Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We constructed mutant receptors by mutating transmembrane Val922 of the human insulin-like growth factor I receptor (IGF-IR). Assays of receptor kinase and autophosphorylation revealed constitutively augmented tyrosine kinase activity of V922E IGF-IR in both transient and stable expression. The constitutively active tyrosine kinase of this mutant was verified by promoted tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1) in the absence of IGF-I. In CHO cells stably increasing V922E IGF-IR, both IRS-1 phosphorylation and the IRS-1 associated phosphoinositide 3-kinase activity were stimulated in the absence of IGF-I to the level attained by 1 nM IGF-I stimulation of wild-type IGF-IR, whereas the Ras-mitogen-activated protein kinase pathway was not activated under the same condition. In these CHO cells, V922E IGF-IR significantly stimulated glucose uptake but did not promote mitogenesis in the absence of IGF-I. We thus conclude that the V922E mutation of IGF-IR switches on the intrinsic tyrosine kinase and differentially activates the downstream pathways. This mutant is extremely useful in clarifying the turning-on mechanism of IGF-IR as well as the differential roles of individual downstream pathways of receptor tyrosine kinases.
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PMID:Insulin-like growth factor I receptor activated by a transmembrane mutation. 764 66

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

SH-PTP2 is a nontransmembrane human protein-tyrosine phosphatase that contains two Src homology 2 (SH2) domains and binds to insulin receptor substrate 1 (IRS-1) via these domains in response to insulin. The expression of a catalytically inactive mutant of SH-PTP2 (containing the mutation Cys-459-->Ser) in Chinese hamster ovary cells that overexpress human insulin receptors (CHO-IR cells) markedly attenuated insulin-stimulated Ras activation. Expression of mutant SH-PTP2 also inhibited MAP kinase activation in response to insulin but not in response to 12-O-tetradecanoyl phorbol-13-acetate. In contrast, the insulin-induced association of phosphoinositide 3-kinase activity with IRS-1 was not affected by the expression of inactive SH-PTP2. Furthermore, the expression of mutant SH-PTP2 had no effect on the binding of Grb2 to IRS-1, on the tyrosine phosphorylation of Shc, or on the formation of the complex between Shc and Grb2 in response to insulin. However, the amount of SH-PTP2 bound to IRS-1 in insulin-treated CHO-IR cells expressing mutant SH-PTP2 was greater than that observed in CHO-IR cells overexpressing wild-type SH-PTP2. Recombinant SH-PTP2 specifically dephosphorylated a synthetic phosphopeptide corresponding to the sequence surrounding Tyr-1172 of IRS-1, a putative binding site for SH-PTP2. Additionally, phenylarsine oxide, an inhibitor of protein-tyrosine phosphatases, inactivated SH-PTP2 in vitro and increased the insulin-induced association of SH-PTP2 with IRS-1. These results suggest that SH-PTP2 may regulate an upstream element necessary for Ras activation in response to insulin and that this upstream element may be required for the Grb2- or Shc-dependent pathway. Furthermore, these results are consistent with the notion that SH-PTP2 may bind to IRS-1 through its SH2 domains in response to insulin and dephosphorylate the phosphotyrosine residue to which it binds, thereby regulating its association with IRS-1.
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PMID:Role of SH-PTP2, a protein-tyrosine phosphatase with Src homology 2 domains, in insulin-stimulated Ras activation. 793 86

The roles of gastrin and sodium vanadate in proliferation were examined in cultured IEC-6 cells that are mitotically active and derived originally from jejunal crypts of the rat intestine. Incubation of the cells in the presence of gastrin at a concentration of 250 ng/ml or of sodium vanadate at a concentration of 0.2 mM leads to a 60% increase in cell growth in 24 hr. The stimulated growth in both cases was inhibited by genistein, a tyrosine kinase inhibitor. Incubation in the presence of gastrin and sodium vanadate together produced a small, albeit significant, potentiation of growth of the cells. Gastrin as well as sodium vanadate also promoted the phosphorylation on tyrosine of a similar group of proteins with molecular masses of 42, 45, 52, 60, 78, and 120 kDa. The phosphorylations were rapidly occurring as early as 5 min and lasted for only 15 min. Several proteins were detected in normal IEC-6 cells, including GTPase activating protein, raf1 kinase, phospholipase C gamma-1, and phosphoinositide 3-kinase. The results suggest that gastrin and sodium vanadate induce growth of IEC-6 cells by stimulation of tyrosine kinase and/or inhibition of tyrosine phosphatase. The gastrin and sodium vanadate effects also involve the phosphorylation of a number of proteins, the identities of which are not known at present but may include some of the kinases that are frequently associated with cell growth, such as mitogen-activated protein kinase, raf1 kinase, phosphoinositide 3-kinase, and others.
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PMID:Role of tyrosine kinase and phosphotyrosine phosphatase in growth of the intestinal crypt cell (IEC-6) line. 845 7

