Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.10.1 (ERK)
 95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The proto-oncogene c-MET encodes a transmembrane tyrosine kinase receptor for hepatocyte growth factor/scatter factor (HGF/SF). HGF/SF stimulates the proliferation and motility of various cell types. Because HGF/SF is also a melanocyte mitogen, we investigated the biological role of HGF/SF, including c-Met expression, activation and signal transduction, in normal and malignant human melanocytes. We show that HGF/SF is mitogenic in the presence of synergistic factors, such as basic fibroblast growth factor (bFGF) and mast cell growth factor (MGF) and that, by itself, it stimulates the motility of normal human melanocytes. The ligand also maintained high levels of tyrosinase activity and melanin content in theses cells. Signal transduction by HGF/SF included phosphorylation of tyrosyl residues on c-Met, a cascade of tyrosine phosphorylations on several other proteins and activation of microtubule-associated protein kinase/extracellular signal-regulated kinase. Met expression and activity are normal in human melanomas, and constitutive activity of HGF/SF in retrovirally infected autonomously proliferative mouse melanocytes is insufficient to confer the malignant phenotype. Our findings suggest that activation of Met in response to HGF/SF may contribute to malignant progression synergistically with the aberrant expression of bFGF in malignant melanocytes and that, in addition, the peptide may promote dispersion of factor-dependent melanocytes from early stages of primary melanomas to ectopic sites.
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PMID:Met and hepatocyte growth factor/scatter factor signal transduction in normal melanocytes and melanoma cells. 133 34

Expression of oncogenic ras in PC12 cells causes neuronal differentiation and sustained protein tyrosine phosphorylation and activity of extracellular signal-regulated kinases (ERKs), p42erk2 and p44erk1. Oncogenic N-ras-induced neuronal differentiation is inhibited by compounds that block ERK protein tyrosine phosphorylation or ERK activity, indicating that ERKs are not only activated by p21ras but serve as the primary downstream effectors of p21ras. Treatment of PC12 cells with nerve growth factor or fibroblast growth factor results in neuronal differentiation and in a sustained elevation of p21ras activity, of ERK activity, and of ERK tyrosine phosphorylation. Epidermal growth factor, which does not cause neuronal differentiation, stimulates only transient (< 1 hr) activation of p21ras and ERKs. These data indicate that transient activation of p21ras and, consequently, ERKs is not sufficient for induction of neuronal differentiation. Prolonged ERK activity is required: a consequence of sustained activation of p21ras by the growth factor receptor protein tyrosine kinase.
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PMID:PC12 cell neuronal differentiation is associated with prolonged p21ras activity and consequent prolonged ERK activity. 138 73

Apoptosis plays an important role during neuronal development, and defects in apoptosis may underlie various neurodegenerative disorders. To characterize molecular mechanisms that regulate neuronal apoptosis, the contributions to cell death of mitogen-activated protein (MAP) kinase family members, including ERK (extracellular signal-regulated kinase), JNK (c-JUN NH2-terminal protein kinase), and p38, were examined after withdrawal of nerve growth factor (NGF) from rat PC-12 pheochromocytoma cells. NGF withdrawal led to sustained activation of the JNK and p38 enzymes and inhibition of ERKs. The effects of dominant-interfering or constitutively activated forms of various components of the JNK-p38 and ERK signaling pathways demonstrated that activation of JNK and p38 and concurrent inhibition of ERK are critical for induction of apoptosis in these cells. Therefore, the dynamic balance between growth factor-activated ERK and stress-activated JNK-p38 pathways may be important in determining whether a cell survives or undergoes apoptosis.
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PMID:Opposing effects of ERK and JNK-p38 MAP kinases on apoptosis. 748 20

