Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Upon ligand-induced tyrosine phosphorylation, the platelet-derived growth factor (PDGF) receptor (PDGFR) beta subunit associates with PLC-gamma 1, RasGAP, P13K, and a 64 kd protein. To determine the relative role of each of these associated proteins in PDGFR signaling, we constructed a PDGFR mutant (F5) unable to bind any of them and a panel of "add-back" mutants that could bind only one of the receptor-associated proteins. F5 PDGFR failed to activate PLC-gamma 1, P13K, or Ras and was unable to trigger DNA synthesis. Permitting association of F5 PDGFR with either PLC-gamma 1 or P13K restored Ras activation and a mitogenic response. Surprisingly, even though binding of the 64 kd protein almost fully restored Ras activation, it did not rescue the receptor's ability to trigger DNA synthesis. Thus Ras activation is insufficient to trigger PDGF-dependent DNA synthesis, and PLC-gamma 1 and P13K are independent downstream mediators of PDGF's mitogenic signal.
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PMID:Phospholipase C-gamma 1 and phosphatidylinositol 3 kinase are the downstream mediators of the PDGF receptor's mitogenic signal. 768 95

The SH2-containing tyrosine phosphatase Shp-2 appears to function downstream of a variety of growth factor receptors and might play a positive role in cell proliferation. Here we report that expression of the beta subunit of platelet-derived growth factor receptor (PDGFR-beta) was specifically downregulated in mutant fibroblasts lacking a functional Shp-2, while the levels of PDGFR-alpha EGFR and IGFIR were not changed. PDGF-stimulated DNA synthesis and extracellular signal regulated kinase (Erk) activation was severely suppressed in mutant cells. RasGAP, that responds to activation of PDGFR-beta but not PDGFR-alpha, was not phosphorylated on tyrosine in mutant cells upon PDGF-treatment. Northern blot analysis failed to detect PDGFR-beta mRNA in mutant cells. The transcription initiation from the PDGFR-beta gene promoter was not significantly changed, but the half-life of its mRNA was shortened in Shp-2 mutant cells. These observations indicate that Shp-2 not only participates in transmission of signals from growth factor receptors but also plays a specific role in the control of the PDGFR-beta expression. We propose that this is an important mechanism for the positive control of cell proliferation by Shp-2.
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PMID:Downregulation of platelet-derived growth factor receptor-beta in Shp-2 mutant fibroblast cell lines. 969 37

In relation to the activation of the Src-family of tyrosine kinases during early morphogenetic events of gastrulation in Xenopus, we have identified two multiprotein complexes. The first complex, including RasGAP, p190 RhoGAP and p62, was previously characterized in murine fibroblasts overexpressing c-Src or transformed by v-Src and has been correlated with cytoskeleton remodelling. A second complex, not identified in other models includes tyrosine-phosphorylated p66SHC, Grb2, RasGAP and p190 RhoGAP. The association with p66SHC, considered as a negative regulator of ERK (extracellular signal-regulated kinase), p120RasGAP and p190RhoGAP, suggests a possible mechanism for coupling Ras and Rho signalling pathways. The interaction of RasGAP and p190 RhoGAP in two multiprotein complexes could constitute an additional level of Rho regulation during morphogenetic events of gastrulation.
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PMID:Formation of complexes involving RasGAP and p190 RhoGAP during morphogenetic events of the gastrulation in xenopus. 1050 83

Although the 100-kDa Ras GTPase-activating protein (p100 RasGAP) has been reported to exist specifically in human placental trophoblasts, the molecular mechanisms responsible for regulating its expression remain unclear. In this study we used okadaic acid, an inhibitor of serine/threonine phosphatase 1 and 2 A, as a probe to explore the signaling pathway regulating the expression of p100 RasGAP in JEG-3 human placental choriocarcinoma cells. Treatment of JEG-3 cells with okadaic acid provoked dose- and time-dependent stimulation of p100 RasGAP expression without marked modification of expression of p120 RasGAP, another isoform of RasGAP. Co-treatment of cells with okadaic acid and the protein kinase C activator, phorbol 12-myristate 13-acetate, exerted an additive effect on p100 RasGAP induction. Moreover, the response of the p100 RasGAP de novo synthesis to okadaic acid was not affected by the selective inhibitor of protein kinase C, GF 109203X. Thus this study identified a novel signaling pathway regulating p100 RasGAP expression, which is independent of protein kinase C. In addition, okadaic acid treatment resulted in the activation of ERK2 (p42 MAP kinase) and the induction of both c-Jun and c-Fos proteins without activating JNK (c-Jun NH2-terminal kinase). Significantly, blockade of c-Jun expression with antisense c-jun oligonucleotides suppressed p100 RasGAP expression. Taken together, it is concluded that okadaic acid induces the expression of p100 RasGAP protein in JEG-3 cells preceded by activation of ERK and AP-1 cascade, and that this okadaic acid-induced p100 RasGAP expression is independent of protein kinase C-mediated pathway but requires c-Jun/AP-1 function.
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PMID:A protein kinase C-independent pathway leading to c-Jun-dependent expression of 100-kDa Ras GTPase-activating protein in JEG-3 human choriocarcinoma cells. 1071 88