Two cDNA clones homologous with human neuropeptide (NP) Y-Y1 receptor have been isolated from a mouse bone marrow cDNA library. One was thought to be the cognate of the human NPY-Y1 receptor, termed Y1 alpha receptor, and the other form, termed Y1 beta receptor, differed from the Y1 alpha receptor in the seventh transmembrane domain and C-terminal tail. Analysis of the mouse genomic DNA showed that both receptors originated from a single gene. The different peptide sequences of the Y1 beta receptor were encoded by separate exons, hence, these receptors were generated by differential RNA splicing. High affinity binding of [125I]NPY to each receptor expressed in Chinese hamster ovary (CHO) cells and sequestration of [125I]NPY after binding to each receptor were observed. In the CHO cells expressing the Y1 alpha receptor, intracellular Ca2+ increase, inhibition of forskolin-induced cAMP accumulation, and mitogen-activated protein kinase (MAPK) activation were observed by stimulation of NPY, and these responses were abolished by pretreatment with pertussis toxin. Since wortmannin completely inhibited NPY-elicited MAPK activation, we speculate that wortmannin-sensitive signaling molecule(s) such as phosphoinositide 3-kinase may lie between pertussis toxin-sensitive G-protein and MAPK. In contrast, these intracellular signals were not detected in CHO cells expressing the Y1 beta receptor. Northern blots and reverse transcriptase-polymerase chain reaction analyses indicated that the Y1 alpha receptor was highly expressed in the brain, heart, kidney, spleen, skeletal muscle, and lung, whereas the Y1 beta receptor mRNA was not detected in these tissues. However, the Y1 beta receptor was expressed in mouse embryonic developmental stage (7 and 11 days), bone marrow cells and several hematopoietic cell lines. These results suggest that the Y1 beta receptor is an embryonic and a bone marrow form of the NPY-Y1 receptor, which decreases in the expression during development and differentiation.
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PMID:Identification of two isoforms of mouse neuropeptide Y-Y1 receptor generated by alternative splicing. Isolation, genomic structure, and functional expression of the receptors. 853 Apr 15

The tyrosine kinase class of receptors induces mitogen-activated protein kinase (MAPK) activation through the sequential interaction of the signaling proteins Grb2, Sos, Ras, Raf, and MEK. Receptors coupled to heterotrimeric guanine triphosphate-binding protein (G protein) stimulate MAPK through Gbetagamma subunits, but the subsequent intervening molecules are still poorly defined. Overexpression of phosphoinositide 3-kinase gamma (PI3Kgamma) in COS-7 cells activated MAPK in a Gbetagamma-dependent fashion, and expression of a catalytically inactive mutant of PI3Kgamma abolished the stimulation of MAPK by Gbetagamma or in response to stimulation of muscarinic (m2) G protein-coupled receptors. Signaling from PI3Kgamma to MAPK appears to require a tyrosine kinase, Shc, Grb2, Sos, Ras, and Raf. These findings indicate that PI3Kgamma mediates Gbetagamma-dependent regulation of the MAPK signaling pathway.
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PMID:Linkage of G protein-coupled receptors to the MAPK signaling pathway through PI 3-kinase gamma. 899 38

Homodimerization of the erythropoietin (EPO) receptor (EPO-R) in response to EPO binding transiently activates the receptor-associated protein tyrosine kinase JAK2. Tyrosine phosphorylation of the EPO-R creates "docking sites" for SH2 domain(s) in signaling molecules such as the protein tyrosine phosphatases SH-PTP1 and SH-PTP2, phosphoinositide 3-kinase (PI3 kinase), and STAT5. However, little is known about the specific intracellular signals essential for proliferation and differentiation of erythroid progenitors. Here we show that an EPO-R containing only one cytosolic (phospho)tyrosine residue, Y479, induces a signal transduction pathway sufficient for proliferation and differentiation of fetal liver progenitors of erythroid colony-forming units from EPO-R(-/-) mice as well as for proliferation of cultured hematopoietic cells. This cascade involves sequential EPO-induced recruitment of PI3 kinase to the EPO-R and activation of mitogen-activated protein kinase activity, independent of the Shc/Grb2-adapter pathway and of STAT5. Protein kinase C epsilon may be one of the mediators connecting PI3 kinase with the mitogen-activated protein kinase signaling cascade. Our results identify a signaling cascade important in vivo for erythroid cell proliferation and differentiation.
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PMID:Identification of a novel pathway important for proliferation and differentiation of primary erythroid progenitors. 909 38