Members of the Rho family of small guanosine triphosphatases (GTPases) regulate the organization of the actin cytoskeleton; Rho controls the assembly of actin stress fibers and focal adhesion complexes, Rac regulates actin filament accumulation at the plasma membrane to produce lamellipodia and membrane ruffles, and Cdc42 stimulates the formation of filopodia. When microinjected into quiescent fibroblasts, Rho, Rac, and Cdc42 stimulated cell cycle progression through G1 and subsequent DNA synthesis. Furthermore, microinjection of dominant negative forms of Rac and Cdc42 or of the Rho inhibitor C3 transferase blocked serum-induced DNA synthesis. Unlike Ras, none of the Rho GTPases activated the mitogen-activated protein kinase (MAPK) cascade that contains the protein kinases c-Raf1, MEK (MAPK or ERK kinase), and ERK (extracellular signal-regulated kinase). Instead, Rac and Cdc42, but not Rho, stimulated a distinct MAP kinase, the c-Jun kinase JNK/SAPK (Jun NH2-terminal kinase or stress-activated protein kinase). Rho, Rac, and Cdc42 control signal transduction pathways that are essential for cell growth.
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PMID:An essential role for Rho, Rac, and Cdc42 GTPases in cell cycle progression through G1. 765 75

A number of different intracellular signaling pathways have been shown to be activated by receptor tyrosine kinases. These activation events include the phosphoinositide 3-kinase, 70 kDa S6 kinase, mitogen-activated protein kinase (MAPK), phospholipase C-gamma, and the Jak/STAT pathways. The precise role of each of these pathways in cell signaling remains to be resolved, but studies on the differentiation of mammalian PC12 cells in tissue culture and the genetics of cell fate determination in Drosophila and Caenorhabditis suggest that the extracellular signal-regulated kinase (ERK-regulated) MAPK pathway may be sufficient for these cellular responses. Experiments with PC12 cells also suggest that the duration of ERK activation is critical for cell signaling decisions.
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PMID:Specificity of receptor tyrosine kinase signaling: transient versus sustained extracellular signal-regulated kinase activation. 783 38

Up-regulation of ERK (extracellular signal-regulated kinase or MAP kinase) and MEK (ERK kinase or MAPK kinase) expression after rat facial nerve injury was demonstrated by in situ hybridization histochemistry and immunohistochemistry. These two enzymes play roles in one of the major intracellular signal cascade pathways involving receptor tyrosine kinase common to growth factor receptors, and transcription factors. Significant increases in ERK1 mRNA levels were observed from day 3 after facial nerve transection, with the highest level of expression from 1 to 2 weeks after the operation. This high level of mRNA expression then decreased gradually to the normal level. ERK1-like immunoreactivity showed a similar time course to that of its mRNA expression; however, the decay profile was more prolonged. The up-regulation of MEK, the ERK kinase/MAPK kinase, was also detected by immunohistochemistry. The protein expression profiles were almost equivalent, but the MEK expression was slightly advanced, suggesting that the observed up-regulation of MEK was not due to that of ERK. The receptor tyrosine kinase signal transduction pathway via MEK-ERK located downstream of growth factor receptors seems vital as a regulator of the synthesis of molecules that play important roles in the recovery process following injury or/and regeneration.
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PMID:Up-regulation of ERK (MAP kinase) and MEK (MAP kinase kinase) transcription after rat facial nerve transection. 783 28

The present study revealed that the pineal gland expressed basic fibroblast growth factor (bFGF) and FGF-receptor 1 (FGFR1/flg), suggesting that bFGF in the pineal gland acts in an autocrine or paracrine manner, which is mediated by FGFR1/flg. The present study also examined gene expression of the extracellular signal-regulated kinase (ERK) family (ERK1-3) which may be intracellular signal mediators of growth factors. ERK1 [mitogen-activated protein kinase (MAP-kinase)] was strongly expressed throughout the pineal gland, while expression of ERK2 and ERK3 was not found. These findings suggest the presence of a signal pathway from bFGF to ERK1 via FGFR1/flg in the pineal gland.
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PMID:Growth factors and extracellular signal-regulated kinases (mitogen-activated protein kinase) in the rat pineal gland. 812 4