Mutating tyrosines 579 and 581 of the beta platelet-derived growth factor receptor (betaPDGFR) tyrosine kinase to phenylalanines (the F2 mutation) impair activation of the receptor in response to ligand, but mutation of the analogous tyrosines in the alphaPDGFR has no effect on ligand-dependent receptor activation. We have found that the F2 mutation has only a modest effect on ligand-dependent activation of a chimeric PDGFR composed of the extracellular and transmembrane domains of the alphaPDGFR and the cytoplasmic domain of the betaPDGFR by three measures: (1) the ability to phosphorylate endogenous and exogenous protein substrates in vitro, (2) phosphorylation of tyrosine 857, and (3) binding of the effector proteins PLCgamma, RasGAP, and SHP-2. Conversely, the F2 mutation substantially impairs ligand-dependent activation of chimeric PDGFRs that consist of either the extracellular domain alone or the extracellular and transmembrane domains of the betaPDGFR and all remaining sequence from the alphaPDGFR by two measures: (1) phosphorylation of endogenous protein substrates in vitro and (2) binding of PLCgamma and SHP-2. Our results indicate that the requirement of tyrosines 579 and 581 for maximal activation of the betaPDGFR in response to ligand is primarily determined by noncytoplasmic regions of the receptor.
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PMID:The requirement of tyrosines 579 and 581 for maximal ligand-dependent activation of the betaPDGFR is influenced by noncytoplasmic regions of the receptor. 1128 46

Neural crest-derived melanocyte precursors (MPs) in avian and murine embryos emerge from the dorsal neural tube into a migration staging area (MSA). MPs subsequently migrate from the MSA on a dorsolateral pathway between the dermamyotome and the overlying epithelium. In mouse embryos, MPs express the receptor tyrosine kinase, KIT, and require its cognate ligand, Mast cell growth factor (MGF), for survival and differentiation. Prior to the onset of MP migration, MGF is expressed on the dorsolateral pathway at some distance from cells in the MSA and appears to be required for normal MP development. To learn if MGF is required solely for MP survival on this pathway, or if it also provides directional cues for migration, we uncoupled survival from chemoattractive or motogenic functions of this ligand using mice that carry a targeted mutation at the Neurofibromin (Nf1) locus and consequently lack RAS-GAP function. We show that Nf1-mutant MPs survive in the absence of MGF in vitro and in vivo and that Nf1-mutant MPs disperse normally on the lateral migration pathway in the presence of MGF. In contrast, Nf1-mutant MPs persist in the location of the MSA but are not observed on the lateral migration pathway in double-mutant mice that also lack MGF. We conclude that MGF/KIT function provides a signal required for directed migration of the MPs on the lateral pathway in vivo, independent of its function in survival. We further suggest that the MGF mediates MP migration through a signaling pathway that does not involve RAS.
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PMID:Analysis of melanocyte precursors in Nf1 mutants reveals that MGF/KIT signaling promotes directed cell migration independent of its function in cell survival. 1140 6

A major pathway by which growth factors, such as platelet-derived growth factor (PDGF), regulate cell proliferation is via the receptor tyrosine kinase/Ras/mitogen-activated protein kinase (MAPK) signaling cascade. The output of this pathway is subjected to tight regulation of both positive and negative regulators. One such regulator is p62(dok), the prototype of a newly identified family of adaptor proteins. We recently provided evidence, through the use of p62(dok)-deficient cells, that p62(dok) acts as a negative regulator of growth factor-induced cell proliferation and the Ras/MAPK pathway. We show here that reintroduction of p62(dok) into p62(dok)-(/)- cells can suppress the increased cell proliferation and prolonged MAPK activity seen in these cells, and that plasma membrane recruitment of p62(dok) is essential for its function. We also show that the PDGF-triggered plasma membrane translocation of p62(dok) requires activation of phosphoinositide 3-kinase (PI3-kinase) and binding of its pleckstrin homology (PH) domain to 3'-phosphorylated phosphoinositides. Furthermore, we demonstrate that p62(dok) can exert its negative effect on the PDGFR/MAPK pathway independently of its ability to associate with RasGAP and Nck. We conclude that p62(dok) functions as a negative regulator of the PDGFR/Ras/MAPK signaling pathway through a mechanism involving PI3-kinase-dependent recruitment of p62(dok) to the plasma membrane.
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PMID:Phosphoinositide 3-kinase-dependent membrane recruitment of p62(dok) is essential for its negative effect on mitogen-activated protein (MAP) kinase activation. 1148 46