Isolated skeletal muscle from healthy individuals was used to evaluate the role of phosphoinositide 3-kinase (PI 3-kinase) in insulin signalling pathways regulating mitogen activated protein kinase (MAP-kinase) and protein kinase-B and to investigate whether MAP-kinase was involved in signalling pathways regulating glucose metabolism. Insulin stimulated glycogen synthase activity (approximately 1.7 fold), increased 3-o-methylglucose transport into human skeletal muscle strips (approximately 2 fold) and stimulated phosphorylation of the p42 ERK-2 isoform of MAP-kinase. This phosphorylation of p42 ERK2 was not blocked by the PI 3-kinase inhibitors LY294002 and wortmannin although it was blocked by the MAP-kinase kinase (MEK) inhibitor PD 98059. However, PD98059 (up to 20 micromol/l) did not block insulin activation of glycogen synthase or stimulation of 3-o-methylglucose transport. Wortmannin and LY294002 did block insulin stimulation of protein kinase-B (PKB) phosphorylation and stimulation of 3-o-methylglucose transport was inhibited by wortmannin (IC50 approximately 100 nmol/l). These results indicate that MAP-kinase is activated by insulin in human skeletal muscle by a PI 3-kinase independent pathway. Furthermore this activation is not necessary for insulin stimulation of glucose transport or activation of glycogen synthase in this tissue.
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PMID:Involvement of phosphoinositide 3-kinase in insulin stimulation of MAP-kinase and phosphorylation of protein kinase-B in human skeletal muscle: implications for glucose metabolism. 934 98

We have recently reported (1) that two naturally occurring mutants of the insulin receptor tyrosine kinase domain, Arg-1174 --> Gln and Pro-1178 --> Leu (Gln-1174 and Leu1178, respectively), both found in patients with inherited severe insulin resistance, markedly impaired receptor tyrosine autophosphorylation, with both mutant receptors being unable to mediate the stimulation of glycogen synthesis or mitogenesis by insulin when expressed in Chinese hamster ovary cells. However, these mutations did not fully prevent IRS-1 phosphorylation in response to insulin in these cells, suggesting that IRS-1 alone may not be sufficient to mediate insulin's metabolic and mitogenic effects. In the present study, we have demonstrated that these mutations also impair the ability of the insulin receptor to activate the transcription factor Elk-1 and promote GLUT4 translocation to the plasma membrane. Although at low concentrations of insulin, the mutant receptors were impaired in their ability to stimulate the tyrosine phosphorylation of IRS-1, at higher insulin concentrations we confirmed that the cells expressing the mutant receptors showed significantly increased tyrosine phosphorylation of IRS-1 compared with parental nontransfected cells. In addition, at comparable insulin concentrations, the association of the p85alpha subunit of phosphoinositide 3-kinase (PI3-kinase) with IRS-1 and the enzymatic activity of IRS-1-associated PI3-kinase were significantly enhanced in cells expressing the mutant receptors. In contrast, no significant stimulation of the tyrosine phosphorylation of Shc, GTP loading of Ras, or mitogen-activated protein kinase phosphorylation was seen in cell lines expressing these mutant receptors. Thus, no activation of any measurable mitogenic or metabolic response was detectable, despite significant insulin-induced phosphorylation of IRS-1 and its association with PI3-kinase in cells stably expressing the mutant insulin receptors. These findings suggest that PI3-kinase activation alone may be insufficient to mediate a wide range of the metabolic and mitogenic effects of insulin. Additionally, the data provide support for the notion that insulin activation of Ras is more closely linked with Shc, and not IRS-1, phosphorylation.
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PMID:Two naturally occurring insulin receptor tyrosine kinase domain mutants provide evidence that phosphoinositide 3-kinase activation alone is not sufficient for the mediation of insulin's metabolic and mitogenic effects. 937 4

The epidermal growth factor receptor (EGFR) tyrosine kinase recently was identified as providing a link to mitogen-activated protein kinase (MAPK) in response to G protein-coupled receptor (GPCR) agonists in Rat-1 fibroblasts. This cross-talk pathway is also established in other cell types such as HaCaT keratinocytes, primary mouse astrocytes and COS-7 cells. Transient expression of either Gq- or Gi-coupled receptors in COS-7 cells allowed GPCR agonist-induced EGFR transactivation, and lysophosphatidic acid (LPA)-generated signals involved the docking protein Gab1. The increase in SHC tyrosine phosphorylation and MAPK stimulation through both Gq- and Gi-coupled receptors was reduced strongly upon selective inhibition of EGFR function. Inhibition of phosphoinositide 3-kinase did not affect GPCR-induced stimulation of EGFR tyrosine phosphorylation, but inhibited MAPK stimulation, upon treatment with both GPCR agonists and low doses of EGF. Furthermore, the Src tyrosine kinase inhibitor PP1 strongly interfered with LPA- and EGF-induced tyrosine phosphorylation and MAPK activation downstream of EGFR. Our results demonstrate an essential role for EGFR function in signaling through both Gq- and Gi-coupled receptors and provide novel insights into signal transmission downstream of EGFR for efficient activation of the Ras/MAPK pathway.
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PMID:Signal characteristics of G protein-transactivated EGF receptor. 938 82


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