The induction of proliferation and differentiation in cultured mammalian cells is mediated by a cascade of protein phosphorylations. A key enzyme in this signaling pathway is mitogen-activated protein (MAP) kinase (or ERK, extracellular signal-regulated kinase). We report the recovery of a full-length cDNA clone encoding a MAP kinase from alfalfa. We have named the 44-kD protein encoded by this clone MsERK1. Recombinant MsERK1 (rMsERK1), when overexpressed in Escherichia coli, is recognized by antibodies raised against MAP kinases from rat, Xenopus, and sea star and by anti-phosphotyrosine antibodies. Site-directed mutagenesis of MsERK1 demonstrated that Tyr-215 is either directly or indirectly responsible for recognition of the protein by anti-phosphotyrosine antibodies. Semipurified rMsERK1 phosphorylated itself and a model substrate, myelin basic protein, in vitro, but the Tyr-215 mutant did neither. Genomic DNA gel blot analysis suggested that the gene that encodes MsERK1 is either a member of a small multigene family or a member of a polymorphic allelic series in alfalfa. Because MAP kinase activation has been associated with mitotic stimulation in animal systems, such an enzyme may play a role in the mitogenic induction of symbiotic root nodules on alfalfa by Rhizobium signal molecules.
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PMID:MsERK1: a mitogen-activated protein kinase from a flowering plant. 843 46

A paradigm has been established whereby mutant tyrosine kinase receptors such as the v-erbB and v-fms gene products function as oncoproteins in the absence of ligand. A spontaneously occurring deletional mutant of the human epidermal growth factor receptor (EGFR-vIII) has been isolated from astrocytic neoplasms and transforms NIH3T3 cells in the absence of ligand. The EGFRvIII is constitutively complexed with the majority of cellular GRB2, suggesting a link to the Ras-Mitogen-activated protein (MAP) kinase pathway (D. Moscatello, R. B. Montgomery, P. Sundareshan, H. McDanel, M. Y. Wong, and A. J. Wong, submitted for publication). In this report, we document that expression of EGFRvIII in fibroblasts is associated with downstream activation of mitogen-activated protein (MAP) kinase/extracellular signal-regulated kinase (MEK) and modest activation of p42 and p44 MAP kinases. The presence of EGFRvIII suppresses activation of p42 and p44 MAP kinases by phorbol 12-myristate 13-acetate (PMA) and serum; however, MEK activation by PMA is not suppressed by EGFRvIII. Basal and PMA-stimulated MAP kinase activity in EGFRvIII-transfected cells is augmented by the tyrosine phosphatase inhibitor sodium vanadate. EGFR-vIII is capable of transducing downstream signals through MAP kinase as evidenced by activation of cytoplasmic phospholipase A2 at levels similar to that induced by intact EGFR. Our results suggest that EGFR-vIII constitutively activates downstream signal transduction through MAP kinase, and this chronic stimulation of the MAP kinase pathway may represent one means by which mutant EGFR transduces an oncogenic signal.
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PMID:Differential modulation of mitogen-activated protein (MAP) kinase/extracellular signal-related kinase kinase and MAP kinase activities by a mutant epidermal growth factor receptor. 853 Apr 89

Protein-tyrosine kinases (PTKs) of the JAK family have been characterized on the basis of their ability to mediate the rapid induction of transcription of interferon-responsive genes through the stimulation of a class of latent cytoplasmic transcription factors known as signal transducers and activators of transcription (STATs). STAT activation, which has been described as being Ras-independent, requires tyrosine phosphorylation, but STAT transactivating activity is enhanced by phosphorylation on serine as well, probably by extracellular signal-regulated kinase/mitogen-activated protein kinase(s) (ERK/MAPK). STATs can be activated upon binding of ligands to receptor PTKs, to G-protein-linked receptors, and to cytokine receptors. Whether JAKs are required for the activation of signaling pathways other than that leading to STAT activation is not known. The binding of growth hormone (GH) to its receptor (GHR) activates JAK2 and STATs as well as ERK/MAP kinases. We have used a transient transfection system in 293 cells to evaluate the requirement for JAK2 in the activation of ERK2/MAPK by GH. We found that JAK2 is required for GH-simulated activation of ERK2/MAPK. Employing the transient expression of dominant negative forms of H-Ras and Raf-1, we determined that the GHR/JAK2-mediated activation of ERK2/MAPK is dependent on both Ras and Raf. Thus, JAK protein-tyrosine kinases may represent a common component in the activation of the ERK2/MAPK and STAT signaling pathways, which appear to bifurcate upstream of Ras activation but converge with ERK/MAPK phosphorylation of STATs.
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PMID:JAK2, Ras, and Raf are required for activation of extracellular signal-regulated kinase/mitogen-activated protein kinase by growth hormone. 853 33


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