Various mitogenic stimuli such as epidermal growth factor (EGF), fibroblast growth factor (FGF), and phorbol 12,13-dibutyrate (PDBu) activate the Ras-Raf-MEK-ERK pathway, but the regulatory mechanism of this pathway remains to be investigated. Here we found that in 293 cells, mammalian Sprouty2 and Sprouty4 were rapidly induced by EGF, FGF, and PDBu in an ERK pathway-dependent manner. Forced expression of Sprouty2 and Sprouty4 inhibited FGF-induced ERK activation but did not affect EGF- or PDBu-induced ERK activation. To examine whether endogenous Sproutys were also selective inhibitors, we generated a dominant negative form of Sprouty2 (Y55A) and Sprouty4 (Y53A) in which conserved tyrosine residues were mutated. These mutants reverted the suppressive effect of both Sprouty2 and Sprouty4 but not that of RasGAP or SPRED (Sprouty-related EVH1 domain-containing protein), another Sprouty-related Ras suppressor. Expression of dominant negative Sprouty2 and Sprouty4 enhanced and prolonged FGF- but not EGF-induced ERK activation in 293 cells. In PC12 cells, endogenous Sprouty4 was also induced by FGF. Overexpression of wild-type Sprouty4 blocked FGF-induced differentiation, whereas Y53A-Sprouty4 enhanced it. These observations suggest that endogenous Sprouty2 and Sprouty4 are physiological negative feedback regulators of growth factor-mediated ERK pathway and that there are Sprouty-sensitive and -insensitive ERK activation pathways. Finding a dominant negative form of Sproutys will facilitate the study of the molecular mechanism and physiological function of Sproutys.
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PMID:Identification of a dominant negative mutant of Sprouty that potentiates fibroblast growth factor- but not epidermal growth factor-induced ERK activation. 1149 95

The mortality rate from coronary artery disease (CAD) in France is approximately 50% compared to other European countries and the United States ("French paradox"). Epidemiological studies indicate an inverse relationship between moderate wine consumption and CAD mortality. Here, we demonstrate that preincubation of vascular smooth muscle cells (VSMCs) with red wine, but not white wine, inhibits ligand binding and the subsequent tyrosine phosphorylation of the platelet-derived growth factor beta receptor (betaPDGFR), which plays a critical role in the pathogenesis of atherosclerosis. As a consequence, red wine abrogates the ligand-induced recruitment of betaPDGFR-associated signaling molecules (RasGAP, SHP-2, PI3K, PLCgamma), PDGF-dependent downstream events such as Erk activation and induction of immediate early genes, and VSMC proliferation and migration. Wine analysis revealed flavonoids of the catechin family as major constituents of red wine, and these were identified as potent inhibitors of betaPDGFR signaling. Importantly, the concentrations of red wine/catechins shown to inhibit the PDGFR in vitro correlate with the serum levels after red wine consumption in humans. We conclude that nonalcoholic constituents of red wine, which accumulate during the "mash fermentation," inhibit betaPDGFR activation and PDGF-dependent cellular responses in VSMCs. Therefore, catechin-mediated inhibition of betaPDGFR signaling offers a molecular explanation for the "French paradox."
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PMID:Inhibition of the PDGF receptor by red wine flavonoids provides a molecular explanation for the "French paradox". 1239 93

Mitogen-induced changes in the actin cytoskeleton are accompanied by changes in the tyrosine phosphorylation of several proteins in focal adhesions. In this study, we have investigated the role of RAFTK (also termed Pyk2/CAK-beta), a cytoplasmic tyrosine kinase related to focal adhesion kinase (FAK), in heregulin-mediated signal transduction in breast cancer cells. Stimulation of T47D cells with heregulin (HRG) induced the tyrosine phosphorylation of RAFTK and the formation of a multiprotein complex. Maximal phosphorylation of the proteins participating in this complex occurred within 2 h of HRG stimulation. Analyses of the members of the HRG-stimulated complex revealed that RAFTK associated with p190 RhoGAP (p190), RasGAP, c-Abl as well as with the focal adhesion molecules p130cas and paxillin. c-Abl was found to be associated with RAFTK through the region of RAFTK containing amino acids 419-1009. Site-directed mutagenesis of Y881 aa within the RAFTK sequence abolished the binding of RAFTK to c-Abl, indicating that the tyrosine residue 881 of RAFTK is the c-Abl binding site within the RAFTK molecule. Overexpression of wild-type RAFTK significantly enhanced breast cancer cell invasion, while overexpression of the mutants Tyr402 or Tyr881 of RAFTK inhibited this migration. Therefore, RAFTK serves as a mediator and an integration point between focal adhesion molecules in HRG-mediated signaling in T47D breast cancer cells.
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PMID:Coupling of RAFTK/Pyk2 kinase with c-Abl and their role in the migration of breast cancer cells. 1465 52


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