-04)) # ::id bio.mskcc_0001.7 ::date 2014-11-05T22:08:42 ::annotator SDL-AMR-09 ::preferred # ::snt In regard to C-Raf, ERK-dependent feedback phosphorylation has been shown to instigate a regulatory cycle whereby phosphorylation of the feedback sites down-modulates C-Raf signaling, after which the hyperphosphorylated C-Raf protein is dephosphorylated and returned to a signaling-competent state through dephosphorylation events involving protein phosphatase 2A (PP2A) and the Pin1 prolyl-isomerase (8). # ::save-date Mon Jul 20, 2015 ::file bio_mskcc_0001_7.txt (s / show-01 :ARG0 (p3 / publication :ARG1-of (c2 / cite-01 :ARG2 8)) :ARG1 (i / instigate-01 :ARG0 (p / phosphorylate-01 :ARG1 (p2 / protein-segment :part-of (e / enzyme :name (n / name :op1 "C-Raf")) :destination-of (f / feedback)) :ARG0-of (d / depend-01 :ARG1 (e2 / enzyme :name (n2 / name :op1 "ERK")))) :ARG1 (c / cycle-02 :ARG1-of (r / regulate-01) :subevent (d2 / downmodulate-01 :ARG1 (s2 / signal-07 :ARG0 e) :ARG2 p :op1-of (a / after :time-of (d3 / dephosphorylate-01 :ARG1 (e3 / enzyme :name (n3 / name :op1 "C-Raf") :ARG3-of (h / hyperphosphorylate-01)) :ARG0-of (a2 / activate-01 :ARG1 s2) :ARG1-of (i2 / involve-01 :ARG2 (a3 / and :op1 (e4 / enzyme :name (n4 / name :op1 "protein" :op2 "phosphatase" :op3 "2A")) :op2 (p4 / prolyl-isomerase :name (n5 / name :op1 "Pin1")))))))))) # ::id bio.mskcc_0001.8 ::date 2014-11-06T21:40:56 ::annotator SDL-AMR-09 ::preferred # ::snt For B-Raf, two ERK-dependent feedback sites, S750 and T753, have been identified, and phosphorylation of these sites has been reported to have a negative regulatory effect # ::save-date Thu May 28, 2015 ::file bio_mskcc_0001_8.txt (a / and :op1 (i / identify-01 :ARG1 (a2 / and :op1 (a3 / amino-acid :mod 750 :name (n4 / name :op1 "serine")) :op2 (a4 / amino-acid :mod 753 :name (n3 / name :op1 "threonine")) :part-of (e / enzyme :name (n / name :op1 "B-Raf")) :destination-of (f / feedback :ARG0-of (d / depend-01 :ARG1 (e2 / enzyme :name (n2 / name :op1 "ERK")))))) :op2 (r / report-01 :ARG1 (a5 / affect-01 :ARG0 (p / phosphorylate-01 :ARG1 a2) :ARG2 (d2 / downregulate-01)))) # ::id bio.mskcc_0001.9 ::date 2014-11-06T21:57:03 ::annotator SDL-AMR-09 ::preferred # ::snt Here we find that both normal and oncogenic B-Raf proteins are phosphorylated on four S/TP sites (S151, T401, S750, and T753) by activated ERK. # ::save-date Wed Dec 9, 2015 ::file bio_mskcc_0001_9.txt (f / find-01 :ARG0 (w / we) :ARG1 (p / phosphorylate-01 :ARG1 (a / and :op1 (a2 / amino-acid :mod 151 :name (n / name :op1 "serine")) :op2 (a3 / amino-acid :mod 401 :name (n2 / name :op1 "threonine")) :op3 (a4 / amino-acid :mod 750 :name (n3 / name :op1 "serine")) :op4 (a5 / amino-acid :mod 753 :name (n4 / name :op1 "threonine")) :part-of (e / enzyme :name (n5 / name :op1 "B-Raf"))) :ARG2 (e2 / enzyme :name (n7 / name :op1 "ERK") :ARG1-of (a6 / activate-01)) :condition (o / or :op1 (n6 / normal-02 :ARG1 e) :op2 (c / cause-01 :ARG0 e :ARG1 (d / disease :wiki "Cancer" :name (n8 / name :op1 "cancer"))))) :medium (h / here)) # ::id bio.mskcc_0001.10 ::date 2014-11-06T22:59:41 ::annotator SDL-AMR-09 ::preferred # ::snt Previously, we found that in response to growth factor treatment, signaling from C-Raf is downregulated by ERK-dependent feedback phosphorylation on S/TP sites and that C-Raf is subsequently dephosphorylated and returned to a signaling-competent state through the activities of PP2A and the Pin1 prolyl-isomerase (8) # ::save-date Wed Feb 24, 2016 ::file bio_mskcc_0001_10.txt (f2 / find-01 :ARG0 (w / we) :ARG1 (a / and :op1 (d2 / downregulate-01 :ARG0 (p / phosphorylate-01 :ARG1 (a4 / amino-acid :mod (o / or :op1 (a6 / amino-acid :name (n7 / name :op1 "serine")) :op2 (a7 / amino-acid :name (n8 / name :op1 "threonine"))) :part-of (e / enzyme :name (n / name :op1 "C-Raf")) :destination-of (f / feedback)) :ARG0-of (d / depend-01 :ARG1 (e2 / enzyme :name (n2 / name :op1 "ERK")))) :ARG1 (s2 / signal-07 :ARG0 e)) :op2 (a8 / and :op1 (d3 / dephosphorylate-01 :ARG1 e) :op2 (r / return-03 :ARG1 e :ARG2 (s3 / state :mod s2)) :manner (a9 / activity-06 :ARG0 (a3 / and :op1 (e4 / enzyme :name (n4 / name :op1 "PP2A")) :op2 (p4 / prolyl-isomerase :name (n5 / name :op1 "Pin1")))) :time (a5 / after :op1 d2)) :ARG0-of (r2 / respond-01 :ARG1 (t / treat-04 :ARG2 (g / growth-factor)))) :ARG1-of (d4 / describe-01 :ARG0 (p3 / publication :ARG1-of (c2 / cite-01 :ARG2 8))) :time (p2 / previous)) # ::id bio.mskcc_0001.11 ::date 2014-11-09T19:29:37 ::annotator SDL-AMR-09 ::preferred # ::snt The Pin1 prolyl-isomerase binds specifically to phosphorylated S/TP (pS/TP) motifs (33), and isomerization of the pS/TP bond is required for PP2A to efficiently dephosphorylate certain proteins, such as cdc25C, Myc, and C-Raf (16). # ::save-date Fri Jan 1, 2016 ::file bio_mskcc_0001_11.txt (a / and :op1 (b / bind-01 :ARG1 (p7 / prolyl-isomerase :name (n / name :op1 "Pin1")) :ARG2 (p / protein-segment :ARG3-of (p2 / phosphorylate-01) :mod (s2 / slash :op1 (a3 / amino-acid :name (n6 / name :op1 "serine")) :op2 (a4 / amino-acid :name (n7 / name :op1 "threonine")))) :ARG1-of (s / specific-02) :ARG1-of (d / describe-01 :ARG0 (p3 / publication :ARG1-of (c / cite-01 :ARG2 33)))) :op2 (r / require-01 :ARG0 (d2 / dephosphorylate-01 :ARG1 (p4 / protein :example (a2 / and :op1 (e3 / enzyme :name (n3 / name :op1 "cdc25C")) :op2 (p5 / protein :name (n4 / name :op1 "Myc")) :op3 (e4 / enzyme :name (n5 / name :op1 "C-Raf"))) :mod (c3 / certain)) :ARG2 (e2 / enzyme :name (n2 / name :op1 "PP2A")) :ARG2-of (e5 / efficient-01 :ARG1 e2)) :ARG1 (i / isomerize-01 :ARG1 (b2 / bond :part-of p)) :ARG1-of (d3 / describe-01 :ARG0 (p6 / publication :ARG1-of (c2 / cite-01 :ARG2 16))))) # ::id bio.mskcc_0001.12 ::date 2014-11-09T20:58:01 ::annotator SDL-AMR-09 ::preferred # ::snt Complex formation between B-Raf and Pin1 correlated with the phosphorylation of B-Raf on S/TP sites (Fig. 1C) and this interaction could be blocked when the MEK inhibitor U0126 was used to prevent ERK activation and the S/TP phosphorylation of B-Raf (Fig. 1D). # ::save-date Sat Jan 16, 2016 ::file bio_mskcc_0001_12.txt (a / and :op1 (c / correlate-01 :ARG1 (f / form-01 :ARG1 (m / macro-molecular-complex) :ARG2 (a2 / and :op1 (e / enzyme :name (n / name :op1 "B-Raf")) :op2 (e2 / enzyme :name (n2 / name :op1 "Pin1")))) :ARG2 (p / phosphorylate-01 :ARG1 (p2 / protein-segment :part-of e :mod (s2 / slash :op1 (a5 / amino-acid :name (n6 / name :op1 "serine")) :op2 (a6 / amino-acid :name (n7 / name :op1 "threonine"))))) :ARG1-of (d / describe-01 :ARG0 (f2 / figure :mod "1C"))) :op2 (p3 / possible-01 :ARG1 (b / block-01 :ARG1 f) :condition (u / use-01 :ARG1 (s / small-molecule :name (n3 / name :op1 "U0126") :ARG0-of (i / inhibit-01 :ARG1 (p6 / protein-family :name (n4 / name :op1 "MEK")))) :ARG2 (p4 / prevent-01 :ARG0 s :ARG1 (a3 / and :op1 (a4 / activate-01 :ARG1 (e4 / enzyme :name (n5 / name :op1 "ERK"))) :op2 (p5 / phosphorylate-01 :ARG1 p2)))) :ARG1-of (d2 / describe-01 :ARG0 (f3 / figure :mod "1D")))) # ::id bio.mskcc_0001.13 ::date 2014-11-16T16:37:31 ::annotator SDL-AMR-09 ::preferred # ::snt Together, these findings indicate that Pin1 is needed for the efficient dephosphorylation of B-Raf and are consistent with the model that S/TP phosphorylation inhibits Raf signaling. # ::save-date Fri Jan 1, 2016 ::file bio_mskcc_0001_13.txt (a / and :op1 (i / indicate-01 :ARG0 (t / thing :ARG1-of (f / find-01) :mod (t3 / this)) :ARG1 (n4 / need-01 :ARG1 (e / enzyme :name (n2 / name :op1 "Pin1")) :purpose (d / dephosphorylate-01 :ARG1 (e2 / enzyme :name (n / name :op1 "B-Raf")) :ARG2-of (e3 / efficient-01)))) :op2 (c / consistent-01 :ARG1 t :ARG2 (m / model :topic (i2 / inhibit-01 :ARG0 (p / phosphorylate-01 :ARG1 (p2 / protein-segment :mod (s2 / slash :op1 (a2 / amino-acid :name (n5 / name :op1 "serine")) :op2 (a3 / amino-acid :name (n6 / name :op1 "threonine"))))) :ARG1 (s / signal-07 :ARG0 (e4 / enzyme :name (n3 / name :op1 "Raf")))))) :mod (t2 / together)) # ::id bio.mskcc_0001.14 ::date 2014-11-16T16:54:17 ::annotator SDL-AMR-09 ::preferred # ::snt Eluting in HPLC fractions 78 to 79 was a peptide phosphorylated on S750 and T753, the previously identified ERK sites, and eluting in fractions 26 and 58 to 59 were peptides phosphorylated at S151 and T401, respectively. # ::save-date Fri Jan 1, 2016 ::file bio_mskcc_0001_14.txt (a / and :op1 (e / elute-01 :ARG1 (p / peptide :part (a2 / amino-acid :mod 750 :name (n / name :op1 "serine") :part-of (p4 / protein-segment :part-of (e2 / enzyme :name (n3 / name :op1 "ERK")) :ARG1-of (i / identify-01 :time (p5 / previous))) :ARG3-of p2) :part (a3 / amino-acid :mod 753 :name (n2 / name :op1 "threonine") :ARG3-of (p2 / phosphorylate-01) :part-of p4)) :ARG2 (f / fraction :mod (b / between :op1 78 :op2 79) :mod (c / chromatography :mod (l / liquid :ARG1-of (p10 / perform-02 :ARG1-of (h / high-02)))))) :op2 (e3 / elute-01 :ARG1 (p6 / peptide :part (a5 / amino-acid :mod 151 :name (n4 / name :op1 "serine") :ARG3-of p2)) :ARG2 (f3 / fraction :mod 26)) :op3 (e4 / elute-01 :ARG1 (p9 / peptide :part (a6 / amino-acid :mod 401 :name (n5 / name :op1 "threonine") :ARG3-of p2)) :ARG2 (f4 / fraction :mod (b2 / between :op1 58 :op2 59)))) # ::id bio.mskcc_0001.15 ::date 2014-11-16T17:31:43 ::annotator SDL-AMR-09 ::preferred # ::snt All four of these identified sites are followed by a proline residue, and their phosphorylation could be blocked by pretreating cells with the MEK inhibitor U0126 (Fig. 2A), suggesting that these residues are feedback targets of the proline-directed kinase, ERK. # ::save-date Sat Jan 16, 2016 ::file bio_mskcc_0001_15.txt (a / and :op1 (f / follow-01 :ARG1 (r / residue :mod (a3 / amino-acid :name (n / name :op1 "proline"))) :ARG2 (p / protein-segment :quant 4 :mod (a2 / all) :mod (t / this) :ARG1-of (i2 / identify-01))) :op2 (p2 / possible-01 :ARG1 (b / block-01 :ARG0 (t2 / treat-04 :ARG1 (c / cell) :ARG2 (s / small-molecule :name (n2 / name :op1 "U0126") :ARG0-of (i / inhibit-01 :ARG1 (p4 / protein-family :name (n3 / name :op1 "MEK")))) :time (b2 / before)) :ARG1 (p3 / phosphorylate-01 :ARG1 p)) :ARG1-of (d / describe-01 :ARG0 (f2 / figure :mod "2A"))) :ARG0-of (s2 / suggest-01 :ARG1 (f3 / feedback :destination r :source (k / kinase :name (n4 / name :op1 "ERK") :ARG1-of (d2 / direct-01 :ARG2 p))))) # ::id bio.mskcc_0001.16 ::date 2014-11-16T17:46:13 ::annotator SDL-AMR-09 ::preferred # ::snt Consistent with this model, we found that when purified activated ERK was incubated with kinase-dead B-Raf(K375M) in vitro, ERK strongly phosphorylated B-Raf on the S151, S750, and T753 sites, with phosphorylation of T401 also observed (Fig. 2B). # ::save-date Mon Jul 13, 2015 ::file bio_mskcc_0001_16.txt (f / find-01 :ARG0 (w / we) :ARG1 (a6 / and :op1 (p / phosphorylate-01 :ARG1 (a2 / and :op1 (a3 / amino-acid :mod 151 :name (n4 / name :op1 "serine") :part-of e2) :op2 (a4 / amino-acid :mod 750 :name (n5 / name :op1 "serine") :part-of e2) :op3 (a5 / amino-acid :mod 753 :name (n6 / name :op1 "threonine") :part-of e2)) :ARG2 (e / enzyme :name (n / name :op1 "ERK") :ARG1-of (a / activate-01) :ARG1-of (p2 / purify-01)) :ARG1-of (s / strong-02)) :op2 (p3 / phosphorylate-01 :ARG1 (a7 / amino-acid :mod 401 :name (n7 / name :op1 "threonine") :part-of e2) :ARG2 e :ARG1-of (o / observe-01 :mod (a8 / also))) :condition (i / incubate-01 :ARG1 e :ARG2 (e2 / enzyme :name (n2 / name :op1 "B-Raf") :ARG2-of (m2 / mutate-01 :value "K375M") :ARG0-of (f2 / function-01 :polarity - :ARG1 (k / kinase))) :manner (i2 / in-vitro)) :ARG1-of (d / describe-01 :ARG0 (f3 / figure :mod "2B"))) :ARG1-of (c / consistent-01 :ARG2 (m / model :mod (t / this)))) # ::id bio.mskcc_0001.17 ::date 2014-11-16T18:19:06 ::annotator SDL-AMR-09 ::preferred # ::snt These findings are similar to what has been observed for C-Raf (8) and suggest that feedback phosphorylation is a conserved mechanism used to disrupt the Ras/Raf interaction. # ::save-date Sat Jun 13, 2015 ::file bio_mskcc_0001_17.txt (a / and :op1 (r / resemble-01 :ARG1 (t / thing :ARG1-of (f / find-01) :mod (t2 / this)) :ARG2 (t3 / thing :ARG1-of (o / observe-01) :topic (e / enzyme :name (n / name :op1 "C-Raf"))) :ARG1-of (d / describe-01 :ARG0 (p / publication :ARG1-of (c / cite-01 :ARG2 8)))) :op2 (s / suggest-01 :ARG0 t :ARG1 (m / mechanism :ARG1-of (c2 / conserve-01) :ARG1-of (u / use-01 :ARG2 (d2 / disrupt-01 :ARG0 m :ARG1 (i / interact-01 :ARG0 (a2 / and :op1 (e3 / enzyme :name (n3 / name :op1 "Ras")) :op2 (e2 / enzyme :name (n2 / name :op1 "Raf")))))) :domain (p3 / phosphorylate-01 :subevent-of (f2 / feedback))))) # ::id bio.mskcc_0001.18 ::date 2014-11-16T20:11:46 ::annotator SDL-AMR-09 ::preferred # ::snt Consistent with these data, we found that B-Raf interacted with C-Raf in an inducible and transient manner following growth factor treatment (Fig. 3B and C). # ::save-date Wed Feb 24, 2016 ::file bio_mskcc_0001_18.txt (f / find-01 :ARG0 (w / we) :ARG1 (i / interact-01 :ARG0 (e / enzyme :name (n / name :op1 "B-Raf")) :ARG1 (e2 / enzyme :name (n2 / name :op1 "C-Raf")) :ARG2-of (i2 / induce-01) :ARG1-of (t2 / transient-02) :ARG2-of (f4 / follow-01 :ARG1 (t3 / treat-04 :ARG2 (g / growth-factor)))) :ARG1-of (c / consistent-01 :ARG2 (d / data :mod (t / this))) :ARG1-of (d2 / describe-01 :ARG0 (a2 / and :op1 (f2 / figure :mod "3B") :op2 (f3 / figure :mod "3C")))) # ::id bio.mskcc_0001.19 ::date 2014-11-21T12:13:54 ::annotator SDL-AMR-09 ::preferred # ::snt In addition, when B-Raf feedback phosphorylation was prevented, either by U0126 treatment or by mutation of all the feedback sites, an increase in the basal level of heterodimerization with C-Raf was observed, and heterodimerization in response to growth factor treatment was increased and prolonged (Fig. 3B and C). # ::save-date Wed Feb 24, 2016 ::file bio_mskcc_0001_19.txt (a2 / and :op2 (a / and :op1 (o / observe-01 :ARG1 (i / increase-01 :ARG1 (l / level :mod (b / basal) :degree-of (h / heterodimerize-01 :ARG1 e :ARG2 (e2 / enzyme :name (n3 / name :op1 "C-Raf")))))) :op2 (i2 / increase-01 :ARG1 (h2 / heterodimerize-01 :ARG2-of (r / respond-01 :ARG1 (t2 / treat-04 :ARG2 (g / growth-factor))))) :op3 (p / prolong-01 :ARG1 h2) :condition (p2 / prevent-01 :ARG0 (o2 / or :op1 (t / treat-04 :ARG2 (s / small-molecule :name (n2 / name :op1 "U0126"))) :op2 (m / mutate-01 :ARG1 (p4 / protein-segment :part-of e :destination-of f :mod (a3 / all)))) :ARG1 (p3 / phosphorylate-01 :ARG1 (e / enzyme :name (n / name :op1 "B-Raf")) :subevent-of (f / feedback))) :ARG1-of (d / describe-01 :ARG0 (a4 / and :op1 (f2 / figure :mod "3B") :op2 (f3 / figure :mod "3C"))))) # ::id bio.mskcc_0001.20 ::date 2014-11-21T12:36:32 ::annotator SDL-AMR-09 ::preferred # ::snt These findings support a model whereby feedback phosphorylation disrupts Raf heterodimerization. # ::save-date Mon Nov 24, 2014 ::file bio_mskcc_0001_20.txt (s / support-01 :ARG0 (t / thing :ARG1-of (f / find-01) :mod (t2 / this)) :ARG1 (m / model :topic (d / disrupt-01 :ARG0 (p / phosphorylate-01 :ARG1 e :subevent-of (f2 / feedback)) :ARG1 (h / heterodimerize-01 :ARG1 (e / enzyme :name (n / name :op1 "Raf")))))) # ::id bio.mskcc_0001.21 ::date 2014-11-21T12:49:56 ::annotator SDL-AMR-09 ::preferred # ::snt Unlike WT B-Raf, oncogenic B-Raf proteins have been shown to heterodimerize constitutively with C-Raf in a Ras-independent manner (11). # ::save-date Wed Dec 9, 2015 ::file bio_mskcc_0001_21.txt (c5 / contrast-01 :ARG1 (h / heterodimerize-01 :ARG1 (e / enzyme :name (n / name :op1 "B-Raf") :ARG0-of (c / cause-01 :ARG1 (d2 / disease :wiki "Cancer" :name (n5 / name :op1 "cancer")))) :ARG2 (e2 / enzyme :name (n2 / name :op1 "C-Raf")) :mod (c3 / constitutive) :ARG0-of (d / depend-01 :polarity - :ARG1 (e4 / enzyme :name (n3 / name :op1 "Ras"))) :ARG1-of (s / show-01 :ARG0 (p2 / publication :ARG1-of (c4 / cite-01 :ARG2 11)))) :ARG2 (h2 / heterodimerize-01 :ARG1 (e3 / enzyme :name (n4 / name :op1 "B-Raf") :mod (w / wild-type)) :ARG2 e2 :mod (c6 / constitutive :polarity -))) # ::id bio.mskcc_0001.22 ::date 2014-11-28T17:28:12 ::annotator SDL-AMR-09 ::preferred # ::snt When we next examined the effect of feedback phosphorylation on the ability of oncogenic B-Raf to form heterodimers with C-Raf, we found that the levels of endogenous C-Raf associating with B-Raf proteins of high (V600E), intermediate (G466A), and impaired (D594G) kinase activities all increased when the feedback sites were mutated, indicating that feedback phosphorylation also inhibits the heterodimerization of oncogenic B-Raf proteins (Fig. 3D). # ::save-date Fri Jan 1, 2016 ::file bio_mskcc_0001_22.txt (f / find-01 :ARG0 (w / we) :ARG1 (i / increase-01 :ARG1 (a / and :op1 (l / level :quant-of (e / enzyme :name (n / name :op1 "C-Raf") :ARG1-of (a2 / associate-01 :ARG2 (e2 / enzyme :name (n2 / name :op1 "B-Raf") :ARG2-of (m / mutate-01 :value "V600E") :ARG0-of (a3 / act-01 :ARG1 (k / kinase) :ARG1-of (h / high-02)))) :mod (e7 / endogenous))) :op2 (l2 / level :quant-of (e3 / enzyme :name (n3 / name :op1 "C-Raf") :ARG1-of (a5 / associate-01 :ARG2 (e5 / enzyme :name (n5 / name :op1 "B-Raf") :ARG2-of (m2 / mutate-01 :value "G466A") :ARG0-of (a4 / act-01 :ARG1 (k2 / kinase) :degree (i2 / intermediate)))) :mod (e8 / endogenous))) :op3 (l3 / level :quant-of (e4 / enzyme :name (n4 / name :op1 "C-Raf") :ARG1-of (a6 / associate-01 :ARG2 (e6 / enzyme :name (n6 / name :op1 "B-Raf") :ARG2-of (m3 / mutate-01 :value "D594G") :ARG0-of (a7 / activity-06 :ARG1-of (i3 / impair-01)))) :mod (e9 / endogenous)))) :condition (m4 / mutate-01 :ARG1 (p / protein-segment :part-of (e10 / enzyme :name (n7 / name :op1 "B-Raf")) :destination-of (f2 / feedback))) :ARG0-of (i4 / indicate-01 :ARG1 (i5 / inhibit-01 :ARG0 p2 :ARG1 (h3 / heterodimerize-01 :ARG1 e12 :ARG2 e13) :mod (a9 / also))) :ARG1-of (d / describe-01 :ARG0 (f4 / figure :mod "3D"))) :manner (e11 / examine-01 :ARG0 w :ARG1 (a8 / affect-01 :ARG0 (p2 / phosphorylate-01 :subevent-of (f3 / feedback)) :ARG1 (p3 / possible-01 :ARG1 (h2 / heterodimerize-01 :ARG1 (e12 / enzyme :name (n9 / name :op1 "B-Raf") :ARG0-of (c / cause-01 :ARG1 (d2 / disease :wiki "Cancer" :name (n11 / name :op1 "cancer")))) :ARG2 (e13 / enzyme :name (n10 / name :op1 "C-Raf"))))) :time (n8 / next))) # ::id bio.mskcc_0001.23 ::date 2014-11-28T18:08:23 ::annotator SDL-AMR-09 ::preferred # ::snt Previous studies have shown that, for both normal and oncogenic B-Raf proteins to heterodimerize with C-Raf, the C-terminal 14-3-3 binding site of C-Raf (S621) must be intact (11, 27) (Fig. 3E). # ::save-date Wed Dec 9, 2015 ::file bio_mskcc_0001_23.txt (s / show-01 :ARG0 (s2 / study :time (p / previous) :ARG1-of (c / cite-01 :ARG2 (a / and :op1 11 :op2 27))) :ARG1 (a2 / and :op1 (r / require-01 :ARG0 (h / heterodimerize-01 :ARG1 (e / enzyme :name (n / name :op1 "B-Raf") :ARG0-of (c2 / cause-01 :ARG1 (d2 / disease :wiki "Cancer" :name (n8 / name :op1 "cancer")))) :ARG2 (e2 / enzyme :name (n2 / name :op1 "C-Raf"))) :ARG1 (i / intact :domain (a3 / amino-acid :mod 621 :name (n3 / name :op1 "serine") :part-of (p2 / protein-segment :name (n4 / name :op1 "C-terminus") :part-of e2) :ARG1-of (b / bind-01 :ARG2 (p3 / protein :name (n5 / name :op1 "14-3-3")))))) :op2 (r2 / require-01 :ARG0 (h2 / heterodimerize-01 :ARG1 (e3 / enzyme :name (n6 / name :op1 "B-Raf") :ARG1-of (n7 / normal-02)) :ARG2 e2) :ARG1 i) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "3E")))) # ::id bio.mskcc_0001.24 ::date 2014-11-29T14:06:52 ::annotator SDL-AMR-09 ::preferred # ::snt To determine whether binding of 14-3-3 to B-Raf is also required for heterodimerization, B-Raf proteins containing lanine substitutions in the two 14-3-3 binding sites, S365 and S729 (2), were examined for their abilities to heterodimerize with C-Raf in response to growth factor treatment. # ::save-date Wed Feb 24, 2016 ::file bio_mskcc_0001_24.txt (e / examine-01 :ARG1 (p2 / possible-01 :mode interrogative :ARG1 (h / heterodimerize-01 :ARG1 (e2 / enzyme :name (n / name :op1 "B-Raf") :part (a / amino-acid :name (n2 / name :op1 "alanine") :ARG1-of (s / substitute-01 :ARG3 (a2 / amino-acid :mod 365 :name (n3 / name :op1 "serine") :ARG1-of (b / bind-01 :ARG2 (p / protein :name (n6 / name :op1 "14-3-3")))))) :part (a3 / amino-acid :name (n4 / name :op1 "alanine") :ARG1-of (s2 / substitute-01 :ARG2 (a4 / amino-acid :mod 729 :name (n5 / name :op1 "serine") :ARG1-of (b2 / bind-01 :ARG2 p))))) :ARG2 (e3 / enzyme :name (n7 / name :op1 "C-Raf")) :ARG2-of (r / respond-01 :ARG1 (t / treat-04 :ARG2 (g / growth-factor))))) :purpose (d / determine-01 :ARG1 (r2 / require-01 :mode interrogative :ARG0 (h2 / heterodimerize-01 :ARG1 e4 :ARG2 e3) :ARG1 (b3 / bind-01 :ARG1 p :ARG2 (e4 / enzyme :name (n9 / name :op1 "B-Raf"))) :mod (a5 / also)))) # ::id bio.mskcc_0001.25 ::date 2014-11-29T21:20:25 ::annotator SDL-AMR-09 ::preferred # ::snt Not surprisingly, given that mutation of the S365 14-3-3 binding site enhances the membrane localization of B-Raf (2), increased heterodimerization with C-Raf was observed for S365A B-Raf compared to WT B-Raf (Fig. 3F). # ::save-date Sat Nov 29, 2014 ::file bio_mskcc_0001_25.txt (o / observe-01 :ARG1 (i / increase-01 :ARG1 (h / heterodimerize-01 :ARG1 (e / enzyme :name (n / name :op1 "B-Raf") :ARG2-of (m / mutate-01 :value "S365A")) :ARG2 (e2 / enzyme :name (n2 / name :op1 "C-Raf"))) :compared-to (h2 / heterodimerize-01 :ARG1 (e3 / enzyme :name (n3 / name :op1 "B-Raf") :mod (w / wild-type)) :ARG2 e2) :ARG1-of (c / cause-01 :ARG0 (e4 / enhance-01 :ARG0 (m2 / mutate-01 :ARG1 (a / amino-acid :mod 365 :name (n4 / name :op1 "serine") :ARG1-of (b / bind-01 :ARG2 (p / protein :name (n5 / name :op1 "14-3-3"))))) :ARG1 (b2 / be-located-at-91 :ARG1 e2 :ARG2 (m3 / membrane)) :ARG1-of (d / describe-01 :ARG0 (p2 / publication :ARG1-of (c2 / cite-01 :ARG2 2))))) :ARG0-of (s / surprise-01 :polarity -) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "3F")))) # ::id bio.mskcc_0001.26 ::date 2014-11-29T21:32:40 ::annotator SDL-AMR-09 ::preferred # ::snt In contrast, S729A B-Raf failed to heterodimerize with C-Raf in response to growth factor treatment, and mutation of this site disrupted the constitutive interaction of oncogenic B-Raf proteins and C-Raf (Fig. 3F), indicating that heterodimerization with C-Raf is dependent on the C-terminal S729 14-3-3 binding site of B-Raf. # ::save-date Wed Feb 24, 2016 ::file bio_mskcc_0001_26.txt (c / contrast-01 :ARG2 (a / and :op1 (f / fail-01 :ARG1 (h / heterodimerize-01 :ARG1 (e / enzyme :name (n / name :op1 "B-Raf") :ARG2-of (m / mutate-01 :value "S729A")) :ARG2 (e2 / enzyme :name (n2 / name :op1 "C-Raf")) :ARG0-of (r / respond-01 :ARG1 (t / treat-04 :ARG2 (g / growth-factor))))) :op2 (d / disrupt-01 :ARG0 m :ARG1 (i / interact-01 :ARG0 (e3 / enzyme :name (n4 / name :op1 "B-Raf") :ARG0-of (c2 / cause-01 :ARG1 (d4 / disease :wiki "Cancer" :name (n9 / name :op1 "cancer")))) :ARG1 e2 :mod (c4 / constitutive))) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure :mod "3F")) :ARG0-of (i2 / indicate-01 :ARG1 (d3 / depend-01 :ARG0 (h2 / heterodimerize-01 :ARG1 (e4 / enzyme :name (n5 / name :op1 "B-Raf")) :ARG2 e2) :ARG1 (a2 / amino-acid :mod 729 :name (n6 / name :op1 "serine") :part-of (p / protein-segment :name (n7 / name :op1 "C-terminus") :part-of e4) :ARG1-of (b / bind-01 :ARG2 (p2 / protein :name (n8 / name :op1 "14-3-3")))))))) # ::id bio.mskcc_0001.27 ::date 2015-01-19T22:53:44 ::annotator SDL-AMR-09 ::preferred # ::snt Previous studies have found that all oncogenic B-Raf proteins can activate C-Raf and that heterodimerization with C-Raf is required for kinase-impaired oncogenic B-Raf proteins to mediate ERK activation in vivo (31). # ::save-date Fri Jan 1, 2016 ::file bio_mskcc_0001_27.txt (f / find-01 :ARG0 (s / study :time (p / previous)) :ARG1 (a / and :op1 (p2 / possible-01 :ARG1 (a2 / activate-01 :ARG0 (e / enzyme :name (n / name :op1 "B-Raf") :mod (a3 / all) :ARG0-of (c / cause-01 :ARG1 (d2 / disease :wiki "Cancer" :name (n5 / name :op1 "cancer")))) :ARG1 (e2 / enzyme :name (n2 / name :op1 "C-Raf")))) :op2 (r / require-01 :ARG0 (m / mediate-01 :ARG0 (e3 / enzyme :name (n3 / name :op1 "B-Raf") :ARG0-of c :ARG0-of (a5 / activate-01 :ARG1 e2 :ARG1-of (i / impair-01))) :ARG1 (a4 / activate-01 :ARG1 (e4 / enzyme :name (n4 / name :op1 "ERK")) :manner (i2 / in-vivo))) :ARG1 (h / heterodimerize-01 :ARG1 e :ARG2 e2))) :ARG1-of (d / describe-01 :ARG0 (p3 / publication :ARG1-of (c3 / cite-01 :ARG2 31)))) # ::id bio.mskcc_0001.28 ::date 2015-01-20T11:13:17 ::annotator SDL-AMR-09 ::preferred # ::snt Therefore, to further investigate both the impact of feedback phosphorylation and the contribution of heterodimerization to oncogenic B-Raf function, we examined the transformation potential of oncogenic B-Raf proteins containing mutations in either the feedback phosphorylation sites (which exhibit increased heterodimerization) or the S729 14-3-3 binding site (which are unable to heterodimerize). # ::save-date Fri Jan 1, 2016 ::file bio_mskcc_0001_28.txt (i / infer-01 :ARG1 (e / examine-01 :ARG0 (w / we) :ARG1 (p / possible-01 :ARG1 (t / transform-01 :ARG0 (e2 / enzyme :name (n / name :op1 "B-Raf") :ARG0-of (c / cause-01 :ARG1 (d / disease :wiki "Cancer" :name (n5 / name :op1 "cancer"))) :ARG2-of (m / mutate-01 :ARG1 (o / or :op1 (p2 / protein-segment :ARG1-of (p3 / phosphorylate-01 :subevent-of (f / feedback)) :ARG0-of (e3 / exhibit-01 :ARG1 (h / heterodimerize-01 :ARG1-of (i2 / increase-01)))) :op2 (a / amino-acid :mod 729 :name (n4 / name :op1 "serine") :ARG1-of (b / bind-01 :ARG2 (p4 / protein :name (n2 / name :op1 "14-3-3"))) :ARG0-of (h2 / heterodimerize-01 :ARG1-of (p5 / possible-01 :polarity -)))))))) :purpose (i3 / investigate-01 :ARG0 w :ARG1 (a2 / and :op1 (i4 / impact-01 :ARG0 (p6 / phosphorylate-01 :subevent-of (f3 / feedback)) :ARG1 f4) :op2 (c4 / contribute-01 :ARG0 (h3 / heterodimerize-01) :ARG2 (f4 / function-01 :ARG0 e2))) :degree (f2 / further)))) # ::id bio.mskcc_0001.29 ::date 2015-01-20T12:45:00 ::annotator SDL-AMR-09 ::preferred # ::snt For these studies, FBm or S729A mutations were incorporated into a number of oncogenic B-Raf proteins that exhibit various levels of kinase activity. # ::save-date Fri Jan 1, 2016 ::file bio_mskcc_0001_29.txt (i / incorporate-02 :ARG1 (o / or :op1 (e3 / enzyme :name (n3 / name :op1 "B-Raf") :ARG2-of (m / mutate-01) :ARG1-of (h / have-part-91 :polarity - :ARG2 (p / protein-segment :destination-of (f / feedback)))) :op2 (e4 / enzyme :name (n4 / name :op1 "B-Raf") :ARG2-of (m2 / mutate-01 :value "S729A"))) :ARG2 (e / enzyme :name (n / name :op1 "B-Raf") :ARG0-of (c / cause-01 :ARG1 (d / disease :wiki "Cancer" :name (n5 / name :op1 "cancer"))) :quant (n2 / number) :ARG0-of (e2 / exhibit-01 :ARG1 (l / level :mod (v / various) :degree-of (a / activity-06 :ARG0 (k / kinase))))) :purpose (s / study :mod (t / this))) # ::id bio.mskcc_0001.30 ::date 2015-01-20T14:21:50 ::annotator SDL-AMR-09 ::preferred # ::snt The proteins were then expressed in NIH 3T3 cells and examined for their abilities to alter cell morphology and induce focus formation. # ::save-date Wed Jun 3, 2015 ::file bio_mskcc_0001_30.txt (a / and :op1 (e / express-03 :ARG2 (p / protein) :ARG3 (c / cell-line :name (n / name :op1 "NIH" :op2 "3T3"))) :op2 (e2 / examine-01 :ARG1 (p2 / possible-01 :mode interrogative :ARG1 (a2 / and :op1 (a3 / alter-01 :ARG0 p :ARG1 (m / morphology :mod (c2 / cell))) :op2 (i / induce-01 :ARG0 p :ARG2 (f / form-01 :ARG1 (f2 / focus)))))) :time (t / then)) # ::id bio.mskcc_0001.31 ::date 2015-01-20T14:44:20 ::annotator SDL-AMR-09 ::preferred # ::snt As shown in Fig. 4A, the FBm or S729A mutation had no effect on transformation induced by the V600E or G469A B-Raf protein, both of which possess high kinase activity. # ::save-date Fri Jan 1, 2016 ::file bio_mskcc_0001_31.txt (a2 / affect-01 :polarity - :ARG0 (o / or :op1 (m / mutate-01 :ARG1 (e / enzyme :name (n / name :op1 "B-Raf") :ARG1-of (h2 / have-part-91 :polarity - :ARG2 (p / protein-segment :destination-of (f2 / feedback))))) :op2 (m3 / mutate-01 :value "S729A")) :ARG1 (t / transform-01 :ARG2-of (i / induce-01 :ARG0 (o2 / or :op1 (e2 / enzyme :name (n2 / name :op1 "B-Raf") :ARG2-of (m4 / mutate-01 :value "V600E")) :op2 (e3 / enzyme :name (n3 / name :op1 "B-Raf") :ARG2-of (m5 / mutate-01 :value "G469A")) :ARG0-of (a / activity-06 :ARG1-of (h / high-02))))) :ARG1-of (s / show-01 :ARG0 (f / figure :mod "4A"))) # ::id bio.mskcc_0001.32 ::date 2015-01-20T15:12:00 ::annotator SDL-AMR-09 ::preferred # ::snt However, mutation of the feedback sites significantly increased the transforming activities of B-Raf proteins with intermediate or impaired kinase activity (Fig. 4A). # ::save-date Mon Jan 4, 2016 ::file bio_mskcc_0001_32.txt (c / contrast-01 :ARG2 (i / increase-01 :ARG0 (m / mutate-01 :ARG1 (p / protein-segment :destination-of (f / feedback))) :ARG1 (o / or :op1 (a / activity-06 :ARG0 (e / enzyme :name (n / name :op1 "B-Raf")) :ARG1 (k / kinase) :degree (i3 / intermediate)) :op2 (a2 / activity-06 :ARG0 e :ARG1 k :ARG1-of (i2 / impair-01)) :ARG0-of (t / transform-01)) :ARG2 (s / significant-02) :ARG1-of (d / describe-01 :ARG0 (f2 / figure :mod "4A")))) # ::id bio.mskcc_0001.33 ::date 2015-01-20T22:53:13 ::annotator SDL-AMR-09 ::preferred # ::snt The total number of foci observed and, often, the sizes of the foci were increased, and cells within the foci exhibited a more transformed appearance. # ::save-date Thu Feb 5, 2015 ::file bio_mskcc_0001_33.txt (a / and :op1 (i / increase-01 :ARG1 (a3 / and :op1 (n / number :ARG2-of (t / total-01 :ARG1 (f / focus :ARG1-of (o / observe-01)))) :op2 (s / size :poss f)) :frequency (o2 / often)) :op3 (e / exhibit-01 :ARG0 (c / cell :location f) :ARG1 (a2 / appear-02 :ARG1 c :ARG1-of (t2 / transform-01 :degree (m / more))))) # ::id bio.mskcc_0001.34 ::date 2015-01-21T02:29:01 ::annotator SDL-AMR-09 ::preferred # ::snt In contrast, the S729A mutation reduced the transforming activities of the oncogenic proteins with intermediate or impaired kinase activity, causing a reduction in focus number and a flatter cell morphology (Fig. 4A). # ::save-date Fri Jan 1, 2016 ::file bio_mskcc_0001_34.txt (c / contrast-01 :ARG2 (r / reduce-01 :ARG0 (m / mutate-01 :value "S729A") :ARG1 (o2 / or :op1 (a / activity-06 :ARG0 (p / protein :ARG0-of (c2 / cause-01 :ARG1 (d2 / disease :wiki "Cancer" :name (n2 / name :op1 "cancer")))) :ARG1 (k / kinase) :degree (i / intermediate)) :op2 (a2 / activity-06 :ARG0 (p2 / protein :ARG0-of c2) :ARG1 k :ARG1-of (i2 / impair-01)) :ARG0-of (t / transform-01)) :ARG0-of (c4 / cause-01 :ARG1 (a4 / and :op1 (r2 / reduce-01 :ARG1 (n / number :quant-of (f / focus))) :op2 (m2 / morphology :mod (c5 / cell) :ARG1-of (f2 / flat-06 :degree (m3 / more))))) :ARG1-of (d / describe-01 :ARG0 (f3 / figure :mod "4A")))) # ::id bio.mskcc_0001.35 ::date 2015-01-21T03:05:03 ::annotator SDL-AMR-09 ::preferred # ::snt Examination of activated phospho-MEK levels revealed that the FBm and S729 mutations had no effect on MEK activation induced by the high-activity V600E B-Raf protein; however, the FBm and S729A mutations increased and decreased, respectively, the abilities of the intermediate G466A and kinase-impaired D594G B-Raf proteins to activate MEK (Fig. 4B), indicating a correlation between the transformation potential of these proteins and their ability to activate ERK cascade signaling in vivo. # ::save-date Sun Jul 26, 2015 ::file bio_mskcc_0001_35.txt (r2 / reveal-01 :ARG0 (e / examine-01 :ARG1 (l / level :degree-of (e2 / enzyme :name (n / name :op1 "MEK") :ARG3-of (p / phosphorylate-01) :ARG1-of (a / activate-01)))) :ARG1 (c / contrast-01 :ARG1 (a2 / affect-01 :polarity - :ARG0 (a3 / and :op1 (m7 / mutate-01 :ARG1 (e9 / enzyme :name (n2 / name :op1 "B-Raf") :ARG1-of (h2 / have-part-91 :polarity - :ARG2 (p5 / protein-segment :destination-of (f2 / feedback))))) :op2 (m / mutate-01 :ARG1 (a11 / amino-acid :mod 729 :name (n9 / name :op1 "serine")))) :ARG1 (a4 / activate-01 :ARG1 (e3 / enzyme :name (n3 / name :op1 "MEK")) :ARG2-of (i / induce-01 :ARG0 (e4 / enzyme :name (n4 / name :op1 "B-Raf") :ARG2-of (m3 / mutate-01 :value "V600E") :ARG0-of (a5 / activity-06 :ARG1-of (h / high-02)))))) :ARG2 (a6 / and :op1 (i2 / increase-01 :ARG0 (a7 / and :op1 m7 :op2 (m4 / mutate-01 :value "S729A")) :ARG1 (p2 / possible-01 :ARG1 (a8 / activate-01 :ARG0 (a9 / and :op1 (e5 / enzyme :name (n5 / name :op1 "B-Raf") :ARG2-of (m5 / mutate-01 :value "G466A" :degree (i3 / intermediate))) :op2 (e6 / enzyme :name (n6 / name :op1 "B-Raf") :ARG2-of (m6 / mutate-01 :value "D594G") :mod (i4 / impair-01 :ARG1 (k / kinase)))) :ARG1 e3))) :op2 (d / decrease-01 :ARG0 a7) :mod (r / respective) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "4B")) :ARG0-of (i5 / indicate-01 :ARG1 (c2 / correlate-01 :ARG1 (p3 / possible-01 :ARG1 (t / transform-01 :ARG0 a9)) :ARG2 (p4 / possible-01 :ARG1 (a10 / activate-01 :ARG0 a9 :ARG1 (s / signal-07 :ARG0 (e8 / enzyme :name (n8 / name :op1 "ERK")) :manner (i6 / in-vivo) :subevent-of (c3 / cascade))))))))) # ::id bio.mskcc_0001.36 ::date 2015-01-21T05:10:00 ::annotator SDL-AMR-09 ::preferred # ::snt Not unexpectedly, for all of the oncogenic B-Raf proteins, the S729A mutation, which disrupts heterodimerization with C-Raf, caused a >90% decrease in C-Raf activity levels (Fig. 5B). # ::save-date Wed Dec 9, 2015 ::file bio_mskcc_0001_36.txt (c / cause-01 :ARG0 (m / mutate-01 :value "S729A" :ARG2 (e / enzyme :name (n / name :op1 "B-Raf") :mod (a / all) :ARG0-of (c2 / cause-01 :ARG1 (d4 / disease :wiki "Cancer" :name (n3 / name :op1 "cancer")))) :ARG0-of (d / disrupt-01 :ARG1 (h / heterodimerize-01 :ARG1 e :ARG2 (e2 / enzyme :name (n2 / name :op1 "C-Raf"))))) :ARG1 (d2 / decrease-01 :ARG1 (l / level :degree-of (a2 / activity-06 :ARG0 e2)) :ARG2 (m2 / more-than :op1 (p / percentage-entity :value 90))) :ARG1-of (e3 / expect-01) :ARG1-of (d3 / describe-01 :ARG0 (f / figure :mod "5B"))) # ::id bio.mskcc_0001.37 ::date 2015-01-21T07:29:54 ::annotator SDL-AMR-09 ::preferred # ::snt Together, these findings indicate a correlation between the changes in the transformation potentials of the intermediate and impaired oncogenic B-Raf proteins and their abilities to heterodimerize and activate C-Raf. # ::save-date Wed Dec 9, 2015 ::file bio_mskcc_0001_37.txt (i / indicate-01 :ARG0 (t / thing :ARG1-of (f / find-01) :mod (t2 / this)) :ARG1 (c / correlate-01 :ARG1 (c2 / change-01 :ARG1 (p / possible-01 :ARG1 (t4 / transform-01 :ARG0 (a / and :op1 (e / enzyme :name (n / name :op1 "B-Raf") :mod (i2 / intermediate) :ARG0-of (c3 / cause-01 :ARG1 (d / disease :wiki "Cancer" :name (n4 / name :op1 "cancer")))) :op2 (e2 / enzyme :name (n2 / name :op1 "B-Raf") :ARG1-of (i3 / impair-01)))))) :ARG2 (c5 / capable-01 :ARG1 a :ARG2 (a2 / and :op1 (h / heterodimerize-01 :ARG1 a :ARG2 (e3 / enzyme :name (n3 / name :op1 "C-Raf"))) :op2 (a3 / activate-01 :ARG0 a :ARG1 e3)))) :mod (t3 / together)) # ::id bio.mskcc_0001.38 ::date 2015-01-21T09:11:56 ::annotator SDL-AMR-09 ::preferred # ::snt To investigate the contributions of the various feedback sites to the overall effect of feedback phosphorylation on B-Raf function, we generated a panel of mutants in which specific feedback phosphorylation sites were incorporated into either WT B-Raf or the intermediate-activity G466A B-Raf protein. # ::save-date Fri Jul 24, 2015 ::file bio_mskcc_0001_38.txt (g / generate-01 :ARG0 (w / we) :ARG1 (p / panel :consist-of (e / enzyme :name (n / name :op1 "B-Raf") :ARG2-of (m / mutate-01 :ARG1-of (c2 / cause-01 :ARG0 (i / incorporate-02 :ARG1 (p2 / protein-segment :part-of e :ARG1-of (p3 / phosphorylate-01 :subevent-of (f / feedback) :ARG1-of (s / specific-02))) :ARG2 (o / or :op1 (e2 / enzyme :name (n2 / name :op1 "B-Raf") :mod (w2 / wild-type)) :op2 (e3 / enzyme :name (n3 / name :op1 "B-Raf") :ARG2-of (m2 / mutate-01 :value "G466A") :ARG0-of (a / activity-06 :degree (i2 / intermediate))))))))) :purpose (i3 / investigate-01 :ARG0 w :ARG1 (t / thing :ARG1-of (c / contribute-01 :ARG0 (p4 / protein-segment :mod (v / various) :destination-of f) :ARG2 (a2 / affect-01 :ARG0 p3 :ARG1 (f2 / function-01 :ARG0 (e4 / enzyme :name (n4 / name :op1 "B-Raf"))) :mod (o2 / overall)))))) # ::id bio.mskcc_0001.39 ::date 2015-01-21T12:14:33 ::annotator SDL-AMR-09 ::preferred # ::snt The mutant proteins were then examined for their abilities to heterodimerize with C-Raf and to bind activated Ras under conditions where feedback phosphorylation was induced (in cycling cells for the G466A mutants and in cells treated with PDGF for 30 min for the WT B-Raf mutants). # ::save-date Sun Jan 17, 2016 ::file bio_mskcc_0001_39.txt (e / examine-01 :ARG1 (p2 / possible-01 :mode interrogative :ARG1 (a / and :op1 (h / heterodimerize-01 :ARG1 (p / protein :ARG2-of (m / mutate-01) :ARG1-of (m2 / mean-01 :ARG2 (a3 / and :op1 (e4 / enzyme :name (n3 / name :op1 "B-Raf") :ARG2-of (m3 / mutate-01 :value "G466A") :location (c / cell :ARG1-of (c2 / cycle-02))) :op2 (e5 / enzyme :name (n4 / name :op1 "B-Raf") :ARG2-of m :mod (w / wild-type) :location (c3 / cell :ARG1-of (t2 / treat-04 :ARG2 (p4 / protein :name (n5 / name :op1 "PDGF")) :duration (t3 / temporal-quantity :quant 30 :unit (m4 / minute)))))))) :ARG2 (e2 / enzyme :name (n / name :op1 "C-Raf"))) :op2 (b / bind-01 :ARG1 (e3 / enzyme :name (n2 / name :op1 "Ras") :ARG1-of (a2 / activate-01))) :condition (i / induce-01 :ARG2 (p3 / phosphorylate-01 :subevent-of (f / feedback))))) :time (t / then)) # ::id bio.mskcc_0001.40 ::date 2015-01-21T13:09:21 ::annotator SDL-AMR-09 ::preferred # ::snt As shown in Fig. 6A, only mutation of the S151 feedback site, which is in close proximity to the Ras binding domain (residues 155 to 227), was found to significantly increase binding to activated Ras. # ::save-date Fri Jan 1, 2016 ::file bio_mskcc_0001_40.txt (f / find-01 :ARG1 (i / increase-01 :ARG0 (m / mutate-01 :ARG1 (a / amino-acid :mod 151 :name (n / name :op1 "serine") :part-of (p / protein-segment :destination-of (f2 / feedback) :ARG1-of (c / close-10 :ARG2 (d / domain :ARG2-of (b / bind-01 :ARG1 (e / enzyme :name (n2 / name :op1 "Ras"))) :ARG1-of (m2 / mean-01 :ARG2 (v / value-interval :op1 (r / residue :mod (a3 / amino-acid :value 155)) :op2 (r2 / residue :mod (a4 / amino-acid :value 227)))))))) :mod (o / only)) :ARG1 (b3 / bind-01 :ARG2 (e4 / enzyme :name (n5 / name :op1 "Ras") :ARG1-of (a2 / activate-01))) :ARG2 (s / significant-02)) :ARG1-of (s2 / show-01 :ARG0 (f3 / figure :mod "6A"))) # ::id bio.mskcc_0001.41 ::date 2015-01-21T14:06:45 ::annotator SDL-AMR-09 ::preferred # ::snt In contrast, mutation of S151A, T401A, and S750A T753A were all found to increase C-Raf binding (Fig. 6A), a finding consistent with peptide studies suggesting that there are multiple points of contact between heterodimerized B- and C-Raf proteins (27). # ::save-date Tue Jun 16, 2015 ::file bio_mskcc_0001_41.txt (c / contrast-01 :ARG2 (f / find-01 :ARG1 (i / increase-01 :ARG0 (a / and :op1 (m / mutate-01 :value "S151A") :op2 (m2 / mutate-01 :value "T401A") :op3 (m3 / mutate-01 :value "S750A") :op4 (m4 / mutate-01 :value "T753A")) :ARG1 (b / bind-01 :ARG1 (e / enzyme :name (n5 / name :op1 "C-Raf"))) :ARG1-of (d / describe-01 :ARG0 (f2 / figure :mod "6A"))) :ARG1-of (c2 / consistent-01 :ARG2 (s / study-01 :ARG1 (p / peptide) :ARG0-of (s2 / suggest-01 :ARG1 (c3 / contact-01 :ARG0 (e2 / enzyme :name (n6 / name :op1 "B-Raf") :ARG1-of (h / heterodimerize-01)) :ARG1 (e3 / enzyme :name (n7 / name :op1 "C-Raf") :ARG1-of h) :quant (m5 / multiple))) :ARG1-of (d2 / describe-01 :ARG0 (p2 / publication :ARG1-of (c4 / cite-01 :ARG2 27))))))) # ::id bio.mskcc_0001.42 ::date 2015-01-21T14:42:13 ::annotator SDL-AMR-09 ::preferred # ::snt Interestingly, when the S729A mutation was introduced into the FBm mutant, binding to C-Raf was abolished (Fig. 6A), indicating that the increased heterodimerization observed when the feedback sites are mutated is still dependent on 14-3-3 binding. # ::save-date Mon Feb 9, 2015 ::file bio_mskcc_0001_42.txt (a / abolish-01 :ARG1 (b / bind-01 :ARG2 (e / enzyme :wiki "C-Raf" :name (n / name :op1 "C-Raf"))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "6A")) :time (i / introduce-02 :ARG1 (m / mutate-01 :value "S729A") :ARG2 (e2 / enzyme :wiki - :name (n3 / name :op1 "B-Raf") :ARG2-of (m2 / mutate-01) :ARG1-of (h2 / have-part-91 :polarity - :ARG2 (p / protein-segment :destination-of (f3 / feedback))))) :manner (i2 / interesting) :ARG0-of (i3 / indicate-01 :ARG1 (d2 / depend-01 :ARG0 (h / heterodimerize-01 :ARG1-of (i4 / increase-01) :ARG1-of (o / observe-01 :time (m3 / mutate-01 :ARG1 (p2 / protein-segment :destination-of (f2 / feedback))))) :ARG1 (b2 / bind-01 :ARG2 (p3 / protein :wiki "14-3-3_protein" :name (n4 / name :op1 "14-3-3"))) :mod (s / still)))) # ::id bio.mskcc_0001.43 ::date 2014-11-21T12:50:26 ::annotator SDL-AMR-09 ::preferred # ::snt Given that oncogenic B-Raf proteins are targets of feedback phosphorylation, we next examined whether they might also be dephosphorylated and recycled in a manner involving the PP2A phosphatase and the Pin1 prolyl-isomerase. # ::save-date Wed Dec 9, 2015 ::file bio_mskcc_0001_43.txt (e / examine-01 :ARG0 (w / we) :ARG1 (p2 / possible-01 :mode interrogative :ARG1 (a / and :op1 (d / dephosphorylate-01 :ARG1 e2) :op2 (r / recycle-01 :ARG1 e2) :mod (a2 / also) :manner (i / involve-01 :ARG1 (a3 / and :op1 (p4 / phosphatase :name (n2 / name :op1 "PP2A")) :op2 (p3 / prolyl-isomerase :name (n3 / name :op1 "Pin1"))) :ARG2 a))) :ARG1-of (c / cause-01 :ARG0 (t / target-01 :ARG0 (p / phosphorylate-01 :subevent-of (f / feedback)) :ARG1 (e2 / enzyme :name (n / name :op1 "B-Raf") :ARG0-of (c2 / cause-01 :ARG1 (d2 / disease :wiki "Cancer" :name (n5 / name :op1 "cancer")))))) :time (n4 / next)) # ::id bio.mskcc_0001.44 ::date 2014-11-21T13:03:30 ::annotator SDL-AMR-09 ::preferred # ::snt As indicated in Fig. 7A, when PP2A was inhibited with okadaic acid treatment, slower-migrating forms of the V600E, G466A, and D594G B-Raf proteins were found to accumulate. # ::save-date Wed Nov 11, 2015 ::file bio_mskcc_0001_44.txt (f / find-01 :ARG1 (a / accumulate-01 :ARG1 (a2 / and :op1 (e2 / enzyme :name (n / name :op1 "B-Raf") :ARG2-of (m / mutate-01 :value "V600E")) :op2 (e3 / enzyme :name (n4 / name :op1 "B-Raf") :ARG2-of (m4 / mutate-01 :value "G466A")) :op3 (e4 / enzyme :name (n5 / name :op1 "B-Raf") :ARG2-of (m5 / mutate-01 :value "D594G")) :ARG0-of (m2 / migrate-01 :ARG1-of (s / slow-05 :degree (m3 / more)))) :condition (i / inhibit-01 :ARG1 (e / enzyme :name (n3 / name :op1 "PP2A")) :instrument (t / treat-04 :ARG2 (s2 / small-molecule :name (n2 / name :op1 "okadaic" :op2 "acid"))))) :ARG1-of (i2 / indicate-01 :ARG0 (f2 / figure :mod "7A"))) # ::id bio.mskcc_0001.45 ::date 2014-11-21T13:16:55 ::annotator SDL-AMR-09 ::preferred # ::snt Moreover, given their constitutive phosphorylation on S/TP sites (Fig. 3D), these oncogenic B-Raf mutants were found to interact constitutively with Pin1 (Fig. 7B), indicating that oncogenic B-Raf proteins are dephosphorylated and recycled. # ::save-date Fri Jan 1, 2016 ::file bio_mskcc_0001_45.txt (a / and :op2 (f / find-01 :ARG1 (i / interact-01 :ARG0 (e / enzyme :name (n / name :op1 "B-Raf") :ARG2-of (m / mutate-01) :ARG0-of (c3 / cause-01 :ARG1 (d4 / disease :wiki "Cancer" :name (n3 / name :op1 "cancer"))) :mod (t / this)) :ARG1 (e2 / enzyme :name (n2 / name :op1 "Pin1")) :mod (c5 / constitutive) :ARG1-of (d2 / describe-01 :ARG0 (f3 / figure :mod "7B")) :ARG0-of (i2 / indicate-01 :ARG1 (a2 / and :op1 (d3 / dephosphorylate-01 :ARG1 e) :op2 (r / recycle-01 :ARG1 e))) :ARG1-of (c / cause-01 :ARG0 (p / phosphorylate-01 :ARG2 (p2 / protein-segment :part-of e :mod (s / slash :op1 (a3 / amino-acid :name (n4 / name :op1 "serine")) :op2 (a4 / amino-acid :name (n5 / name :op1 "threonine")))) :mod (c2 / constitutive) :ARG1-of (d / describe-01 :ARG0 (f2 / figure :mod "3D"))))))) # ::id bio.mskcc_0001.46 ::date 2014-11-21T15:05:26 ::annotator SDL-AMR-09 ::preferred # ::snt Consistent with the model that Pin1 influences B-Raf signaling by facilitating the dephosphorylation of the feedback sites, overexpression of the Pin1 proteins had no effect on the transformation potential of G466A FBm-B-Raf, which lacks the sites of feedback phosphorylation. # ::save-date Fri Jan 1, 2016 ::file bio_mskcc_0001_46.txt (a / affect-01 :polarity - :ARG0 (o / overexpress-01 :ARG1 (e2 / enzyme :name (n / name :op1 "Pin1"))) :ARG1 (p / possible-01 :ARG1 (t2 / transform-01 :ARG0 (e3 / enzyme :name (n2 / name :op1 "B-Raf") :ARG2-of (m / mutate-01 :value "G466A") :ARG1-of (h / have-part-91 :polarity - :ARG2 (p2 / protein-segment :ARG1-of (p3 / phosphorylate-01 :subevent (f / feedback))))))) :ARG1-of (c / consistent-01 :ARG2 (m2 / model :topic (i / influence-01 :ARG0 e2 :ARG1 (s / signal-07 :ARG0 (e5 / enzyme :name (n4 / name :op1 "B-Raf"))) :manner (f2 / facilitate-01 :ARG0 (e4 / enzyme) :ARG1 (d / dephosphorylate-01 :ARG1 (p4 / protein-segment :part-of e5 :destination-of (f3 / feedback)))))))) # ::id bio.mskcc_0001.47 ::date 2014-11-22T17:41:50 ::annotator SDL-AMR-09 ::preferred # ::snt Previous studies have found that both the C-Raf and B-Raf proteins are targets of ERK-dependent feedback phosphorylation # ::save-date Sat Nov 22, 2014 ::file bio_mskcc_0001_47.txt (f / find-01 :ARG0 (s / study :time (p / previous)) :ARG1 (t / target-01 :ARG0 (p2 / phosphorylate-01 :subevent-of (f2 / feedback) :ARG0-of (d / depend-01 :ARG1 (e / enzyme :name (n / name :op1 "ERK")))) :ARG1 (a / and :op1 (e2 / enzyme :name (n2 / name :op1 "C-Raf")) :op2 (e3 / enzyme :name (n3 / name :op1 "B-Raf"))))) # ::id bio.mskcc_0001.48 ::date 2014-11-22T19:04:35 ::annotator SDL-AMR-09 ::preferred # ::snt In the case of C-Raf, six sites of feedback phosphorylation have been identified, five of which are direct targets of activated ERK (8) # ::save-date Fri Jul 24, 2015 ::file bio_mskcc_0001_48.txt (i / identify-01 :ARG1 (p / protein-segment :quant 6 :part-of (e / enzyme :name (n / name :op1 "C-Raf")) :ARG1-of (p2 / phosphorylate-01 :subevent-of (f / feedback)) :ARG2-of (i2 / include-91 :ARG1 (p3 / protein-segment :quant 5 :ARG1-of (t / target-01 :ARG0 (e2 / enzyme :name (n2 / name :op1 "ERK") :ARG1-of (a / activate-01)) :ARG1-of (d / direct-02))))) :ARG1-of (d2 / describe-01 :ARG0 (p4 / publication :ARG1-of (c / cite-01 :ARG2 8)))) # ::id bio.mskcc_0001.49 ::date 2014-11-22T19:09:15 ::annotator SDL-AMR-09 ::preferred # ::snt For B-Raf, previous work by Brummer et al. (3) identified the C-terminal S750 and T753 residues as sites phosphorylated by activated ERK. # ::save-date Tue Jun 9, 2015 ::file bio_mskcc_0001_49.txt (i / identify-01 :ARG0 (p / publication :ARG1-of (w / work-12 :ARG0 (a / and :op1 (p2 / person :name (n / name :op1 "Brummer")) :op2 (p3 / person :mod (o / other))) :time (p6 / previous)) :ARG1-of (c / cite-01 :ARG2 3)) :ARG1 (a2 / and :op1 (r / residue :mod (a3 / amino-acid :mod 750 :name (n2 / name :op1 "serine")) :part-of (p4 / protein-segment :name (n4 / name :op1 "C-terminus") :part-of (e2 / enzyme :name (n6 / name :op1 "B-Raf")))) :op2 (r2 / residue :mod (a4 / amino-acid :mod 753 :name (n3 / name :op1 "threonine")) :part-of p4)) :ARG2 (p5 / phosphorylate-01 :ARG1 a2 :ARG2 (e / enzyme :name (n5 / name :op1 "ERK") :ARG1-of (a5 / activate-01)))) # ::id bio.mskcc_0001.50 ::date 2014-11-22T19:21:02 ::annotator SDL-AMR-09 ::preferred # ::snt Through metabolic labeling experiments, we find here that in addition to the S750 and T753 sites, B-Raf is feedback phosphorylated on two other sites, S151 and T401. # ::save-date Wed Nov 26, 2014 ::file bio_mskcc_0001_50.txt (f / find-01 :ARG0 (w / we) :ARG1 (p / phosphorylate-01 :ARG1 (a / and :op1 (a2 / amino-acid :mod 750 :name (n / name :op1 "serine")) :op2 (a3 / amino-acid :mod 753 :name (n2 / name :op1 "threonine")) :op3 (a4 / amino-acid :mod 151 :name (n3 / name :op1 "serine")) :op4 (a5 / amino-acid :mod 401 :name (n4 / name :op1 "threonine")) :part-of (e2 / enzyme :name (n5 / name :op1 "B-Raf"))) :subevent-of (f2 / feedback)) :medium (h / here) :manner (e / experiment-01 :ARG2 (l / label-01 :mod (m / metabolism)))) # ::id bio.mskcc_0001.51 ::date 2014-11-22T19:29:50 ::annotator SDL-AMR-09 ::preferred # ::snt These residues are phosphorylated by activated ERK in vitro, # ::save-date Sat Nov 22, 2014 ::file bio_mskcc_0001_51.txt (p / phosphorylate-01 :ARG1 (r / residue :mod (t / this)) :ARG2 (e / enzyme :name (n / name :op1 "ERK") :ARG1-of (a / activate-01)) :manner (i / in-vitro)) # ::id bio.mskcc_0001.52 ::date 2014-11-22T19:31:23 ::annotator SDL-AMR-09 ::preferred # ::snt As has been observed for C-Raf, we find that the hyperphosphorylated B-Raf protein is subsequently dephosphorylated in a manner requiring the activities of the PP2A phosphatase and Pin1 prolyl-isomerase, indicating that the feedback phosphorylation/dephosphorylation cycle is a conserved regulatory mechanism for the Raf proteins. # ::save-date Sun Jan 17, 2016 ::file bio_mskcc_0001_52.txt (f / find-01 :ARG0 (w / we) :ARG1 (d / dephosphorylate-01 :ARG1 (e / enzyme :name (n / name :op1 "B-Raf") :ARG3-of (h / hyperphosphorylate-01)) :ARG1-of (r / resemble-01 :ARG2 (d2 / dephosphorylate-01 :ARG1 (e2 / enzyme :name (n2 / name :op1 "C-Raf") :ARG3-of (h2 / hyperphosphorylate-01)) :ARG1-of (o / observe-01))) :manner (r2 / require-01 :ARG0 d :ARG1 (a2 / and :op1 (a / act-02 :ARG0 (p / phosphatase :name (n3 / name :op1 "PP2A"))) :op2 (a4 / act-02 :ARG0 (p2 / prolyl-isomerase :name (n4 / name :op1 "Pin1"))))) :ARG0-of (i / indicate-01 :ARG1 (m / mechanism :ARG0-of (r3 / regulate-01 :ARG1 (p4 / protein-family :name (n5 / name :op1 "Raf"))) :ARG1-of (c / conserve-01) :domain (c2 / cycle-02 :subevent (p3 / phosphorylate-01) :subevent (d3 / dephosphorylate-01) :mod (f3 / feedback)))) :time (a3 / after :op1 h))) # ::id bio.mskcc_0001.53 ::date 2015-01-21T14:48:03 ::annotator SDL-AMR-09 ::preferred # ::snt Through mutational analysis, we find that feedback phosphorylation disrupts the abilities of B-Raf to bind activated Ras and to heterodimerize with C-Raf. # ::save-date Wed Jan 21, 2015 ::file bio_mskcc_0001_53.txt (f / find-01 :ARG0 (w / we) :ARG1 (d / disrupt-01 :ARG0 (p / phosphorylate-01 :subevent-of (f2 / feedback)) :ARG1 (c / capable-01 :ARG1 (e / enzyme :name (n / name :op1 "B-Raf")) :ARG2 (a2 / and :op1 (b / bind-01 :ARG1 e :ARG2 (e2 / enzyme :name (n2 / name :op1 "Ras") :ARG1-of (a / activate-01))) :op2 (h / heterodimerize-01 :ARG1 e :ARG2 (e3 / enzyme :name (n3 / name :op1 "C-Raf")))))) :manner (a3 / analyze-01 :ARG0 w :ARG1 (m / mutate-01))) # ::id bio.mskcc_0001.54 ::date 2015-01-21T15:23:22 ::annotator SDL-AMR-09 ::preferred # ::snt Although phosphorylation of the S151 site appears to have the greatest effect on Ras binding, our results indicate that phosphorylation of all the feedback sites contributes to the inhibition of C-Raf binding. # ::save-date Thu Feb 5, 2015 ::file bio_mskcc_0001_54.txt (i / indicate-01 :ARG0 (t / thing :ARG2-of (r / result-01) :poss (w / we)) :ARG1 (c / contribute-01 :ARG0 (p / phosphorylate-01 :ARG1 (p2 / protein-segment :mod (a / all) :destination-of (f / feedback))) :ARG2 (i2 / inhibit-01 :ARG1 (b / bind-01 :ARG2 (e / enzyme :name (n / name :op1 "C-Raf"))))) :concession (a2 / appear-02 :ARG1 (a3 / affect-01 :ARG0 (p3 / phosphorylate-01 :ARG1 (a4 / amino-acid :mod 151 :name (n2 / name :op1 "serine"))) :ARG1 (b2 / bind-01 :ARG2 (e2 / enzyme :name (n3 / name :op1 "Ras"))) :mod (g / great :degree (m / most))))) # ::id bio.mskcc_0001.55 ::date 2015-01-21T15:38:56 ::annotator SDL-AMR-09 ::preferred # ::snt This finding is consistent with those of peptide binding studies conducted by Rushworth et al. (27) indicating that there are multiple points of contact between heterodimerized B-Raf and C-Raf proteins. # ::save-date Wed Jan 21, 2015 ::file bio_mskcc_0001_55.txt (c / consistent-01 :ARG1 (t / thing :mod (t2 / this) :ARG1-of (f / find-01) :ARG0-of (i / indicate-01 :ARG1 (c4 / contact-01 :ARG0 (e / enzyme :name (n2 / name :op1 "B-Raf") :ARG1-of (h / heterodimerize-01)) :ARG1 (e2 / enzyme :name (n3 / name :op1 "C-Raf") :ARG1-of h) :quant (m / multiple)))) :ARG2 (t3 / thing :ARG1-of (f2 / find-01 :ARG0 (s / study-01 :ARG1 (b / bind-01 :ARG1 (p / peptide)) :ARG1-of (c2 / conduct-01 :ARG0 (a / and :op1 (p2 / person :name (n / name :op1 "Rushworth")) :op2 (p3 / person :mod (o / other)))))) :ARG1-of (d / describe-01 :ARG0 (p4 / publication :ARG1-of (c3 / cite-01 :ARG2 27))))) # ::id bio.mskcc_0001.56 ::date 2015-01-21T15:50:56 ::annotator SDL-AMR-09 ::preferred # ::snt Interestingly, these peptide binding studies also indicate that homodimerized B-Raf and C-Raf proteins have multiple contact points (27), suggesting that feedback phosphorylation of the Raf proteins may disrupt Raf homodimers as well # ::save-date Sun Jan 17, 2016 ::file bio_mskcc_0001_56.txt (i / indicate-01 :ARG0 (s / study-01 :ARG1 (b / bind-01 :ARG1 (p / peptide)) :mod (t / this)) :ARG1 (c / contact-01 :ARG0 (a2 / and :op1 (e / enzyme :wiki - :name (n / name :op1 "B-Raf")) :op2 (e2 / enzyme :wiki "C-Raf" :name (n2 / name :op1 "C-Raf")) :ARG3-of (h / homodimerize-01)) :quant (m / multiple)) :manner (i2 / interesting) :mod (a / also) :ARG1-of (d / describe-01 :ARG0 (p2 / publication :ARG1-of (c2 / cite-01 :ARG2 27))) :ARG0-of (s2 / suggest-01 :ARG1 (p3 / possible-01 :ARG1 (d2 / disrupt-01 :ARG0 (p4 / phosphorylate-01 :ARG1 (p5 / protein-family :wiki "RAF_kinase" :name (n3 / name :op1 "Raf")) :subevent-of (f / feedback)) :ARG1 (h2 / homodimer :part p5) :mod (a3 / as-well))))) # ::id bio.mskcc_0001.57 ::date 2014-11-24T15:21:00 ::annotator SDL-AMR-09 ::preferred # ::snt Taken together, these findings suggest a model whereby the binding of a 14-3-3 dimer to the C-terminal pS621 site of C-Raf and the C-terminal pS729 site of B-Raf provides the stable docking event that then allows the two proteins to make additional contacts (Fig. 9). # ::save-date Fri Jan 1, 2016 ::file bio_mskcc_0001_57.txt (s / suggest-01 :ARG0 (t / thing :ARG1-of (f / find-01) :mod (t2 / this) :ARG1-of (t3 / take-01 :mod (t4 / together))) :ARG1 (m / model :topic (p / provide-01 :ARG0 (a / and :op1 (b / bind-01 :ARG1 (d / dimer :mod (p6 / protein :name (n / name :op1 "14-3-3"))) :ARG2 (a2 / amino-acid :mod 621 :name (n2 / name :op1 "serine") :ARG3-of (p2 / phosphorylate-01) :part-of (p3 / protein-segment :name (n3 / name :op1 "C-terminus") :part-of (e / enzyme :name (n4 / name :op1 "C-Raf"))))) :op2 (b3 / bind-01 :ARG1 d :ARG2 (a3 / amino-acid :mod 729 :name (n5 / name :op1 "serine") :ARG3-of (p4 / phosphorylate-01) :part-of (p5 / protein-segment :name (n6 / name :op1 "C-terminus") :part-of (e2 / enzyme :name (n7 / name :op1 "B-Raf")))))) :ARG1 (d2 / dock-01 :ARG0-of (a4 / allow-01 :ARG1 (c / contact-01 :ARG0 e :ARG1 e2 :mod (a5 / additional) :time (a6 / after :op1 a))) :ARG1-of (s2 / stable-03)))) :ARG1-of (d3 / describe-01 :ARG0 (f2 / figure :mod 9))) # ::id bio.ras_0001.1 ::date 2014-08-13T14:22:25 ::annotator SDL-AMR-09 ::preferred # ::snt The most frequently mutated oncogenes in the deadliest cancers responsible for human mortality are KRAS , PIK3CA and BRAF . # ::save-date Wed Dec 9, 2015 ::file bio_ras_0001_1.txt (o / oncogene :domain (a / and :op1 (g / gene :name (n / name :op1 "KRAS")) :op2 (g2 / gene :name (n2 / name :op1 "PIK3CA")) :op3 (g3 / gene :name (n3 / name :op1 "BRAF"))) :ARG1-of (m2 / mutate-01 :ARG1-of (f / frequent-02 :degree (m3 / most))) :location (d / disease :wiki "Cancer" :name (n4 / name :op1 "cancer") :ARG0-of (k / kill-01 :ARG1 (h / human) :degree (m / most)))) # ::id bio.ras_0001.2 ::date 2014-08-13T16:12:45 ::annotator SDL-AMR-09 ::preferred # ::snt Importantly the signaling enzymes encoded by PIK3CA and BRAF are , in part , regulated by direct binding to activated forms of the Ras proteins suggesting that dysregulation of this key step in signaling is critical for tumor formation . # ::save-date Sat Jan 16, 2016 ::file bio_ras_0001_2.txt (r / regulate-01 :ARG0 (b / bind-01 :ARG1 e :ARG2 (e3 / enzyme :name (n3 / name :op1 "Ras") :ARG1-of (a2 / activate-01)) :ARG1-of (d / direct-02)) :ARG1 (e / enzyme :ARG0-of (s / signal-07) :ARG1-of (e2 / encode-01 :ARG0 (a / and :op1 (g / gene :name (n / name :op1 "PIK3CA")) :op2 (g2 / gene :name (n2 / name :op1 "BRAF"))))) :degree (p / part) :mod (i / important) :ARG0-of (s2 / suggest-01 :ARG1 (c / critical-02 :ARG1 (i2 / impair-01 :ARG1 r) :ARG2 (f / form-01 :ARG1 (t / tumor))))) # ::id bio.ras_0001.3 ::date 2014-08-13T16:08:20 ::annotator SDL-AMR-09 ::preferred # ::snt Ras acts as a molecular switch that is activated upon GTP loading and deactivated upon hydrolysis of GTP to GDP . # ::save-date Wed Dec 10, 2014 ::file bio_ras_0001_3.txt (s / switch :domain (e / enzyme :name (n / name :op1 "Ras")) :ARG1-of (a / activate-01 :ARG0 (l / load-01 :ARG1 e :ARG2 (s2 / small-molecule :name (n2 / name :op1 "GTP")))) :ARG1-of (d / deactivate-01 :ARG0 (h / hydrolyze-01 :ARG1 s2 :ARG3 (s3 / small-molecule :name (n3 / name :op1 "GDP")))) :mod (m / molecule)) # ::id bio.ras_0001.4 ::date 2014-08-13T17:11:08 ::annotator SDL-AMR-09 ::preferred # ::snt This switch mechanism is common to a wide variety of GTP - binding proteins and is mediated by a conserved structure called the G - domain that consists of five conserved G boxes . # ::save-date Fri Jan 15, 2016 ::file bio_ras_0001_4.txt (s / share-01 :ARG0 (p / protein :ARG2-of (b / bind-01 :ARG1 (s4 / small-molecule :name (n / name :op1 "GTP"))) :mod (v / various :ARG1-of (w / wide-02))) :ARG1 (m / mechanism :topic (s2 / switch) :mod (t / this)) :manner (p2 / protein-segment :name (n2 / name :op1 "G-domain") :ARG1-of (c2 / conserve-01) :part (p3 / protein-segment :quant 5 :name (n3 / name :op1 "G" :op2 "box") :ARG1-of (c3 / conserve-01)))) # ::id bio.ras_0001.5 ::date 2014-08-13T18:43:18 ::annotator SDL-AMR-09 ::preferred # ::snt Under physiological conditions , the rate of GDP or GTP release from the G - domain is slow . # ::save-date Thu Sep 25, 2014 ::file bio_ras_0001_5.txt (s / slow-05 :ARG1 (r / release-01 :ARG1 (o / or :op1 (s2 / small-molecule :name (n / name :op1 "GDP")) :op2 (s3 / small-molecule :name (n2 / name :op1 "GTP"))) :ARG2 (p3 / protein-segment :name (n3 / name :op1 "G-domain"))) :condition (p2 / physiology)) # ::id bio.ras_0001.6 ::date 2014-08-13T16:59:02 ::annotator SDL-AMR-09 ::preferred # ::snt As a consequence the GDP produced by GTP hydrolysis on Ras is trapped and the bulk of cellular Ras accumulates in the GDP - bound ‘off’ state , despite the high GTP / GDP ratio in the cytosol ( 1 – 3 ) . # ::save-date Sun Jul 26, 2015 ::file bio_ras_0001_6.txt (c / cause-01 :ARG1 (a / and :op1 (t / trap-01 :ARG1 (s / small-molecule :name (n / name :op1 "GDP") :ARG3-of (h / hydrolyze-01 :ARG1 (s2 / small-molecule :name (n2 / name :op1 "GTP") :ARG1-of (b3 / bind-01 :ARG2 (e / enzyme :name (n3 / name :op1 "Ras"))))))) :op2 (a2 / accumulate-01 :ARG1 (e3 / enzyme :name (n4 / name :op1 "Ras") :ARG1-of (i / include-91 :ARG2 (e2 / enzyme :name (n5 / name :op1 "Ras") :location (c5 / cell)) :ARG3 (b / bulk)) :ARG1-of (d / deactivate-01) :ARG2-of (b2 / bind-01 :ARG1 s)) :concession (h2 / high-02 :ARG1 (r / ratio-of :op1 s2 :op2 s :location (c6 / cytosol))))) :ARG1-of (a3 / attest-01 :ARG0 (p4 / publication :ARG1-of (c7 / cite-01 :ARG2 (v / value-interval :op1 1 :op2 3))))) # ::id bio.ras_0001.7 ::date 2014-08-13T18:57:28 ::annotator SDL-AMR-09 ::preferred # ::snt Growth factors can turn on Ras by activating Guanine nucleotide Exchange Factors ( GEFs ) or by inhibiting the GTPase Activating Proteins ( GAPs ) or by both mechanisms . # ::save-date Wed Feb 24, 2016 ::file bio_ras_0001_7.txt (p5 / possible-01 :ARG1 (t / turn-on-13 :ARG0 (g / growth-factor) :ARG1 (e2 / enzyme :name (n / name :op1 "Ras")) :manner (o / or :op1 (a / activate-01 :ARG0 g :ARG1 (p2 / protein :name (n2 / name :op1 "guanine" :op2 "nucleotide" :op3 "exchange" :op4 "factor"))) :op2 (i / inhibit-01 :ARG0 g :ARG1 (p3 / protein :ARG0-of (a2 / activate-01 :ARG1 (e / enzyme :name (n3 / name :op1 "GTPase"))))) :op3 (a3 / and :op1 a :op2 i)))) # ::id bio.ras_0001.8 ::date 2014-08-13T19:05:56 ::annotator SDL-AMR-09 ::preferred # ::snt RasGEFs bind to Ras and lower the transition energy for the nucleotide exchange of the bound GDP for the more abundant cytosolic GTP , whereas RasGAPs bind to Ras and catalyze GTP hydrolysis . # ::save-date Fri Jan 1, 2016 ::file bio_ras_0001_8.txt (c / contrast-01 :ARG1 (a / and :op1 (b / bind-01 :ARG1 (p / protein :name (n / name :op1 "RasGEF")) :ARG2 (e3 / enzyme :name (n2 / name :op1 "Ras"))) :op2 (l / lower-05 :ARG0 p :ARG1 (e / energy :mod (t / transition-01) :poss (e2 / exchange-01 :ARG1 (s2 / small-molecule :name (n4 / name :op1 "GDP") :ARG1-of (b2 / bind-01 :ARG2 e3)) :ARG3 (s / small-molecule :name (n5 / name :op1 "GTP") :mod (a2 / abundant :degree (m / more) :compared-to s2) :location (c3 / cytosol)))))) :ARG2 (a3 / and :op1 (b3 / bind-01 :ARG1 (p5 / protein :name (n3 / name :op1 "RasGAP")) :ARG2 e3) :op2 (c2 / catalyze-01 :ARG0 p5 :ARG1 (h / hydrolyze-01 :ARG1 s)))) # ::id bio.ras_0001.9 ::date 2014-08-13T20:35:42 ::annotator SDL-AMR-09 ::preferred # ::snt The most prevalent oncogenic mutations in Ras ( Gly12 and Gly13 in the G1 box , and Gln61 in the G3 box ) preserve the GTP bound state by inhibiting intrinsic GTPase activity and by interfering with the ability of GAPs . # ::save-date Wed Dec 9, 2015 ::file bio_ras_0001_9.txt (p / preserve-01 :ARG0 (m / mutation :ARG1-of (p2 / prevail-02 :degree (m2 / most) :compared-to (e / enzyme :name (n / name :op1 "Ras"))) :ARG0-of (c / cause-01 :ARG1 (d / disease :wiki "Cancer" :name (n10 / name :op1 "cancer"))) :location (a / and :op1 (p4 / protein-segment :name (n2 / name :op1 "Gly12") :location (p7 / protein-segment :name (n5 / name :op1 "G1" :op2 "box") :location e)) :op2 (p5 / protein-segment :name (n3 / name :op1 "Gly13") :location p7) :op3 (p6 / protein-segment :name (n4 / name :op1 "Gln61") :location (p8 / protein-segment :name (n6 / name :op1 "G3" :op2 "box") :location e)))) :ARG1 (b / bind-01 :ARG1 (s / small-molecule :name (n7 / name :op1 "GTP")) :ARG2 e) :manner (a2 / and :op1 (i / inhibit-01 :ARG0 m :ARG1 (a3 / activity-06 :ARG0 (e2 / enzyme :name (n8 / name :op1 "GTPase")) :mod (i3 / intrinsic))) :op2 (i2 / interfere-01 :ARG0 m :ARG1 (c4 / capable-01 :ARG1 (p10 / protein :name (n9 / name :op1 "GAP")))))) # ::id bio.ras_0001.10 ::date 2014-08-13T21:50:34 ::annotator SDL-AMR-09 ::preferred # ::snt Other less frequently observed mutations , such as those found in the G4 and G5 boxes , increase the rate of nucleotide exchange , thereby mimicking the GEFs and increasing the GTP - bound state ( 1 – 7 ) . # ::save-date Sat Jul 25, 2015 ::file bio_ras_0001_10.txt (i / increase-01 :ARG0 (m / mutation :ARG1-of (o / observe-01 :ARG1-of (f / frequent-02 :degree (l / less))) :mod (o2 / other) :example (m2 / mutation :location (o3 / or :op1 (p / protein-segment :name (n / name :op1 "G4" :op2 "box")) :op2 (p2 / protein-segment :name (n2 / name :op1 "G5" :op2 "box"))))) :ARG1 (r / rate :degree-of (e / exchange-01 :ARG1 (n3 / nucleotide))) :manner-of (m3 / mimic-01 :ARG0 m :ARG1 (p3 / protein :name (n4 / name :op1 "GEF"))) :ARG0-of (c / cause-01 :ARG1 (i2 / increase-01 :ARG1 (n7 / number :quant-of (e2 / enzyme :name (n5 / name :op1 "Ras") :ARG2-of (b / bind-01 :ARG1 (s / small-molecule :name (n6 / name :op1 "GTP"))))))) :ARG1-of (a / attest-01 :ARG0 (p6 / publication :ARG1-of (c2 / cite-01 :ARG2 (v / value-interval :op1 1 :op2 7))))) # ::id bio.ras_0002.1 ::date 2015-01-13T21:00:03 ::annotator SDL-AMR-09 ::preferred # ::snt Activated Ras controls diverse signaling pathways that ultimately determine Ras - induced cellular responses such as cell proliferation , survival , differentiation and motility . # ::save-date Wed Jun 3, 2015 ::file bio_ras_0002_1.txt (c / control-01 :ARG0 (e / enzyme :name (n / name :op1 "Ras") :ARG1-of (a / activate-01)) :ARG1 (p / pathway :mod (d / diverse) :ARG0-of (s / signal-07) :ARG0-of (d2 / determine-01 :ARG1 (r / respond-01 :ARG0 (c2 / cell) :ARG2 (a2 / and :op1 (p2 / proliferate-01 :ARG0 c2) :op2 (s2 / survive-01 :ARG0 c2) :op3 (d3 / differentiate-01 :ARG1 c2) :op4 (m / motility :mod c2)) :ARG2-of (i / induce-01 :ARG0 e)) :time (u / ultimate)))) # ::id bio.ras_0002.2 ::date 2015-01-13T20:53:19 ::annotator SDL-AMR-09 ::preferred # ::snt These multiple Ras functions depend on its binding to a range of functionally diverse effector molecules such as Raf , PI3K , AF6 and RASSFs ( 1 ) . # ::save-date Thu Feb 5, 2015 ::file bio_ras_0002_2.txt (d / depend-01 :ARG0 (t3 / thing :quant (m / multiple) :mod (t / this) :ARG1-of (f / function-01 :ARG0 (e / enzyme :name (n / name :op1 "Ras")))) :ARG1 (b / bind-01 :ARG1 e :ARG2 (m2 / molecule :mod (e3 / effector) :example (a / and :op1 (e2 / enzyme :name (n2 / name :op1 "Raf")) :op2 (e4 / enzyme :name (n3 / name :op1 "PI3K")) :op3 (e5 / enzyme :name (n4 / name :op1 "AF6")) :op4 (p / protein :name (n5 / name :op1 "RASSF"))) :quant (r / range) :ARG0-of (f2 / function-01 :mod (d2 / diverse)))) :ARG1-of (d3 / describe-01 :ARG0 (p2 / publication :ARG1-of (c / cite-01 :ARG2 1)))) # ::id bio.ras_0002.3 ::date 2015-01-14T04:48:20 ::annotator SDL-AMR-09 ::preferred # ::snt The enhancement of specific effector pathways plays a critical role in maintaining an appropriate biological response ( 8 ) . # ::save-date Fri Jan 1, 2016 ::file bio_ras_0002_3.txt (p / play-02 :ARG0 (e / enhance-01 :ARG1 (p2 / pathway :mod (e2 / effector) :ARG1-of (s / specific-02))) :ARG1 (r / role :ARG1-of (c / critical-02 :ARG2 (m / maintain-01 :ARG0 e :ARG1 (t / thing :ARG2-of (r2 / respond-01) :mod (b / biology) :ARG1-of (a / appropriate-02))))) :ARG1-of (d / describe-01 :ARG2 (p3 / publication :ARG1-of (c2 / cite-01 :ARG2 8)))) # ::id bio.ras_0002.4 ::date 2015-01-14T06:53:00 ::annotator SDL-AMR-09 ::preferred # ::snt The specificity in Ras - induced signaling is primarily determined by the balance between Ras affinity for each of its effectors and the local concentrations of those effectors . # ::save-date Sun Jul 26, 2015 ::file bio_ras_0002_4.txt (d / determine-01 :ARG0 (b / balance-01 :ARG1 (a / affinity :poss (e / enzyme :name (n / name :op1 "Ras")) :topic (e2 / effector :mod (e3 / each) :poss e)) :ARG2 (c / concentrate-02 :ARG1 e2 :ARG1-of (l / local-02))) :ARG1 (s / specificity :mod (s2 / signal-07 :ARG2-of (i / induce-01 :ARG0 e))) :mod (p / primary)) # ::id bio.ras_0002.5 ::date 2015-01-14T07:23:18 ::annotator SDL-AMR-09 ::preferred # ::snt In addition , scaffold proteins have been shown to guide activation of specific effector pathway(s) . For example , SHOC2 / Sur-8 bridges Ras and Raf to specifically enhance the Raf / MEK / ERK pathway without enhancing PI3K / AKT signaling ( 9 , 10 ) . # ::save-date Fri Jul 24, 2015 ::file bio_ras_0002_5.txt (m / multi-sentence :snt1 (a4 / and :op2 (s / show-01 :ARG1 (g / guide-01 :ARG0 (p / protein :mod (s5 / scaffold)) :ARG1 (a / activate-01 :ARG1 (p2 / pathway :mod (e5 / effector) :mod (s2 / specific)))))) :snt2 (e8 / exemplify-01 :ARG0 (b / bridge-01 :ARG0 (m2 / macro-molecular-complex :part (e3 / enzyme :name (n3 / name :op1 "SHOC2")) :part (e4 / enzyme :name (n4 / name :op1 "Sur-8"))) :ARG1 (e / enzyme :name (n / name :op1 "Ras")) :ARG2 (e2 / enzyme :name (n2 / name :op1 "Raf")) :purpose (e6 / enhance-01 :ARG0 m2 :ARG1 (p4 / pathway :name (n7 / name :op1 "Raf/MEK/ERK")) :ARG1-of (s3 / specific-02)) :manner (e7 / enhance-01 :polarity - :ARG0 m2 :ARG1 (s4 / signal-07 :ARG0 (p5 / pathway :name (n8 / name :op1 "PI3K/AKT")))) :ARG1-of (d / describe-01 :ARG0 (p6 / publication :ARG1-of (c / cite-01 :ARG2 (a3 / and :op1 9 :op2 10))))))) # ::id bio.ras_0003.1 ::date 2015-01-19T01:16:07 ::annotator SDL-AMR-09 ::preferred # ::snt We utilized an unbiased mass spectrometry - based approach to identify ubiquitination sites of Ras . # ::save-date Mon Jan 19, 2015 ::file bio_ras_0003_1.txt (u / utilize-01 :ARG0 (w / we) :ARG1 (a / approach-02 :ARG1-of (b / bias-01 :polarity -) :ARG1-of (b2 / base-02 :ARG2 (s / spectrometry :mod (m / mass)))) :purpose (i / identify-01 :ARG0 w :ARG1 (p / protein-segment :part-of (e / enzyme :name (n / name :op1 "Ras")) :ARG1-of (u2 / ubiquitinate-01)))) # ::id bio.ras_0003.2 ::date 2015-01-19T01:53:15 ::annotator SDL-AMR-09 ::preferred # ::snt His - tagged ubiquitin and Flag - tagged K-Ras4B ( K-Ras hereafter ) were expressed in HEK293T cells at levels similar to endogenous K-Ras ( Fig. 1B ) and subjected to sequential affinity chromatography . # ::save-date Fri Feb 6, 2015 ::file bio_ras_0003_2.txt (a3 / and :op1 (e2 / express-03 :ARG2 (a / and :op1 (p / protein :name (n / name :op1 "ubiquitin") :ARG1-of (t / tag-01 :ARG2 (a2 / amino-acid :name (n3 / name :op1 "histidine")))) :op2 (e / enzyme :name (n2 / name :op1 "K-Ras4B") :name (n7 / name :op1 "K-Ras") :ARG1-of (t2 / tag-01 :ARG2 (p2 / protein-segment :name (n4 / name :op1 "Flag"))))) :ARG3 (c / cell-line :name (n5 / name :op1 "HEK293T")) :degree (l / level :ARG1-of (r / resemble-01 :ARG2 (l2 / level :degree-of (e4 / express-03 :ARG2 (e3 / enzyme :name (n6 / name :op1 "K-Ras") :mod (e5 / endogenous)))))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "1B"))) :op2 (s / subject-01 :ARG1 a :ARG2 (c2 / chromatography :mod (a4 / affinity) :mod (s2 / sequence)))) # ::id bio.ras_0003.3 ::date 2015-01-19T02:56:52 ::annotator SDL-AMR-09 ::preferred # ::snt His - ubiquitinated proteins were purified by Co2+ metal affinity chromatography in 8M urea denaturing conditions . # ::save-date Mon Oct 26, 2015 ::file bio_ras_0003_3.txt (p / purify-01 :ARG1 (p2 / protein :ARG3-of (u / ubiquitinate-01 :mod (a / amino-acid :name (n / name :op1 "histidine")))) :manner (c / chromatography :mod (a2 / affinity :topic (c3 / copper :ARG1-of (i / ionize-01 :value "2+"))) :condition (d2 / denature-01 :ARG1 p2 :ARG4 (s / small-molecule :name (n3 / name :op1 "urea") :mod (c2 / concentration-quantity :quant 8 :unit (m / molar)))))) # ::id bio.ras_0003.4 ::date 2015-01-19T05:25:54 ::annotator SDL-AMR-09 ::preferred # ::snt His - ubiquitinated K-Ras was subsequently purified with anti - Flag resin . # ::save-date Mon Jan 19, 2015 ::file bio_ras_0003_4.txt (p / purify-01 :ARG1 (e / enzyme :name (n / name :op1 "K-Ras") :ARG3-of (u / ubiquitinate-01 :mod (a / amino-acid :name (n2 / name :op1 "histidine")))) :time (s / subsequent) :instrument (r / resin :ARG0-of (c / counter-01 :ARG1 (p2 / protein-segment :name (n3 / name :op1 "Flag"))))) # ::id bio.ras_0003.5 ::date 2015-01-19T05:43:28 ::annotator SDL-AMR-09 ::preferred # ::snt Following purification , mono- and di- ubiquitinated K-Ras appeared to be the major ubiquitination forms , which is consistent with the endogenous K-Ras ubiquitination pattern ( Fig. 1 , A and B ) . # ::save-date Thu Jul 30, 2015 ::file bio_ras_0003_5.txt (a / appear-02 :ARG1 (f2 / form :mod (u2 / ubiquitinate-01) :ARG1-of (m / major-02) :domain (e / enzyme :name (n / name :op1 "K-Ras") :ARG3-of (u / ubiquitinate-01 :quant (o / or :op1 1 :op2 2)))) :ARG1-of (f / follow-01 :ARG2 (p / purify-01 :ARG1 e)) :ARG1-of (c / consistent-01 :ARG2 (p2 / pattern :topic (u3 / ubiquitinate-01 :ARG1 (e2 / enzyme :name (n2 / name :op1 "K-Ras") :mod (e3 / endogenous))))) :ARG1-of (d / describe-01 :ARG0 (a2 / and :op1 (f3 / figure :mod "1A") :op2 (f4 / figure :mod "1B")))) # ::id bio.ras_0003.6 ::date 2015-01-19T06:56:05 ::annotator SDL-AMR-09 ::preferred # ::snt H-Ras ubiquitination sites were also determined by the same approach . # ::save-date Fri Feb 6, 2015 ::file bio_ras_0003_6.txt (d / determine-01 :ARG1 (p / protein-segment :ARG1-of (u / ubiquitinate-01) :part-of (e / enzyme :name (n / name :op1 "H-Ras"))) :mod (a / also) :manner (a2 / approach-02 :ARG1-of (s / same-01))) # ::id bio.ras_0003.7 ::date 2015-01-19T07:05:34 ::annotator SDL-AMR-09 ::preferred # ::snt Tandem mass spectrometric analysis of tryptic fragments from the bands migrating at the positions expected for mono- and di- ubiquitinated Ras revealed ubiquitination at Lys residues 104 and 147 of K-Ras , and Lys residues 117 , 147 and 170 for H-Ras ( fig. S1C ) . # ::save-date Sun Jul 5, 2015 ::file bio_ras_0003_7.txt (r / reveal-01 :ARG0 (a / analyze-01 :ARG1 (f / fragment :source (b / band :ARG0-of (m / migrate-01 :ARG2 (p / position :ARG2-of (b2 / be-located-at-91 :ARG1 (e / enzyme :name (n / name :op1 "Ras") :ARG3-of (u / ubiquitinate-01 :quant (o / or :op1 1 :op2 2))) :ARG1-of (e4 / expect-01))))) :mod (e5 / enzyme :name (n9 / name :op1 "trypsin"))) :manner (s / spectrometry :mod (m2 / mass) :mod (t2 / tandem))) :ARG1 (u2 / ubiquitinate-01 :ARG1 (a2 / and :op1 (a3 / and :op1 (r2 / residue :mod (a4 / amino-acid :mod 104 :name (n4 / name :op1 "lysine"))) :op2 (r3 / residue :mod (a5 / amino-acid :mod 147 :name (n5 / name :op1 "lysine"))) :part-of (e2 / enzyme :name (n2 / name :op1 "K-Ras"))) :op2 (a6 / and :op1 (r4 / residue :mod (a7 / amino-acid :mod 117 :name (n6 / name :op1 "lysine"))) :op2 (r5 / residue :mod (a8 / amino-acid :mod 147 :name (n7 / name :op1 "lysine"))) :op3 (r6 / residue :mod (a9 / amino-acid :mod 170 :name (n8 / name :op1 "lysine"))) :part-of (e3 / enzyme :name (n3 / name :op1 "H-Ras"))))) :ARG1-of (d / describe-01 :ARG0 (f2 / figure :mod "S1C"))) # ::id bio.ras_0003.8 ::date 2015-01-19T07:59:53 ::annotator SDL-AMR-09 ::preferred # ::snt The tryptic peptide with ubiquitination at Lys147 ( K147 ) was the most frequently observed peptide for both K-Ras and H-Ras , while Lys117 appeared as a secondary major ubiquitination site in H-Ras . # ::save-date Fri Jan 1, 2016 ::file bio_ras_0003_8.txt (c / contrast-01 :ARG1 (p / peptide :part-of (a / and :op1 (e / enzyme :name (n / name :op1 "K-Ras")) :op2 (e2 / enzyme :name (n2 / name :op1 "H-Ras"))) :domain (p2 / peptide :ARG3-of (h / hydrolyze-01 :ARG2 (e3 / enzyme :name (n3 / name :op1 "trypsin"))) :part (a2 / amino-acid :mod 147 :name (n4 / name :op1 "lysine") :ARG1-of (u / ubiquitinate-01))) :ARG1-of (o / observe-01 :ARG1-of (f / frequent-02 :degree (m / most)))) :ARG2 (a3 / appear-01 :ARG1 (p3 / protein-segment :ARG1-of (m2 / major-02) :ARG1-of (u2 / ubiquitinate-01) :mod (s / secondary) :domain (a4 / amino-acid :mod 117 :name (n5 / name :op1 "lysine")) :part-of e2))) # ::id bmtr_0006.1 ::date 2015-02-25T09:09:15 ::annotator SDL-AMR-09 ::preferred # ::snt A New Dimension to Ras Function: A Novel Role for Nucleotide-Free Ras in Class II Phosphatidylinositol 3-Kinase Beta (PI3KC2β) Regulation (PMC3441633) # ::save-date Thu Feb 4, 2016 ::file bmtr_0006_1.txt (d3 / dimension :ARG1-of (n2 / new-01) :topic (f / function-01 :ARG0 (e / enzyme :name (n / name :op1 "Ras"))) :ARG0-of (m2 / mean-01 :ARG1 (r / role :mod (n3 / novel) :mod (e2 / enzyme :name (n4 / name :op1 "Ras") :ARG1-of (f2 / free-04 :ARG2 (n5 / nucleotide))) :purpose (r2 / regulate-01 :ARG0 e2 :ARG1 (e3 / enzyme :name (n6 / name :op1 "Phosphatidylinositol" :op2 "3-Kinase" :op3 "Beta") :mod (c / class :ord (o / ordinal-entity :value 2)))))) :ARG1-of (d2 / describe-01 :ARG0 (p / publication-91 :ARG8 "PMC3441633"))) # ::id bmtr_0006.2 ::date 2015-02-25T09:23:27 ::annotator SDL-AMR-09 ::preferred # ::snt Ras, like all GTPases, cycles between an inactive GDP-bound state and an active GTP-bound state. # ::save-date Fri Jan 1, 2016 ::file bmtr_0006_2.txt (c / cycle-02 :ARG1 (e / enzyme :name (n / name :op1 "Ras") :ARG1-of (s / same-01 :ARG2 (e2 / enzyme :name (n2 / name :op1 "GTPase") :mod (a / all)))) :ARG3 (e5 / enzyme :name (n5 / name :op1 "Ras") :ARG0-of (a2 / activity-06 :polarity -) :ARG1-of (b2 / bind-01 :ARG2 (s3 / small-molecule :name (n3 / name :op1 "GDP")))) :ARG4 (e4 / enzyme :name (n6 / name :op1 "Ras") :ARG0-of (a3 / activity-06) :ARG1-of (b3 / bind-01 :ARG2 (s5 / small-molecule :name (n4 / name :op1 "GTP"))))) # ::id bmtr_0006.3 ::date 2015-02-25T09:34:42 ::annotator SDL-AMR-09 ::preferred # ::snt The transition from the inactive to active state requires formation of nucleotide-free Ras through the action of exchange factors. # ::save-date Mon Jan 4, 2016 ::file bmtr_0006_3.txt (r / require-01 :ARG0 (t / transition-01 :ARG2 (s2 / state :ARG0-of (a2 / activity-06)) :ARG3 (s / state :ARG0-of (a / activity-06 :polarity -))) :ARG1 (f / form-01 :ARG1 (e / enzyme :name (n / name :op1 "Ras") :ARG1-of (f2 / free-04 :ARG2 (n2 / nucleotide))) :manner (a3 / act-01 :ARG0 (f3 / factor :ARG0-of (e2 / exchange-01))))) # ::id bmtr_0006.4 ::date 2015-02-25T09:44:18 ::annotator SDL-AMR-09 ::preferred # ::snt This state is considered to be a short-lived transition state intermediate in vivo [36] based on the relatively high GTP: GDP ratio in vivo [37], the ability of GTP to dissociate the GEF-Ras complex in vitro [31], and the assumption that there are no proteins in vivo that might stabilize nucleotide-free Ras and prevent GTP loading. # ::save-date Fri Jan 1, 2016 ::file bmtr_0006_4.txt (c / consider-01 :ARG1 (s3 / state :ARG1-of (t / transition-01) :ARG0-of (l / live-01 :ARG1-of (s4 / short-07)) :mod (i / intermediate :manner (i2 / in-vivo)) :ARG1-of (b / base-02 :ARG2 (a / and :op1 (r / ratio-of :op1 (s / small-molecule :name (n / name :op1 "GTP")) :op2 (s2 / small-molecule :wiki "Guanosine_diphosphate" :name (n2 / name :op1 "GDP")) :manner i2 :ARG1-of (h / high-02 :ARG2-of (r2 / relative-05)) :ARG1-of (d2 / describe-01 :ARG0 (p2 / publication-91 :ARG1-of (c2 / cite-01 :ARG2 37)))) :op2 (c5 / capable-01 :ARG1 s :ARG2 (d / dissociate-01 :ARG0 s :ARG1 (m / macro-molecular-complex :part (p3 / protein :name (n4 / name :op1 "GEF")) :part (e / enzyme :name (n3 / name :op1 "Ras"))) :manner (i3 / in-vitro)) :ARG1-of (d3 / describe-01 :ARG0 (p7 / publication-91 :ARG1-of (c3 / cite-01 :ARG2 31)))) :op3 (a2 / assume-02 :ARG1 (p4 / protein :polarity - :manner i2 :ARG0-of (s5 / stabilize-01 :ARG1 (e2 / enzyme :name (n5 / name :op1 "Ras") :ARG1-of (f / free-04 :ARG2 (n6 / nucleotide))) :ARG1-of (p5 / possible-01)) :ARG0-of (p6 / prevent-01 :ARG1 (l2 / load-01 :ARG2 s) :ARG1-of p5))))) :ARG1-of (d4 / describe-01 :ARG0 (p8 / publication-91 :ARG1-of (c4 / cite-01 :ARG2 36))) :mod (t2 / this))) # ::id bmtr_0006.5 ::date 2015-02-25T10:26:21 ::annotator SDL-AMR-09 ::preferred # ::snt However, our results provide the first direct evidence for a protein that may stabilize nucleotide-free Ras in vivo. # ::save-date Fri Jul 24, 2015 ::file bmtr_0006_5.txt (c / contrast-01 :ARG2 (p / provide-01 :ARG0 (t / thing :ARG2-of (r / result-01) :poss (w / we)) :ARG1 (e2 / evidence :ARG1-of (d / direct-02) :ord (o2 / ordinal-entity :value 1) :topic (p2 / protein :ARG0-of (s / stabilize-01 :ARG1 (e / enzyme :name (n / name :op1 "Ras") :ARG1-of (f / free-04 :ARG2 (n2 / nucleotide))) :ARG1-of (p3 / possible-01) :manner (i / in-vivo)))))) # ::id bmtr_0006.6 ::date 2015-02-25T10:37:26 ::annotator SDL-AMR-09 ::preferred # ::snt We demonstrate that the RBD of PI3KC2β binds nucleotide-free Ras in vitro (Fig. 5). # ::save-date Tue May 5, 2015 ::file bmtr_0006_6.txt (d / demonstrate-01 :ARG0 (w / we) :ARG1 (b / bind-01 :ARG1 (p / protein-segment :name (n2 / name :op1 "RBD") :part-of (e2 / enzyme :name (n3 / name :op1 "PI3KC2β"))) :ARG2 (e / enzyme :name (n / name :op1 "Ras") :ARG1-of (f / free-04 :ARG2 (n4 / nucleotide))) :manner (i / in-vitro)) :ARG1-of (d2 / describe-01 :ARG0 (f2 / figure :mod 5))) # ::id bmtr_0006.7 ::date 2015-02-25T10:43:42 ::annotator SDL-AMR-09 ::preferred # ::snt In contrast to the GEF-Ras complex, which is disrupted by addition of guanine nucleotides, the PI3KC2β RBD-Ras complex is stable even in the presence of high concentrations of GTP or GDP. # ::save-date Mon Jan 4, 2016 ::file bmtr_0006_7.txt (s3 / stable-03 :ARG1 (m / macro-molecular-complex :part (p2 / protein-segment :name (n3 / name :op1 "RBD") :part-of (e / enzyme :name (n4 / name :op1 "PI3KC2β"))) :part (e2 / enzyme :name (n5 / name :op1 "Ras"))) :ARG1-of (c2 / contrast-01 :ARG2 (m2 / macro-molecular-complex :part (p3 / protein :name (n6 / name :op1 "GEF")) :part e2 :ARG1-of (d2 / disrupt-01 :ARG0 (a / add-02 :ARG1 (n7 / nucleotide :mod (g2 / guanine)) :ARG2 m2)))) :condition (p / present-02 :ARG1 (c / concentrate-02 :ARG0 (o / or :op1 (s / small-molecule :name (n / name :op1 "GTP")) :op2 (s2 / small-molecule :wiki "Guanosine_diphosphate" :name (n2 / name :op1 "GDP"))) :ARG1-of (h / high-02)) :mod (e3 / even))) # ::id bmtr_0006.8 ::date 2015-02-25T10:59:27 ::annotator SDL-AMR-09 ::preferred # ::snt These data suggest that PI3KC2β binding to nucleotide-free Ras in vivo may prevent loading of nucleotides onto Ras. # ::save-date Tue May 5, 2015 ::file bmtr_0006_8.txt (s / suggest-01 :ARG0 (d2 / data :mod (t / this)) :ARG1 (p / possible-01 :ARG1 (p2 / prevent-01 :ARG0 (b / bind-01 :ARG1 (e2 / enzyme :name (n2 / name :op1 "PI3KC2β")) :ARG2 (e / enzyme :name (n / name :op1 "Ras") :ARG1-of (f / free-04 :ARG2 (n3 / nucleotide))) :manner (i / in-vivo)) :ARG1 (l / load-01 :ARG1 e :ARG2 (n4 / nucleotide))))) # ::id bmtr_0006.9 ::date 2015-02-25T12:27:05 ::annotator SDL-AMR-09 ::preferred # ::snt Although current methods do not allow for detection of nucleotide-free GTPases in vivo, our BiFC results provide additional support for our model. # ::save-date Fri Jan 1, 2016 ::file bmtr_0006_9.txt (p / provide-01 :ARG0 (t / thing :ARG2-of (r / result-01 :ARG1 (c2 / complement-01 :manner (f2 / fluorescence :mod (b / biomolecular)))) :poss w) :ARG1 (s / support-01 :ARG1-of (a / add-02)) :ARG2 (m / model :poss (w / we)) :concession (a2 / allow-01 :polarity - :ARG0 (m2 / method :time (c / current)) :ARG1 (d / detect-01 :ARG1 (e / enzyme :name (n / name :op1 "GTPase") :ARG1-of (f / free-04 :ARG2 (n2 / nucleotide))) :manner (i / in-vivo)))) # ::id bmtr_0006.10 ::date 2015-02-25T12:36:53 ::annotator SDL-AMR-09 ::preferred # ::snt PI3KC2β preferentially interacts with Ras17N, which has a 30-fold lower affinity for nucleotide compared to wild type Ras and therefore should exist for longer periods in the nucleotide-free state. # ::save-date Wed Jun 3, 2015 ::file bmtr_0006_10.txt (i / interact-01 :ARG0 (e2 / enzyme :name (n2 / name :op1 "PI3KC2β")) :ARG1 (e / enzyme :name (n / name :op1 "Ras17N") :ARG0-of (h / have-03 :ARG1 (a / affinity :ARG1-of (l / low-04 :degree (m / more) :compared-to (e4 / enzyme :name (n5 / name :op1 "Ras") :mod (w / wild-type)) :quant (p3 / product-of :op1 30)) :topic (n4 / nucleotide)) :ARG0-of (c / cause-01 :ARG1 (r / recommend-01 :ARG1 (e6 / exist-01 :ARG1 e :ARG2 (s / state :ARG1-of (f / free-04 :ARG2 n4)) :ARG1-of (l2 / long-03 :degree (m3 / more))))))) :ARG1-of (p / prefer-01)) # ::id bmtr_0006.11 ::date 2015-02-26T00:19:31 ::annotator SDL-AMR-09 ::preferred # ::snt As a result, BiFC traps this form of Ras resulting in greater fluorescence complementation for Ras17N (and Ras17N/69N) compared to wild type or constitutively activated Ras (61L or 12V). # ::save-date Mon Jan 4, 2016 ::file bmtr_0006_11.txt (t / trap-01 :ARG0 (c2 / complement-01 :ARG1 (f3 / fluoresce-01 :mod (b2 / biomolecular))) :ARG1 (f / form :mod (e / enzyme :name (n / name :op1 "Ras")) :mod (t2 / this)) :ARG1-of (r / result-01 :ARG2 (c / complement-01 :ARG2 (a3 / and :op1 (e2 / enzyme :name (n2 / name :op1 "Ras17N")) :op2 (e3 / enzyme :name (n3 / name :op1 "Ras17N/69N"))) :mod (f2 / fluorescence) :mod (g2 / great :degree (m2 / more) :compared-to (o / or :op1 (e4 / enzyme :name (n4 / name :op1 "Ras") :mod (w / wild-type)) :op2 (e5 / enzyme :name (n5 / name :op1 "Ras") :ARG2-of (m / mutate-01 :value "61L") :ARG1-of a) :op3 (e6 / enzyme :name (n6 / name :op1 "Ras") :ARG1-of (a / activate-01 :manner (c3 / constitutive)) :ARG2-of (m3 / mutate-01 :value "12V"))))))) # ::id bmtr_0007.1 ::date 2015-02-26T00:31:54 ::annotator SDL-AMR-09 ::preferred # ::snt Phosphorylation of ASPP2 by RAS/MAPK Pathway Is Critical for Its Full Pro-Apoptotic Function (PMC3847091) # ::save-date Mon Dec 21, 2015 ::file bmtr_0007_1.txt (c / critical-02 :ARG1 (p / phosphorylate-01 :ARG1 (p4 / protein :name (n / name :op1 "ASPP2")) :ARG2 (p2 / pathway :name (n2 / name :op1 "RAS/MAPK"))) :ARG3 (f / function-01 :ARG0 p4 :ARG1 (a / apoptosis :ARG1-of (f2 / favor-01 :ARG0 p4)) :degree (f3 / full)) :ARG1-of (d / describe-01 :ARG0 (p3 / publication-91 :ARG8 "PMC3847091"))) # ::id bmtr_0007.2 ::date 2015-02-26T00:42:26 ::annotator SDL-AMR-09 ::preferred # ::snt A synthetic peptide encoding amino acids 824-832, with a phosphoserine at residue 827, was used to raise antibodies. # ::save-date Fri Jan 1, 2016 ::file bmtr_0007_2.txt (u / use-01 :ARG1 (p / peptide :mod (s / synthetic) :ARG0-of (e / encode-01 :ARG1 (a / amino-acid :quant (b2 / between :op1 824 :op2 832) :ARG2-of (i / include-01 :ARG1 (r3 / residue :location 827 :ARG3-of (p2 / phosphorylate-01) :mod (a3 / amino-acid :name (n / name :op1 "serine"))))))) :ARG2 (r2 / raise-01 :ARG1 (a2 / antibody))) # ::id bmtr_0007.3 ::date 2015-02-26T00:55:09 ::annotator SDL-AMR-09 ::preferred # ::snt A polyclonal antibody NGH.S4 was purified by affinity column purification. # ::save-date Mon Mar 9, 2015 ::file bmtr_0007_3.txt (p / purify-01 :ARG0 (p3 / purify-01 :mod (a2 / affinity) :instrument (c / column)) :ARG1 (a3 / antibody :name (n / name :op1 "NGH.S4") :mod (p2 / polyclonal))) # ::id bmtr_0007.4 ::date 2015-02-26T01:00:24 ::annotator SDL-AMR-09 ::preferred # ::snt To test the efficacy of the purified phospho-specific # ::save-date Fri Jul 24, 2015 ::file bmtr_0007_4.txt (t / test-01 :ARG1 (e / efficacy :poss (a / antibody :ARG1-of (p / purify-01) :ARG1-of (s / specific-02 :ARG2 (p2 / phosphorylate-01))))) # ::id bmtr_0007.5 ::date 2015-02-26T01:01:36 ::annotator SDL-AMR-09 ::preferred # ::snt antibody, a non-radioactive in vitro phosphorylation assay was performed on the purified GST-ASPP2 fragment (693-1128) with recombinant MAPK1. # ::save-date Tue Jul 28, 2015 ::file bmtr_0007_5.txt (p2 / perform-02 :ARG1 (a / assay-01 :ARG1 (p / phosphorylate-01 :manner (i / in-vitro) :mod (r / radioactive :polarity -)) :instrument (e / enzyme :name (n2 / name :op1 "MAPK1") :ARG0-of (r2 / recombine-01))) :location (p4 / protein-segment :part-of (p3 / protein :name (n / name :op1 "GST-ASPP2")) :quant (b / between :op1 693 :op2 1128) :ARG1-of (p5 / purify-01))) # ::id bmtr_0007.6 ::date 2015-02-26T01:02:48 ::annotator SDL-AMR-09 ::preferred # ::snt Figure 1C shows that the phosphospecific antibody is specific for the ASPP2 fragment phosphorylated in vitro by MAPK. # ::save-date Mon Dec 21, 2015 ::file bmtr_0007_6.txt (s / show-01 :ARG0 (f / figure :mod "1C") :ARG1 (s2 / specific-02 :ARG1 (a / antibody :ARG1-of (s3 / specific-02 :ARG2 (p2 / phosphorylate-01))) :ARG2 (p4 / protein-segment :part-of (p5 / protein :name (n2 / name :op1 "ASPP2")) :ARG1-of (p3 / phosphorylate-01 :ARG2 (e / enzyme :name (n / name :op1 "MAPK")) :manner (i / in-vitro))))) # ::id bmtr_0007.7 ::date 2015-02-26T01:08:16 ::annotator SDL-AMR-09 ::preferred # ::snt To test whether endogenous ASPP2 could be phosphorylated in cells, Saos2 cells were grown in low serum for 50 hours to remove all background stimulation of RAS, after which the cells were stimulated with EGF and 20% fetal calf serum (FCS). # ::save-date Sun Jan 17, 2016 ::file bmtr_0007_7.txt (g / grow-03 :ARG1 (c / cell-line :name (n2 / name :op1 "Saos2")) :location (s / serum :ARG1-of (l / low-04)) :duration (t2 / temporal-quantity :quant 50 :unit (h2 / hour)) :purpose (r / remove-01 :ARG1 (s2 / stimulate-01 :ARG1 (e / enzyme :name (n / name :op1 "Ras")) :manner (b / background) :mod (a / all))) :purpose (t / test-01 :ARG1 (p3 / possible-01 :mode interrogative :ARG1 (p4 / phosphorylate-01 :ARG1 (p2 / protein :name (n3 / name :op1 "ASPP2") :mod (e3 / endogenous)) :location (c2 / cell)))) :op1-of (a2 / after :time-of (s3 / stimulate-01 :ARG1 c :ARG2 (a3 / and :op1 (p5 / protein :name (n4 / name :op1 "EGF")) :op2 (s5 / serum :source (f / fetus :mod (c3 / calf)) :quant (p / percentage-entity :value 20)))))) # ::id bmtr_0007.8 ::date 2015-02-26T01:28:20 ::annotator SDL-AMR-09 ::preferred # ::snt Phosphorylated endogenous ASPP2 was detected by the phospho-specific antibody 30 minutes after RAS stimulation (Figure 1D). # ::save-date Fri Jul 24, 2015 ::file bmtr_0007_8.txt (d / detect-01 :ARG0 (a / antibody :ARG1-of (s / specific-02 :ARG2 p)) :ARG1 (p2 / protein :name (n2 / name :op1 "ASPP2") :mod (e3 / endogenous) :ARG3-of (p / phosphorylate-01)) :time (a2 / after :op1 (s2 / stimulate-01 :ARG1 (e / enzyme :name (n / name :op1 "Ras"))) :quant (t / temporal-quantity :quant 30 :unit (m / minute))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod "1D"))) # ::id bmtr_0007.9 ::date 2015-02-26T01:32:43 ::annotator SDL-AMR-09 ::preferred # ::snt ASPP2 phosphorylation was rapid and transient as 3 hours after EGF stimulation phosphorylated ASPP2 was barely detectable. # ::save-date Sun Jan 17, 2016 ::file bmtr_0007_9.txt (a / and :op1 (r / rapid :domain p2) :op2 (t2 / transient-02 :ARG1 (p2 / phosphorylate-01 :ARG1 (p4 / protein :name (n / name :op1 "ASPP2")))) :ARG1-of (i / infer-01 :ARG2 (p3 / possible-01 :ARG1 (d / detect-01 :ARG1 (p5 / protein :name (n3 / name :op1 "ASPP2") :ARG3-of (p / phosphorylate-01)) :degree (b / bare)) :time (a2 / after :op1 (s / stimulate-01 :ARG2 (p6 / protein :name (n2 / name :op1 "EGF"))) :quant (t / temporal-quantity :quant 3 :unit (h / hour)))))) # ::id bmtr_0007.10 ::date 2015-02-26T01:39:26 ::annotator SDL-AMR-09 ::preferred # ::snt Moreover, with another different phospho-ASPP2 antibody, ES1, ASPP2 phosphorylation was also observed in a human colon cancer cell line HKe3 ER:HRASV12 cells, in which RAS activation is induced upon the addition of 4-hydroxytamoxifen (4-OHT) [2,10,11] (Figure 1E). # ::save-date Wed Dec 9, 2015 ::file bmtr_0007_10.txt (a2 / and :op2 (o / observe-01 :ARG1 (p / phosphorylate-01 :ARG1 (p5 / protein :name (n3 / name :op1 "ASPP2"))) :mod (a / also) :location (c2 / cell-line :name (n4 / name :op1 "HKe3" :op2 "ER") :location-of (i / induce-01 :ARG0 (a6 / add-02 :ARG1 (s2 / small-molecule :name (n5 / name :op1 "4-hydroxytamoxifen"))) :ARG2 (a5 / activate-01 :ARG1 (e / enzyme :name (n2 / name :op1 "Ras")))) :ARG0-of (m2 / mean-01 :ARG1 (c4 / cell :name (n8 / name :op1 "HRASV12"))) :mod (h / human) :mod (d / disease :wiki "Colorectal_cancer" :name (n / name :op1 "colon" :op2 "cancer"))) :instrument (a3 / antibody :name (n7 / name :op1 "ES1") :ARG1-of (d2 / differ-02) :mod (a4 / another) :ARG1-of (s / specific-02 :ARG2 (p4 / protein :name (n6 / name :op1 "ASPP2") :ARG3-of (p2 / phosphorylate-01))))) :ARG1-of (d3 / describe-01 :ARG0 (a7 / and :op1 (f / figure :mod "1E") :op2 (p3 / publication-91 :ARG1-of (c3 / cite-01 :ARG2 (a8 / and :op1 2 :op2 10 :op3 11)))))) # ::id bmtr_0007.11 ::date 2015-02-26T02:06:09 ::annotator SDL-AMR-09 ::preferred # ::snt The phospho-specific antibody for ASPP2 is specific as knockdown of ASPP2 resulted in a lack of detection of phospho-ASPP2. # ::save-date Mon Dec 21, 2015 ::file bmtr_0007_11.txt (s / specific-02 :ARG1 (a / antibody :ARG1-of (s2 / specific-02 :ARG2 p)) :ARG1-of (i / infer-01 :ARG2 (r / result-01 :ARG1 (k / knock-down-02 :ARG1 (p3 / protein :name (n / name :op1 "ASPP2"))) :ARG2 (l / lack-01 :ARG1 (d / detect-01 :ARG1 (p / protein :name (n2 / name :op1 "ASPP2") :ARG3-of (p2 / phosphorylate-01))))))) # ::id bmtr_0007.12 ::date 2015-02-26T02:12:13 ::annotator SDL-AMR-09 ::preferred # ::snt All these demonstrate that ASPP2 is a novel substrate of MAPK and Ser827 of ASPP2 can be phosphorylated by RAS/MAPK pathway. # ::save-date Sun Dec 13, 2015 ::file bmtr_0007_12.txt (d / demonstrate-01 :ARG0 (t / this :mod (a / all)) :ARG1 (a2 / and :op1 (c / catalyze-01 :ARG0 (e / enzyme :name (n / name :op1 "MAPK")) :ARG1 (p5 / protein :name (n3 / name :op1 "ASPP2")) :mod (n6 / novel)) :op2 (p2 / possible-01 :ARG1 (p3 / phosphorylate-01 :ARG1 (a3 / amino-acid :mod 827 :name (n4 / name :op1 "serine") :part-of p5) :ARG2 (p4 / pathway :name (n5 / name :op1 "RAS/MAPK")))))) # ::id pmid_1528_0923.1 ::date 2015-06-18T01:10:09 ::annotator SDL-AMR-09 ::preferred # ::snt Dual blockade of EGFR and ERK1/2 phosphorylation potentiates growth inhibition of breast cancer cells (PMID:15280923) # ::save-date Tue Dec 29, 2015 ::file pmid_1528_0923_1.txt (p2 / potentiate-01 :ARG1 (i / inhibit-01 :ARG1 (g / grow-01 :ARG1 (c / cell :source (d / disease :wiki "Breast_cancer" :name (n / name :op1 "breast" :op2 "cancer"))))) :ARG2 (b / blockade-01 :ARG1 (p3 / phosphorylate-01 :ARG1 (a / and :op1 (e2 / enzyme :name (n3 / name :op1 "EGFR")) :op2 (e3 / enzyme :name (n4 / name :op1 "ERK1/2")))) :mod (d2 / dual)) :ARG1-of (d3 / describe-01 :ARG0 (p4 / publication-91 :ARG8 "PMID15280923"))) # ::id pmid_1528_0923.66 ::date 2015-06-18T02:16:52 ::annotator SDL-AMR-09 ::preferred # ::snt RESULTS # ::save-date Sun Jun 21, 2015 ::file pmid_1528_0923_66.txt (t / thing :ARG2-of (r / result-01)) # ::id pmid_1528_0923.67 ::date 2015-06-18T03:17:13 ::annotator SDL-AMR-09 ::preferred # ::snt Differences in activity of ERK1/2 in the breast cancer cell lines # ::save-date Wed Dec 9, 2015 ::file pmid_1528_0923_67.txt (d / differ-02 :ARG3 (a / act-02 :ARG0 (e / enzyme :name (n / name :op1 "ERK1/2")) :location (c / cell-line :source (d2 / disease :wiki "Breast_cancer" :name (n2 / name :op1 "breast" :op2 "cancer"))))) # ::id pmid_1528_0923.68 ::date 2015-06-18T03:20:56 ::annotator SDL-AMR-09 ::preferred # ::snt Immunoblotting revealed differences in basal levels of ERK1/2 phosphorylation in different breast cancer cell lines, while the expression of ERK1/2 protein, normalised to actin expression, was relatively consistent (Figure 1A). # ::save-date Wed Dec 9, 2015 ::file pmid_1528_0923_68.txt (c / contrast-01 :ARG1 (r / reveal-01 :ARG0 (i / immunoblot-01) :ARG1 (d2 / differ-02 :ARG1 (l / level :mod (b / basal) :quant-of (p2 / phosphorylate-01 :ARG1 (e / enzyme :name (n2 / name :op1 "ERK1/2")) :location (c2 / cell-line :source (d4 / disease :wiki "Breast_cancer" :name (n / name :op1 "breast" :op2 "cancer")) :ARG1-of (d3 / differ-02)))))) :ARG2 (c4 / consistent-01 :ARG1 (e2 / express-03 :ARG2 e :ARG1-of (n3 / normalize-01) :destination (e3 / express-03 :ARG2 (p3 / protein :name (n4 / name :op1 "actin")))) :ARG2-of (r2 / relative-05)) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "1A"))) # ::id pmid_1528_0923.69 ::date 2015-06-18T04:12:42 ::annotator SDL-AMR-09 ::preferred # ::snt To test whether the ERK1/2 activity was only a tissue culture phenomenon, selected cell lines were injected into the mammary fatpads of nude mice, and protein lysates were prepared from the tumours. # ::save-date Mon Dec 21, 2015 ::file pmid_1528_0923_69.txt (a / and :op1 (i / inject-01 :ARG1 (c / cell-line :ARG1-of (s / select-01)) :ARG2 (f / fatpad :source (b / breast) :part-of (m / mouse :mod (n / nude)))) :op2 (p / prepare-01 :ARG1 (l / lysate :mod (p2 / protein)) :ARG2 (t / tumor)) :purpose (t2 / test-01 :ARG1 (p3 / phenomenon :mod (c2 / culture-01 :ARG1 (t3 / tissue)) :mod (o / only) :domain (a2 / activity-06 :mode interrogative :ARG0 (e / enzyme :name (n2 / name :op1 "ERK1/2")))))) # ::id pmid_1528_0923.70 ::date 2015-06-18T05:40:38 ::annotator SDL-AMR-09 ::preferred # ::snt Taking into account the fact that lysates were of a mixture of tumour cells and surrounding stromal and infiltrating host cells, the immunoblotting of the tumour-derived proteins showed similar results to those obtained using lysates of cultured cells. # ::save-date Tue Jun 30, 2015 ::file pmid_1528_0923_70.txt (c / consider-02 :ARG1 (l / lysate :source (m / mix-01 :ARG1 (c2 / cell :mod (t / tumor)) :ARG2 (a / and :op1 (c3 / cell :mod (s / stroma) :ARG1-of (s2 / surround-01)) :op2 (c4 / cell :mod (h / host) :ARG0-of (i / infiltrate-01))))) :ARG2 (s3 / show-01 :ARG0 (i2 / immunoblot-01 :ARG1 (p / protein :ARG1-of (d / derive-01 :ARG2 t))) :ARG1 (t2 / thing :ARG1-of (r3 / resemble-01 :ARG2 (t3 / thing :ARG1-of (o / obtain-01 :ARG2 (l2 / lysate :source (c5 / cell :ARG1-of (c6 / culture-01)))) :ARG2-of (r2 / result-01))) :ARG2-of (r / result-01)))) # ::id pmid_1528_0923.71 ::date 2015-06-18T06:26:09 ::annotator SDL-AMR-09 ::preferred # ::snt MDA-MB-231 and MDA-MB-435 tumour lysates showed high levels of p-ERK1/2 in comparison to MDA-MB-468 and GI101A tumours (Figure 1B). # ::save-date Mon Dec 21, 2015 ::file pmid_1528_0923_71.txt (s / show-01 :ARG0 (l / lysate :source (a / and :op1 (c / cell-line :name (n / name :op1 "MDA-MB-231")) :op2 (c2 / cell-line :name (n2 / name :op1 "MDA-MB-435")) :mod (t / tumor))) :ARG1 (l2 / level :ARG1-of (h / high-02) :quant-of (e / enzyme :name (n3 / name :op1 "ERK1/2") :ARG3-of (p / phosphorylate-01)) :ARG1-of (c3 / compare-01 :ARG2 (a2 / and :op1 (c4 / cell-line :name (n4 / name :op1 "MDA-MB-468")) :op2 (c5 / cell-line :name (n5 / name :op1 "GI101A")) :mod (t2 / tumor)))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "1B"))) # ::id pmid_1528_0923.72 ::date 2015-06-18T06:52:55 ::annotator SDL-AMR-09 ::preferred # ::snt Elevated ERK activity does not necessarily correlate with the status of EGFR and HER2 in breast cancer cells # ::save-date Sat Jan 16, 2016 ::file pmid_1528_0923_72.txt (c / correlate-01 :ARG1 (a / activity-06 :ARG0 (e / enzyme :name (n6 / name :op1 "ERK")) :ARG1-of (e5 / elevate-01)) :ARG2 (s / status :poss (a2 / and :op1 (e6 / enzyme :name (n7 / name :op1 "EGFR")) :op2 (e7 / enzyme :name (n8 / name :op1 "HER2")) :location (c2 / cell :source (d / disease :wiki "Breast_cancer" :name (n / name :op1 "breast" :op2 "cancer"))))) :ARG1-of (n5 / need-01 :polarity -)) # ::id pmid_1528_0923.73 ::date 2015-06-18T07:16:08 ::annotator SDL-AMR-09 ::preferred # ::snt Since ERK1/2 can be activated via EGFR and HER2 signalling, relative expression levels of these growth factor receptors were measured in the panel of cell lines, to test if there was a correlation between ERK activation and receptor expression levels. # ::save-date Wed Feb 24, 2016 ::file pmid_1528_0923_73.txt (c / cause-01 :ARG0 (p / possible-01 :ARG1 (a / activate-01 :ARG1 (e4 / enzyme :name (n5 / name :op1 "ERK1/2")) :manner (s2 / signal-07 :ARG0 (a2 / and :op1 (e5 / enzyme :name (n6 / name :op1 "EGFR")) :op2 (e6 / enzyme :name (n7 / name :op1 "HER2")))))) :ARG1 (m / measure-01 :ARG1 (l / level :degree-of (e7 / express-03 :ARG2 (r2 / receptor :mod (g / growth-factor))) :ARG1-of (r / relative-05)) :location (p2 / panel :consist-of (c2 / cell-line)) :purpose (t / test-01 :ARG2 (c3 / correlate-01 :mode interrogative :ARG1 (l3 / level :degree-of (a3 / activate-01 :ARG1 (e / enzyme :name (n9 / name :op1 "ERK")))) :ARG2 (l2 / level :degree-of e7))))) # ::id pmid_1528_0923.74 ::date 2015-06-18T08:10:43 ::annotator SDL-AMR-09 ::preferred # ::snt As expected from the heterogeneity seen in clinical specimens of breast cancer, there was variability in expression of EGFR, from high expression in MDA-MB-468 and minimal expression in MDA-MB-435 cells (Figure 1A). # ::save-date Mon Dec 21, 2015 ::file pmid_1528_0923_74.txt (v / vary-01 :ARG1 (e2 / express-03 :ARG2 (e3 / enzyme :name (n3 / name :op1 "EGFR"))) :ARG3 (e4 / express-03 :ARG3 (c / cell-line :name (n4 / name :op1 "MDA-MB-468")) :ARG1-of (h / high-02)) :ARG4 (e5 / express-03 :ARG3 (c2 / cell-line :name (n5 / name :op1 "MDA-MB-435")) :ARG1-of (m / minimal-02)) :ARG1-of (e6 / expect-01 :source (h2 / heterogenous :ARG1-of (s / see-01 :location (s2 / specimen :mod (c3 / clinic) :source (d2 / disease :wiki "Breast_cancer" :name (n / name :op1 "breast" :op2 "cancer")))))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod "1A"))) # ::id pmid_1528_0923.75 ::date 2015-06-19T00:21:32 ::annotator SDL-AMR-09 ::preferred # ::snt Comparing these results with the level of pERK1/2 indicated that there was no direct correlation between levels of these growth factor receptors and basal levels of ERK1/2 phosphorylation. # ::save-date Wed Feb 24, 2016 ::file pmid_1528_0923_75.txt (c / compare-01 :ARG1 (t3 / thing :mod (t / this) :ARG2-of (r / result-01)) :ARG2 (l / level :quant-of (e / enzyme :name (n2 / name :op1 "ERK1/2") :ARG3-of (p / phosphorylate-01))) :ARG0-of (i / indicate-01 :ARG1 (c2 / correlate-01 :polarity - :ARG1 (l2 / level :quant-of (r2 / receptor :mod (g / growth-factor) :mod (t2 / this))) :ARG2 (l3 / level :mod (b / basal) :quant-of (p2 / phosphorylate-01 :ARG1 (e2 / enzyme :name (n4 / name :op1 "ERK1/2")))) :ARG1-of (d / direct-02)))) # ::id pmid_1528_0923.76 ::date 2015-06-19T00:35:28 ::annotator SDL-AMR-09 ::preferred # ::snt Thus, while the MDA-MB-231 cell line with highly activated ERK1/2 expressed a relatively high level of EGFR, other combinations occur. # ::save-date Mon Dec 21, 2015 ::file pmid_1528_0923_76.txt (c / cause-01 :ARG1 (c2 / contrast-01 :ARG1 (e2 / express-03 :ARG1 (l2 / level :quant-of (e3 / enzyme :name (n3 / name :op1 "EGFR")) :ARG1-of (h / high-02 :ARG2-of (r / relative-05))) :ARG3 (c3 / cell-line :name (n2 / name :op1 "MDA-MB-231") :mod (e4 / enzyme :name (n4 / name :op1 "ERK1/2") :ARG1-of (a / activate-01 :ARG1-of (h2 / high-02))))) :ARG2 (c5 / combine-01 :mod (o / other)))) # ::id pmid_1528_0923.77 ::date 2015-06-19T00:53:23 ::annotator SDL-AMR-09 ::preferred # ::snt High pERK1/2 levels were detected in MDA-MB-435 cells, which have very little EGFR, in contrast to the SUM149 cells with high EGFR expression and low ERK1/2 activity. # ::save-date Mon Dec 21, 2015 ::file pmid_1528_0923_77.txt (d / detect-01 :ARG1 (l / level :quant-of (e2 / enzyme :name (n2 / name :op1 "ERK1/2") :ARG3-of (p / phosphorylate-01)) :ARG1-of (h / high-02)) :location (c / cell-line :name (n3 / name :op1 "MDA-MB-435") :ARG0-of (h2 / have-03 :ARG1 (e3 / enzyme :name (n4 / name :op1 "EGFR") :quant (l3 / little :degree (v / very))) :ARG1-of (c2 / contrast-01 :ARG2 (c3 / cell-line :name (n5 / name :op1 "SUM149") :poss (a / and :op1 (e4 / express-03 :ARG2 e3 :ARG1-of h) :op2 (a2 / activity-06 :ARG0 (e / enzyme :name (n / name :op1 "ERK1/2")) :ARG1-of (l2 / low-04)))))))) # ::id pmid_1528_0923.78 ::date 2015-06-21T05:31:55 ::annotator SDL-AMR-09 ::preferred # ::snt Similarly, no correlation was found between the expression of HER2 receptor and the status of pERK (Figure 1A). # ::save-date Sat Jan 16, 2016 ::file pmid_1528_0923_78.txt (f / find-01 :ARG1 (c / correlate-01 :polarity - :ARG1 (e2 / express-03 :ARG2 (r2 / receptor :mod (e3 / enzyme :name (n2 / name :op1 "HER2")))) :ARG2 (s / status :poss (e / enzyme :name (n3 / name :op1 "ERK") :ARG3-of (p / phosphorylate-01)))) :ARG1-of (r / resemble-01) :ARG1-of (d / describe-01 :ARG0 (f2 / figure :mod "1A"))) # ::id pmid_1528_0923.79 ::date 2015-06-21T05:42:15 ::annotator SDL-AMR-09 ::preferred # ::snt PKI166 inhibition of breast cancer cell proliferation # ::save-date Wed Dec 9, 2015 ::file pmid_1528_0923_79.txt (i / inhibit-01 :ARG0 (s / small-molecule :name (n2 / name :op1 "PKI166")) :ARG1 (p / proliferate-01 :ARG0 (c / cell :source (d / disease :wiki "Breast_cancer" :name (n / name :op1 "breast" :op2 "cancer"))))) # ::id pmid_1528_0923.80 ::date 2015-06-21T05:55:48 ::annotator SDL-AMR-09 ::preferred # ::snt Six cell lines with different levels of EGFR expression were selected for treatment with PKI166. # ::save-date Wed Jul 22, 2015 ::file pmid_1528_0923_80.txt (s / select-01 :ARG1 (c / cell-line :quant 6) :ARG3 (t / treat-04 :ARG2 (s2 / small-molecule :name (n3 / name :op1 "PKI166"))) :poss-of (l / level :ARG1-of (d / differ-02) :quant-of (e2 / express-03 :ARG2 (e3 / enzyme :name (n2 / name :op1 "EGFR"))))) # ::id pmid_1528_0923.81 ::date 2015-06-21T06:17:25 ::annotator SDL-AMR-09 ::preferred # ::snt Initial studies used a dose range of 0.1–5.0 μM (data not shown), and the results of treating cells with 0.5 and 5.0 μM are shown in Table 1. # ::save-date Tue Dec 15, 2015 ::file pmid_1528_0923_81.txt (a / and :op1 (u / use-01 :ARG0 (s / study-01 :mod (i / initial)) :ARG1 (r / range-01 :ARG1 (d / dose) :ARG3 (c / concentration-quantity :quant 0.1 :unit (m / micromolar)) :ARG4 (c2 / concentration-quantity :quant 5.0 :unit m)) :ARG1-of (s2 / show-01 :polarity - :ARG0 (d2 / data))) :op2 (s3 / show-01 :ARG1 (t3 / thing :ARG2-of (r2 / result-01 :ARG1 (t / treat-04 :ARG1 (c3 / cell) :ARG2 (a2 / and :op1 (c4 / concentration-quantity :quant 0.5 :unit m) :op2 c2)))) :location (t2 / table :mod 1))) # ::id pmid_1528_0923.82 ::date 2015-06-21T07:44:10 ::annotator SDL-AMR-09 ::preferred # ::snt Growth inhibition was determined from the results of MTT assays, comparing PKI166 treated cells with cells exposed to medium with 0.1% DMSO. # ::save-date Sat Feb 13, 2016 ::file pmid_1528_0923_82.txt (d / determine-01 :ARG1 (i / inhibit-01 :ARG1 (g / grow-01)) :ARG2 (t4 / thing :ARG2-of (r / result-01 :ARG1 (a / assay-01 :instrument (s3 / small-molecule :name (n / name :op1 "MTT"))))) :manner (c / compare-01 :ARG1 (c2 / cell :ARG1-of (t2 / treat-04 :ARG2 (s / small-molecule :name (n2 / name :op1 "PKI166")))) :ARG2 (c3 / cell :ARG1-of (e / expose-01 :ARG2 (m / medium :ARG0-of (h / have-03 :ARG1 (s2 / small-molecule :name (n3 / name :op1 "DMSO") :quant (p2 / percentage-entity :value 0.1)))))))) # ::id pmid_1528_0923.83 ::date 2015-06-21T08:19:01 ::annotator SDL-AMR-09 ::preferred # ::snt Treatment with 0.5 μM PKI166, a concentration less than plasma and tumour concentrations achieved in preclinical models from oral administration of the drug, and the higher dose of 5.0 μM, produced different levels of growth inhibition in different cell lines. # ::save-date Wed Dec 30, 2015 ::file pmid_1528_0923_83.txt (p / produce-01 :ARG0 (a / and :op1 (t / treat-04 :ARG2 (s / small-molecule :name (n / name :op1 "PKI166") :mod (c / concentration-quantity :quant 0.5 :unit (m / micromolar) :mod (l2 / less) :compared-to (c4 / concentration :poss (a2 / and :op1 (p2 / plasma) :op2 (t2 / tumor)) :ARG1-of (a3 / achieve-01 :location (m4 / model :mod (p3 / preclinical) :source (a4 / administer-01 :ARG1 s :path (m5 / mouth)))))))) :op2 (d / dose :mod (c2 / concentration-quantity :quant 5.0 :unit (m2 / micromolar)) :ARG1-of (h / high-02 :degree (m3 / more)))) :ARG1 (l / level :ARG1-of (d2 / differ-02) :quant-of (i / inhibit-01 :ARG1 (g / grow-01))) :location (c3 / cell-line :ARG1-of d2)) # ::id pmid_1528_0923.84 ::date 2015-06-21T09:11:05 ::annotator SDL-AMR-09 ::preferred # ::snt As expected, cells expressing low levels of EGFR and HER2, GI101A, MDA-MB-435 showed least growth inhibition. # ::save-date Tue Jun 30, 2015 ::file pmid_1528_0923_84.txt (s / show-01 :ARG0 (c / cell :ARG3-of (e3 / express-03 :ARG2 (l / level :ARG1-of (l2 / low-04) :quant-of (a / and :op1 (e / enzyme :name (n / name :op1 "EGFR")) :op2 (e2 / enzyme :name (n2 / name :op1 "HER2"))))) :ARG1-of (m / mean-01 :ARG2 (a2 / and :op1 (c2 / cell-line :name (n3 / name :op1 "GI101A")) :op2 (c3 / cell-line :name (n4 / name :op1 "MDA-MB-435"))))) :ARG1 (i / inhibit-01 :ARG1 (g / grow-01) :degree (l3 / least)) :ARG1-of (e4 / expect-01)) # ::id pmid_1528_0923.85 ::date 2015-06-21T09:24:57 ::annotator SDL-AMR-09 ::preferred # ::snt However, not all of the high EGFR-expressing lines were sensitive to PKI166. # ::save-date Mon Dec 21, 2015 ::file pmid_1528_0923_85.txt (c / contrast-01 :ARG2 (s / sensitive-03 :ARG0 (l / line :ARG3-of (e / express-03 :ARG2 (e2 / enzyme :name (n / name :op1 "EGFR")) :ARG1-of (h / high-02)) :mod (a / all :polarity -)) :ARG1 (s2 / small-molecule :name (n2 / name :op1 "PKI166")))) # ::id pmid_1528_0923.86 ::date 2015-06-21T09:55:03 ::annotator SDL-AMR-09 ::preferred # ::snt The lower dose produced 46 and 21% growth inhibition of SUM149 and MDA-MB-468 cells, respectively, but had little effect (3.3% inhibition) on the growth of MDA-MB-231 cells. # ::save-date Fri Dec 18, 2015 ::file pmid_1528_0923_86.txt (c / contrast-01 :ARG1 (p3 / produce-01 :ARG0 (d / dose :ARG1-of (l / low-04 :degree (m2 / more))) :ARG1 (a / and :op1 (i / inhibit-01 :ARG1 (g / grow-01 :ARG1 (c2 / cell-line :name (n / name :op1 "SUM149"))) :quant (p4 / percentage-entity :value 46)) :op2 (i2 / inhibit-01 :ARG1 (g2 / grow-01 :ARG1 (c3 / cell-line :name (n2 / name :op1 "MDA-MB-468"))) :quant (p5 / percentage-entity :value 21))) :mod (r / respective)) :ARG2 (a2 / affect-01 :ARG0 d :ARG1 (g3 / grow-01 :ARG1 (c4 / cell-line :name (n3 / name :op1 "MDA-MB-231"))) :degree (l3 / little) :ARG1-of (m3 / mean-01 :ARG2 (i3 / inhibit-01 :quant (p6 / percentage-entity :value 3.3))))) # ::id pmid_1528_0923.87 ::date 2015-06-21T10:26:54 ::annotator SDL-AMR-09 ::preferred # ::snt The SKBR3 cells, expressing EGFR and also high levels of HER2, were most sensitive, showing 55% growth inhibition with 0.5 μM and 76% inhibition with 5.0 μM PKI166. # ::save-date Mon Dec 21, 2015 ::file pmid_1528_0923_87.txt (e / express-03 :ARG2 (a / and :op1 (e2 / enzyme :name (n2 / name :op1 "EGFR")) :op2 (l / level :ARG1-of (h / high-02) :quant-of (e3 / enzyme :name (n3 / name :op1 "HER2")))) :ARG3 (c / cell-line :name (n / name :op1 "SKBR3") :ARG0-of (s / sensitive-03 :degree (m / most))) :manner (s2 / show-01 :ARG0 c :ARG1 (a2 / and :op1 (i / inhibit-01 :ARG0 (s3 / small-molecule :name (n4 / name :op1 "PKI166") :mod (c2 / concentration-quantity :quant 0.5 :unit (m2 / micromolar))) :ARG1 (g / grow-01) :quant (p / percentage-entity :value 55)) :op2 (i2 / inhibit-01 :ARG0 (s4 / small-molecule :name (n5 / name :op1 "PKI166") :mod (c3 / concentration-quantity :quant 5.0 :unit m2)) :quant (p2 / percentage-entity :value 76))))) # ::id pmid_1528_0923.88 ::date 2015-06-21T10:57:30 ::annotator SDL-AMR-09 ::preferred # ::snt PKI166 inhibits phosphorylation of EGFR and HER2 in breast cancer cells # ::save-date Wed Dec 9, 2015 ::file pmid_1528_0923_88.txt (i / inhibit-01 :ARG0 (s / small-molecule :name (n4 / name :op1 "PKI166")) :ARG1 (p2 / phosphorylate-01 :ARG1 (a / and :op1 (e3 / enzyme :name (n5 / name :op1 "EGFR")) :op2 (e4 / enzyme :name (n6 / name :op1 "HER2"))) :location (c / cell :source (d / disease :wiki "Breast_cancer" :name (n / name :op1 "breast" :op2 "cancer"))))) # ::id pmid_1528_0923.89 ::date 2015-06-21T11:00:46 ::annotator SDL-AMR-09 ::preferred # ::snt To demonstrate inhibition of EGFR and HER2 phosphorylation by the concentrations of PKI166 used for the growth inhibition assays, cell lysates were prepared from MDA-MB-231, MDA-MB-468, SUM149 and SKBR3 cells after treatment with PKI166 and stimulation with EGF, and phosphorylation of the receptors assessed. # ::save-date Sun Jan 17, 2016 ::file pmid_1528_0923_89.txt (a / and :op1 (p2 / prepare-01 :ARG1 (l / lysate :mod (c / cell)) :ARG2 (a2 / and :op1 (c2 / cell-line :name (n3 / name :op1 "MDA-MB-231")) :op2 (c3 / cell-line :name (n4 / name :op1 "MDA-MB-468")) :op3 (c4 / cell-line :name (n5 / name :op1 "SUM149")) :op4 (c5 / cell-line :name (n6 / name :op1 "SKBR3"))) :time (a3 / after :op1 (a4 / and :op1 (t / treat-04 :ARG2 (s / small-molecule :name (n7 / name :op1 "PKI166"))) :op2 (s2 / stimulate-01 :ARG2 (p / protein :name (n8 / name :op1 "EGF")))))) :op2 (a5 / assess-01 :ARG1 (p3 / phosphorylate-01 :ARG1 (r / receptor))) :purpose (d / demonstrate-01 :ARG1 (i / inhibit-01 :ARG0 (s4 / small-molecule :name (n / name :op1 "PKI166") :ARG1-of (c6 / concentrate-02 :ARG1-of (u / use-01 :ARG2 (a7 / assay-01 :ARG1 (i2 / inhibit-01 :ARG1 (g / grow-01)))))) :ARG1 (p4 / phosphorylate-01 :ARG1 (a6 / and :op1 (e3 / enzyme :name (n9 / name :op1 "EGFR")) :op2 (e4 / enzyme :name (n10 / name :op1 "HER2"))))))) # ::id pmid_1528_0923.90 ::date 2015-06-21T11:17:53 ::annotator SDL-AMR-09 ::preferred # ::snt PKI166 inhibited ligand-induced EGFR phosphorylation in a dose dependent manner in these four cell lines, and also phosphorylation of HER2 in SKBR3 cells, in the absence or presence of 50 ng ml−1 EGF (Figure 2) (data for other cell lines not shown). # ::save-date Sun Jan 17, 2016 ::file pmid_1528_0923_90.txt (a / and :op1 (i / inhibit-01 :ARG0 (s / small-molecule :name (n3 / name :op1 "PKI166")) :ARG1 (p2 / phosphorylate-01 :ARG1 (e3 / enzyme :name (n4 / name :op1 "EGFR")) :ARG2-of (i3 / induce-01 :ARG0 (l / ligand))) :ARG0-of (d / depend-01 :ARG1 (d2 / dose)) :location (c2 / cell-line :quant 4 :mod (t / this))) :op2 (i2 / inhibit-01 :ARG1 (p3 / phosphorylate-01 :ARG1 (e4 / enzyme :name (n5 / name :op1 "HER2")) :location (c3 / cell-line :name (n6 / name :op1 "SKBR3"))) :condition (o / or :op1 (p / protein :name (n7 / name :op1 "EGF") :quant (c5 / concentration-quantity :quant 50 :unit (n8 / nanogram-per-milliliter))) :op2 (a2 / absent-01 :ARG1 p))) :ARG1-of (d3 / describe-01 :ARG0 (f / figure :mod 2)) :ARG1-of (s3 / show-01 :polarity - :ARG0 (d4 / data :topic (c4 / cell-line :mod (o2 / other))))) # ::id pmid_1528_0923.91 ::date 2015-06-21T12:11:40 ::annotator SDL-AMR-09 ::preferred # ::snt Constitutive ERK1/2 phosphorylation as a potential escape mechanism from inhibition by PKI166 # ::save-date Sun Jun 21, 2015 ::file pmid_1528_0923_91.txt (p / provide-01 :ARG0 (p2 / phosphorylate-01 :ARG1 (e / enzyme :name (n / name :op1 "ERK1/2")) :mod (c / constitutive)) :ARG1 (m / mechanism :mod (p3 / potential) :purpose (e2 / escape-01 :ARG1 (i / inhibit-01 :ARG0 (s / small-molecule :name (n2 / name :op1 "PKI166")))))) # ::id pmid_1528_0923.92 ::date 2015-06-21T12:18:34 ::annotator SDL-AMR-09 ::preferred # ::snt Inhibition of growth by PKI166 was most effective in cells with high levels of EGFR and nonactivated ERK1/2 (SUM149, MDA-MB-468) when compared with cells with high EGFR and high basal level of phosphorylated ERK1/2 (MDA-MB-231). # ::save-date Thu Sep 17, 2015 ::file pmid_1528_0923_92.txt (e2 / effective-04 :ARG0 (i / inhibit-01 :ARG0 (s / small-molecule :name (n2 / name :op1 "PKI166")) :ARG1 (g / grow-01)) :degree (m / most) :location (c / cell :ARG0-of (h / have-03 :ARG1 (l / level :ARG1-of (h2 / high-02) :quant-of (a / and :op1 (e3 / enzyme :name (n3 / name :op1 "EGFR")) :op2 (e4 / enzyme :name (n4 / name :op1 "ERK1/2") :ARG1-of (a2 / activate-01 :polarity -))))) :ARG1-of (m2 / mean-01 :ARG2 (a3 / and :op1 (c2 / cell-line :name (n5 / name :op1 "SUM149")) :op2 (c3 / cell-line :name (n6 / name :op1 "MDA-MB-468"))))) :compared-to (c4 / cell :ARG0-of (h3 / have-03 :ARG1 (a4 / and :op1 (l3 / level :ARG1-of (h6 / high-02) :quant-of e3) :op2 (l2 / level :mod (b / basal) :quant-of (e6 / enzyme :name (n8 / name :op1 "ERK1/2") :ARG3-of (p / phosphorylate-01)) :ARG1-of (h5 / high-02)))) :ARG1-of (m3 / mean-01 :ARG2 (c5 / cell-line :name (n9 / name :op1 "MDA-MB-231"))))) # ::id pmid_1528_0923.93 ::date 2015-06-21T13:04:23 ::annotator SDL-AMR-09 ::preferred # ::snt To test whether the basal ERK1/2 activity was providing an escape mechanism from inhibition by PKI166, cells were treated with a combination of PKI166 and UO126, an inhibitor of MEK (Table 1). # ::save-date Sat Jan 16, 2016 ::file pmid_1528_0923_93.txt (t2 / treat-04 :ARG1 (c / cell) :ARG2 (c2 / combine-01 :ARG1 (s / small-molecule :name (n2 / name :op1 "PKI166")) :ARG2 (s2 / small-molecule :name (n3 / name :op1 "UO126") :ARG0-of (i / inhibit-01 :ARG1 (p2 / protein-family :name (n / name :op1 "MEK"))))) :purpose (t3 / test-01 :ARG1 (p / provide-01 :mode interrogative :ARG0 (a / activity-06 :ARG0 (e3 / enzyme :name (n5 / name :op1 "ERK1/2") :mod (b / basal))) :ARG1 (m2 / mechanism :purpose (e4 / escape-01 :ARG1 (i3 / inhibit-01 :ARG0 s))))) :ARG1-of (d / describe-01 :ARG0 (t / table :mod 1))) # ::id pmid_1528_0923.94 ::date 2015-06-15T12:42:09 ::annotator SDL-AMR-09 ::preferred # ::snt GI101A cells, with low EGFR and nonactivated ERK1/2, showed modest growth inhibition when treated with an individual inhibitor and no significant difference with the combination of the two. # ::save-date Sun Jun 21, 2015 ::file pmid_1528_0923_94.txt (s2 / show-01 :ARG0 (c / cell-line :name (n2 / name :op1 "GI101A") :ARG0-of (h / have-03 :ARG1 (a2 / and :op1 (e2 / enzyme :name (n3 / name :op1 "EGFR") :ARG1-of (l / low-04)) :op2 (e3 / enzyme :name (n4 / name :op1 "ERK1/2") :ARG1-of (a3 / activate-01 :polarity -))))) :ARG1 (a4 / and :op1 (i2 / inhibit-01 :ARG1 (g / grow-01) :time (t2 / treat-04 :ARG1 c :ARG2 (m2 / molecular-physical-entity :ARG0-of (i / inhibit-01) :mod (i3 / individual))) :mod (m / modest)) :op2 (d / differ-02 :ARG1 c :ARG2 (c2 / combine-01 :ARG1 (t / thing :quant 2)) :ARG1-of (s / significant-02 :polarity -)))) # ::id pmid_1528_0923.95 ::date 2015-06-15T13:48:11 ::annotator SDL-AMR-09 ::preferred # ::snt MDA-MB-435 cells were significantly inhibited by U0126 alone, and the addition of PKI166 made no difference. # ::save-date Sun Jun 21, 2015 ::file pmid_1528_0923_95.txt (a / and :op1 (i / inhibit-01 :ARG0 (s / small-molecule :name (n / name :op1 "U0126") :mod (a2 / alone)) :ARG1 (c / cell-line :name (n2 / name :op1 "MDA-MB-435")) :ARG1-of (s2 / significant-02)) :op2 (m / make-01 :polarity - :ARG0 (a3 / add-02 :ARG1 (s3 / small-molecule :name (n3 / name :op1 "PKI166"))) :ARG1 (d / differ-02))) # ::id pmid_1528_0923.96 ::date 2015-06-15T13:52:51 ::annotator SDL-AMR-09 ::preferred # ::snt The combination of agents significantly increased the antiproliferative action of PKI166 at the 0.5 and 5.0 μM doses in cells expressing higher levels of EGFR or HER2 (SUM149, MDA-MB-468, SKBR3), including MDA-MB-231 cells. # ::save-date Wed Dec 30, 2015 ::file pmid_1528_0923_96.txt (i / increase-01 :ARG0 (c / combine-01 :ARG1 (a / agent)) :ARG1 (a2 / act-01 :ARG0 (s2 / small-molecule :name (n / name :op1 "PKI166") :ARG2-of (d3 / dose-01 :quant (a4 / and :op1 (c2 / concentration-quantity :quant 0.5 :unit (m / micromolar)) :op2 (c3 / concentration-quantity :quant 5 :unit (m2 / micromolar))))) :ARG0-of (c9 / counter-01 :ARG1 (p / proliferate-01))) :ARG1-of (s / significant-02) :location (c4 / cell :ARG3-of (e / express-03 :ARG2 (o / or :op1 (l / level :quant-of (e2 / enzyme :name (n2 / name :op1 "EGFR")) :ARG1-of (h / high-02 :degree (m3 / more))) :op2 (l2 / level :quant-of (e3 / enzyme :name (n3 / name :op1 "HER2")) :ARG1-of h))) :ARG1-of (m4 / mean-01 :ARG2 (a5 / and :op1 (c5 / cell-line :name (n4 / name :op1 "SUM149")) :op2 (c6 / cell-line :name (n5 / name :op1 "MDA-MB-468")) :op3 (c7 / cell-line :name (n6 / name :op1 "SKBR3")))) :ARG2-of (i2 / include-01 :ARG1 (c8 / cell-line :name (n7 / name :op1 "MDA-MB-231"))))) # ::id pmid_1528_0923.97 ::date 2015-06-15T14:09:53 ::annotator SDL-AMR-09 ::preferred # ::snt Treating the MDA-MB-231 cells with U0126 alone produced 8.5% inhibition, which was not significantly different from control values. # ::save-date Tue Jun 16, 2015 ::file pmid_1528_0923_97.txt (p2 / produce-01 :ARG0 (t / treat-04 :ARG1 (c / cell-line :name (n2 / name :op1 "MDA-MB-231")) :ARG2 (s2 / small-molecule :name (n3 / name :op1 "U0126") :mod (a / alone))) :ARG1 (i / inhibit-01 :quant (p / percentage-entity :value 8.5)) :ARG1-of (d / differ-02 :polarity - :ARG2 (v / value :mod (c2 / control)) :ARG1-of (s / significant-02))) # ::id pmid_1528_0923.98 ::date 2015-06-15T14:13:28 ::annotator SDL-AMR-09 ::preferred # ::snt The addition of U0126 to 0.5 or 5.0 μM PKI166 significantly increased the growth inhibition produced by the receptor tyrosine kinase inhibitor alone (Table 1). # ::save-date Wed Jan 13, 2016 ::file pmid_1528_0923_98.txt (i / increase-01 :ARG0 (a / add-02 :ARG1 (s2 / small-molecule :name (n / name :op1 "U0126")) :ARG2 (o / or :op1 (s3 / small-molecule :name (n2 / name :op1 "PKI166") :quant (c / concentration-quantity :quant 0.5 :unit (m / micromolar))) :op2 (s4 / small-molecule :name (n3 / name :op1 "PKI166") :quant (c2 / concentration-quantity :quant 5 :unit (m3 / micromolar))))) :ARG1 (i2 / inhibit-01 :ARG1 (g / grow-01) :ARG1-of (p / produce-01 :ARG0 (m2 / molecular-physical-entity :ARG0-of (i3 / inhibit-01 :ARG1 (e / enzyme :name (n4 / name :op1 "receptor" :op2 "tyrosine" :op3 "kinase"))) :mod (a2 / alone)))) :ARG2 (s / significant-02) :ARG1-of (d / describe-01 :ARG0 (t / table :mod 1))) # ::id pmid_1528_0923.99 ::date 2015-06-15T14:19:24 ::annotator SDL-AMR-09 ::preferred # ::snt Apoptosis induced by PKI166 and U0126 was assessed by measuring DNA fragmentation by propidium iodide staining and FACS analysis, and determining the proportions of hypodiploid cells. # ::save-date Sun Jun 21, 2015 ::file pmid_1528_0923_99.txt (a8 / assess-01 :ARG0 (a7 / and :op1 (m / measure-01 :ARG1 (f / fragment-01 :ARG0 (a5 / and :op1 (s4 / stain-01 :ARG2 (s3 / small-molecule :name (n4 / name :op1 "propidium" :op2 "iodide"))) :op2 (a6 / analyze-01 :mod (t / thing :name (n5 / name :op1 "FACS")))) :ARG1 (n6 / nucleic-acid :wiki "DNA" :name (n7 / name :op1 "DNA") :name (n3 / name :op1 "DNA")))) :op2 (d2 / determine-01 :ARG1 (p / proportion-01 :ARG1 (c / cell :mod (h / hypodiploid))))) :ARG1 (a3 / apoptosis :ARG2-of (i / induce-01 :ARG0 (a4 / and :op1 (s2 / small-molecule :name (n2 / name :op1 "PKI166")) :op2 (s / small-molecule :name (n / name :op1 "U0126")))))) # ::id pmid_1528_0923.100 ::date 2015-06-15T14:29:24 ::annotator SDL-AMR-09 ::preferred # ::snt This showed that PKI166 alone or in combination with U0126 induced apoptosis in the EGFR or HER2 expressing cell lines MDA-MB-231, MDA-MB-468, SKBR3 and SUM149 cells (Figure 3), although the proportions of hypodiploid cells varied between the different lines. # ::save-date Sun Jan 17, 2016 ::file pmid_1528_0923_100.txt (s2 / show-01 :ARG0 (t / this) :ARG1 (i / induce-01 :ARG0 (o / or :op1 (s3 / small-molecule :name (n4 / name :op1 "PKI166") :mod (a / alone)) :op2 (s4 / small-molecule :name (n9 / name :op1 "PKI166") :ARG1-of (c / combine-01 :ARG2 (s / small-molecule :name (n / name :op1 "U0126"))))) :ARG2 (a2 / apoptosis) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod 3)) :concession (v / vary-01 :ARG1 (p / proportion-01 :ARG1 (c6 / cell :mod (h2 / hypodiploid))) :location (l / line :ARG1-of (d2 / differ-02))) :location (a3 / and :op1 (c2 / cell-line :name (n5 / name :op1 "MDA-MB-231")) :op2 (c3 / cell-line :name (n6 / name :op1 "MDA-MB-468")) :op3 (c4 / cell-line :name (n7 / name :op1 "SKBR3")) :op4 (c5 / cell-line :name (n8 / name :op1 "SUM149")) :ARG3-of (e3 / express-03 :ARG2 (o2 / or :op1 (e / enzyme :name (n2 / name :op1 "EGFR")) :op2 (e2 / enzyme :name (n3 / name :op1 "HER2"))))))) # ::id pmid_1528_0923.101 ::date 2015-06-15T14:47:46 ::annotator SDL-AMR-09 ::preferred # ::snt Similar to the MTT results in Table 1, SKBR3 and SUM 149 cells were most sensitive to treatment with the inhibitors, while the proportions of hypodiploid MDA-MB-231 cells were lower. # ::save-date Sat Feb 13, 2016 ::file pmid_1528_0923_101.txt (c / contrast-01 :ARG1 (s / sensitive-03 :ARG0 (a / and :op1 (c2 / cell-line :name (n / name :op1 "SKBR3")) :op2 (c3 / cell-line :name (n2 / name :op1 "SUM149"))) :ARG1 (t2 / treat-04 :ARG1 a :ARG2 (m3 / molecular-physical-entity :ARG0-of (i2 / inhibit-01))) :degree (m2 / most)) :ARG2 (l / low-04 :ARG1 (p / proportion-01 :ARG1 (c4 / cell-line :name (n3 / name :op1 "MDA-MB-231") :mod (h / hypodiploid))) :degree (m / more)) :ARG1-of (r / resemble-01 :ARG2 (t4 / thing :ARG2-of (r2 / result-01 :ARG1 (s2 / small-molecule :name (n4 / name :op1 "MTT"))) :location (t3 / table :mod 1)))) # ::id pmid_1528_0923.102 ::date 2015-06-16T10:36:10 ::annotator SDL-AMR-09 ::preferred # ::snt Treatment with U0126 alone significantly increased the numbers of MDA-MB-231 in the G1 phase of the cell cycle (89–93% compared with 70–72% of control or PKI 166 treated cells, P<0.001). # ::save-date Wed Dec 30, 2015 ::file pmid_1528_0923_102.txt (i / increase-01 :ARG0 (t / treat-04 :ARG2 (s / small-molecule :name (n / name :op1 "U0126") :mod (a / alone))) :ARG1 (n2 / number-01 :ARG1 (c / cell-line :name (n3 / name :op1 "MDA-MB-231"))) :ARG2 (v / value-interval :op1 (p4 / percentage-entity :value 89) :op2 (p / percentage-entity :value 93)) :ARG1-of (s2 / significant-02) :time (e / event :name (n5 / name :op1 "G1" :op2 "phase") :part-of (c2 / cycle-02 :ARG1 (c3 / cell))) :compared-to (v2 / value-interval :op1 (p5 / percentage-entity :value 70) :op2 (p2 / percentage-entity :value 72) :quant-of (o / or :op1 (c4 / cell :mod (c5 / control)) :op2 (c6 / cell :ARG1-of (t2 / treat-04 :ARG2 (s3 / small-molecule :name (n4 / name :op1 "PKI166")))))) :ARG1-of (s4 / statistical-test-91 :ARG2 (l / less-than :op1 0.001))) # ::id pmid_1528_0923.103 ::date 2015-06-16T10:44:12 ::annotator SDL-AMR-09 ::preferred # ::snt The proportion of SUM149 cells in G1 was significantly increased by treatment with either inhibitor alone and the combination, while apoptosis was significantly increased in cells exposed to PKI166, with or without U0126. # ::save-date Fri Dec 18, 2015 ::file pmid_1528_0923_103.txt (c / contrast-01 :ARG1 (i2 / increase-01 :ARG0 (t2 / treat-04 :ARG2 (a / and :op1 (m / molecular-physical-entity :ARG0-of (i / inhibit-01) :mod (a2 / alone)) :op2 (m2 / molecular-physical-entity :ARG0-of (i4 / inhibit-01) :ARG1-of (c3 / combine-01)))) :ARG1 (p / proportion-01 :ARG1 (c2 / cell-line :name (n2 / name :op1 "SUM149")) :time (e2 / event :name (n4 / name :op1 "G1"))) :ARG2 (s2 / significant-02)) :ARG2 (i3 / increase-01 :ARG1 (a3 / apoptosis) :location (c4 / cell :ARG1-of (e / expose-01 :ARG2 (o / or :op1 (a4 / and :op1 (s4 / small-molecule :name (n3 / name :op1 "PKI166")) :op2 (s / small-molecule :name (n / name :op1 "U0126"))) :op2 s4))) :ARG1-of s2)) # ::id pmid_1528_0923.104 ::date 2015-06-16T10:52:27 ::annotator SDL-AMR-09 ::preferred # ::snt Induction of the cyclin-dependent kinase inhibitor p27KIP1 generally corresponded with increases in the proportion of cells in G1, as shown for MDA-MB-231 and SUM149 (Figure 4). # ::save-date Sat Jan 2, 2016 ::file pmid_1528_0923_104.txt (c / correspond-02 :ARG1 (i2 / induce-01 :ARG2 (p2 / protein :name (n4 / name :op1 "p27KIP1") :ARG0-of (i / inhibit-01 :ARG1 (p3 / protein-family :name (n / name :op1 "cyclin-dependent" :op2 "kinase"))))) :ARG2 (i3 / increase-01 :ARG1 (p / proportion-01 :ARG1 (c2 / cell) :time (e2 / event :name (n5 / name :op1 "G1")))) :ARG1-of (g / general-02) :ARG1-of (s / show-01 :ARG2 (a / and :op1 (c3 / cell-line :name (n2 / name :op1 "MDA-MB-231")) :op2 (c4 / cell-line :name (n3 / name :op1 "SUM149")))) :ARG1-of (d / describe-01 :ARG0 (f / figure :mod 4))) # ::id pmid_1528_0923.105 ::date 2015-06-16T11:00:05 ::annotator SDL-AMR-09 ::preferred # ::snt Differential effect of PKI166 on ERK1/2 phosphorylation # ::save-date Tue Jun 16, 2015 ::file pmid_1528_0923_105.txt (a / affect-01 :ARG0 (s / small-molecule :name (n / name :op1 "PKI166")) :ARG1 (p / phosphorylate-01 :ARG1 (e / enzyme :name (n2 / name :op1 "ERK1/2"))) :ARG1-of (d / differ-02)) # ::id pmid_1528_0923.106 ::date 2015-06-16T11:03:57 ::annotator SDL-AMR-09 ::preferred # ::snt To evaluate whether the antiproliferative effects of EGFR inhibition involve ERK1/2 activation, the status of pERK1/2 was determined in cells exposed to the same concentrations of PKI166 used for the growth inhibition assays, in the presence and absence of U0126 (10 μM) (Figure 5). # ::save-date Wed Mar 2, 2016 ::file pmid_1528_0923_106.txt (d / determine-01 :ARG1 (s2 / status :poss-of (e2 / enzyme :name (n3 / name :op1 "ERK1/2") :ARG3-of (p / phosphorylate-01))) :location (c / cell :ARG1-of (e3 / expose-01 :ARG2 (c2 / concentrate-02 :ARG1 (s3 / small-molecule :name (n4 / name :op1 "PKI166") :ARG1-of (u / use-01 :ARG2 (a / assay-01 :ARG1 (i / inhibit-01 :ARG1 (g / grow-01))))) :ARG1-of (s4 / same-01)) :manner (a2 / and :op1 (p2 / present-02 :ARG1 (s / small-molecule :name (n2 / name :op1 "U0126") :quant (c3 / concentration-quantity :quant 10 :unit (m / micromolar)))) :op2 (a3 / absent-01 :ARG1 s)))) :purpose (e4 / evaluate-01 :ARG1 (i3 / involve-01 :mode interrogative :ARG0 (a4 / affect-01 :ARG0 (i2 / inhibit-01 :ARG1 (e / enzyme :name (n / name :op1 "EGFR"))) :ARG0-of (c4 / counter-01 :ARG1 (p3 / proliferate-01))) :ARG1 (a5 / activate-01 :ARG1 (e5 / enzyme :name (n5 / name :op1 "ERK1/2"))))) :ARG1-of (d2 / describe-01 :ARG0 (f / figure :mod 5))) # ::id pmid_1528_0923.107 ::date 2015-06-16T11:29:16 ::annotator SDL-AMR-09 ::preferred # ::snt U1026 alone inhibited ERK1/2 phosphorylation in MDA-MB-435 cells, with PKI 166 having no effect, as expected from minimal expression of EGFR in these cells. # ::save-date Sun Jun 21, 2015 ::file pmid_1528_0923_107.txt (a / and :op1 (i / inhibit-01 :ARG0 (s / small-molecule :name (n2 / name :op1 "U1026") :mod (a2 / alone)) :ARG1 (p / phosphorylate-01 :ARG1 (e2 / enzyme :name (n3 / name :op1 "ERK1/2"))) :location (c / cell-line :name (n4 / name :op1 "MDA-MB-435"))) :op2 (a3 / affect-01 :polarity - :ARG0 (s2 / small-molecule :name (n5 / name :op1 "PKI166"))) :ARG1-of (e3 / expect-01 :source (e4 / express-03 :ARG2 (e / enzyme :name (n / name :op1 "EGFR")) :ARG3 c :ARG1-of (m / minimal-02)))) # ::id pmid_1528_0923.108 ::date 2015-06-16T11:44:35 ::annotator SDL-AMR-09 ::preferred # ::snt PKI166 inhibited ERK1/2 phosphorylation in SUM149 cells, as did U0126 alone, and further inhibition by the combination of drugs was barely discernible. # ::save-date Tue Jun 16, 2015 ::file pmid_1528_0923_108.txt (a / and :op1 (i / inhibit-01 :ARG0 (s2 / small-molecule :name (n2 / name :op1 "PKI166")) :ARG1 (p / phosphorylate-01 :ARG1 (e / enzyme :name (n3 / name :op1 "ERK1/2"))) :location (c / cell-line :name (n4 / name :op1 "SUM149")) :ARG1-of (r / resemble-01 :ARG2 (s / small-molecule :name (n / name :op1 "U0126") :mod (a2 / alone)))) :op2 (d / discern-01 :ARG1 (i2 / inhibit-01 :ARG0 (c2 / combine-01 :ARG1 (d2 / drug)) :time (f / further)) :degree (b / bare) :ARG1-of (p2 / possible-01))) # ::id pmid_1528_0923.109 ::date 2015-06-16T11:50:30 ::annotator SDL-AMR-09 ::preferred # ::snt Treatment of MDA-MB-468 with either drug resulted in similar inhibition of ERK1/2 phosphorylation, with almost complete elimination of phosphorylated proteins by the combination. # ::save-date Tue Jun 16, 2015 ::file pmid_1528_0923_109.txt (r2 / result-01 :ARG1 (t / treat-04 :ARG1 (c / cell-line :name (n / name :op1 "MDA-MB-468")) :ARG2 (d / drug :mod (e / either))) :ARG2 (a / and :op1 (i / inhibit-01 :ARG1 (p / phosphorylate-01 :ARG1 (e2 / enzyme :name (n2 / name :op1 "ERK1/2"))) :ARG1-of (r / resemble-01)) :op2 (e3 / eliminate-01 :ARG0 (c3 / combine-01) :ARG1 (p2 / protein :ARG3-of (p3 / phosphorylate-01)) :ARG1-of (c2 / complete-01 :mod (a2 / almost))))) # ::id pmid_1528_0923.110 ::date 2015-06-16T11:55:33 ::annotator SDL-AMR-09 ::preferred # ::snt PKI166 alone minimally altered the ERK1/2 status in the MDA-MB-231 cells, and U0126 produced some inhibition, while the combination resulted in a substantial reduction, reflecting the effect on cell proliferation and apoptosis. # ::save-date Sun Jun 21, 2015 ::file pmid_1528_0923_110.txt (c / contrast-01 :ARG1 (a / and :op1 (a2 / alter-01 :ARG0 (s2 / small-molecule :wiki - :name (n2 / name :op1 "PKI166") :mod (a3 / alone)) :ARG1 (s3 / status :mod (e / enzyme :wiki "Extracellular_signal-regulated_kinases" :name (n3 / name :op1 "ERK1/2"))) :ARG1-of (m / minimal-02) :location (c2 / cell-line :wiki - :name (n4 / name :op1 "MDA-MB-231"))) :op2 (p / produce-01 :ARG0 (s4 / small-molecule :wiki "U0126" :name (n5 / name :op1 "U0126")) :ARG1 (i / inhibit-01 :mod (s5 / some)))) :ARG2 (r / result-01 :ARG1 (c3 / combine-01) :ARG2 (r2 / reduce-01 :ARG1 s3 :degree (s6 / substantial)) :ARG1-of (r3 / reflect-01 :ARG2 (a4 / affect-01 :ARG1 (a5 / and :op1 (p2 / proliferate-01 :ARG0 (c4 / cell)) :op2 (a6 / apoptosis)))))) # ::id pmid_1528_0923.111 ::date 2015-06-16T12:02:26 ::annotator SDL-AMR-09 ::preferred # ::snt For SUM149 and MDA-MB-468 cells the combination of the inhibitors almost completely eliminated ERK1/2 phosphorylation after 1 h incubation, although growth inhibition over 72 h was 54–63% with 0.5 μM PKI166 plus 10 μM U0126, and 63–81% with 5.0 μM PKI166 plus 10 μM U0126 (Table 1). # ::save-date Tue Dec 15, 2015 ::file pmid_1528_0923_111.txt (e / eliminate-01 :ARG0 (c / combine-01 :ARG1 (m / molecular-physical-entity :ARG0-of (i / inhibit-01))) :ARG1 (p3 / phosphorylate-01 :ARG1 (e2 / enzyme :name (n / name :op1 "ERK1/2"))) :ARG2 (a3 / and :op1 (c3 / cell-line :name (n2 / name :op1 "SUM149")) :op2 (c4 / cell-line :name (n3 / name :op1 "MDA-MB-468"))) :ARG1-of (c2 / complete-01 :mod (a / almost)) :time (a2 / after :op1 (i2 / incubate-01) :quant (t / temporal-quantity :quant 1 :unit (h / hour))) :concession (a5 / and :op1 (i3 / inhibit-01 :ARG0 (a4 / and :op1 (s2 / small-molecule :name (n4 / name :op1 "PKI166") :quant (c5 / concentration-quantity :quant 0.5 :unit (m2 / micromolar))) :op2 (s / small-molecule :name (n5 / name :op1 "U0126") :quant (c6 / concentration-quantity :quant 10 :unit (m3 / micromolar)))) :ARG1 (g / grow-01) :quant (v / value-interval :op1 (p4 / percentage-entity :value 54) :op2 (p / percentage-entity :value 63)) :duration (o2 / over :op1 (t2 / temporal-quantity :quant 72 :unit (h3 / hour)))) :op2 (i4 / inhibit-01 :ARG0 (a6 / and :op1 (s3 / small-molecule :name (n6 / name :op1 "PKI166") :quant (c7 / concentration-quantity :quant 5 :unit (m4 / micromolar))) :op2 s) :ARG1 (g2 / grow-01) :quant (v2 / value-interval :op1 (p5 / percentage-entity :value 63) :op2 (p2 / percentage-entity :value 81)) :duration o2)) :ARG1-of (d / describe-01 :ARG0 (t3 / table :mod 1))) # ::id pmid_1528_0923.112 ::date 2015-06-16T12:21:26 ::annotator SDL-AMR-09 ::preferred # ::snt Recovery of ERK1/2 phosphorylation in the U0126-treated cells over the period of the growth inhibition assays was not investigated, but the data may also suggest that other signal pathways were contributing to the growth and survival of the cells. # ::save-date Mon Dec 21, 2015 ::file pmid_1528_0923_112.txt (c / contrast-01 :ARG1 (i / investigate-01 :polarity - :ARG1 (r / recover-02 :ARG1 (p / phosphorylate-01 :ARG1 (e / enzyme :name (n / name :op1 "ERK1/2")) :location (c2 / cell :ARG1-of (t / treat-04 :ARG2 (s / small-molecule :name (n2 / name :op1 "U0126"))))) :time (a / assay-01 :ARG1 (i2 / inhibit-01 :ARG1 (g / grow-01))))) :ARG2 (p3 / possible-01 :ARG1 (s2 / suggest-01 :ARG0 (d / data) :ARG1 (c3 / contribute-01 :ARG0 (p4 / pathway :ARG0-of (s3 / signal-07) :mod (o2 / other)) :ARG2 (a3 / and :op1 (g2 / grow-01 :ARG1 (c4 / cell)) :op2 (s4 / survive-01 :ARG0 c4))) :mod (a2 / also)))) # ::id pmid_1528_0923.113 ::date 2015-06-16T12:35:01 ::annotator SDL-AMR-09 ::preferred # ::snt The effects of the inhibitors were not related to downregulation of total ERK1/2 proteins, as the levels did not decrease with treatment (Figure 5). # ::save-date Sun Jun 21, 2015 ::file pmid_1528_0923_113.txt (r2 / relate-01 :polarity - :ARG1 (a / affect-01 :ARG0 (m / molecular-physical-entity :ARG0-of (i2 / inhibit-01))) :ARG2 (d / downregulate-01 :ARG1 (e / enzyme :name (n / name :op1 "ERK1/2") :mod (t2 / total))) :ARG1-of (c / cause-01 :ARG0 (d2 / decrease-01 :polarity - :ARG0 (t3 / treat-04) :ARG1 (l / level))) :ARG1-of (d3 / describe-01 :ARG0 (f / figure :mod 5)))