Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P51812 (mitogen-activated protein)
 10,636 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Signal transduction pathways stimulated by insulin or insulin-like growth factor-I (IGF-I) were compared in transfected NIH3T3 fibroblast cell lines expressing the human insulin receptor, IGF-I receptor, or a chimeric IGF-I receptor with its carboxy-terminal tail replaced with that of the insulin receptor (approximately 1 x 10(6) receptors/cell). Although receptor autophosphorylation was very similar in the three cell lines overexpressing receptors (EC50 = 1-3 nM), there were differences detected in the protein tyrosine phosphorylation stimulated by insulin and IGF-I in these cells. Although no substrates specific for the insulin receptor were detected, phosphorylation of a 170-kilodalton (kDa; IRS-1) and a 70-kDa protein was 10 times more sensitive to insulin than to IGF-I (EC50 = 1.5-2.5 vs. 14-23 nM). The chimeric receptor stimulated significantly lower levels of phosphorylation of several proteins relative to the wild-type IGF-I receptor. Activation of phosphatidylinositol 3'-kinase paralleled phosphorylation of the 170- and 70-kDa proteins. Despite these differences in protein tyrosine phosphorylation, stimulation of mitogen-activated protein (MAP) kinase and DNA synthesis were very similar in the three cell lines overexpressing receptors. Little difference was detected in Shc phosphorylation or MAP kinase activation through the three receptors, although activation of MAP kinase was more efficiently coupled to the platelet-derived growth factor receptor than to any of the overexpressed receptors. All three receptors stimulated DNA synthesis to levels comparable to 10% serum, with similar sensitivities (EC50 = 1.5-3.5 nM).
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PMID:Insulin and insulin-like growth factor-I receptors similarly stimulate deoxyribonucleic acid synthesis despite differences in cellular protein tyrosine phosphorylation. 751 64

SHPTP2 is a ubiquitously expressed tyrosine-specific protein phosphatase that contains two amino-terminal Src homology 2 (SH2) domains responsible for its association with tyrosine-phosphorylated proteins. In this study, expression of dominant interfering mutants of SHPTP2 was found to inhibit insulin stimulation of c-fos reporter gene expression and activation of the 42-kDa (Erk2) and 44-kDa (Erk1) mitogen-activated protein kinases. Cotransfection of dominant interfering SHPTP2 mutants with v-Ras or Grb2 indicated that SHPTP2 regulated insulin signaling either upstream of or in parallel to Ras function. Furthermore, phosphotyrosine blotting and immunoprecipitation identified the 125-kDa focal adhesion kinase (pp125FAK) as a substrate for insulin-dependent tyrosine dephosphorylation. These data demonstrate that SHPTP2 functions as a positive regulator of insulin action and that insulin signaling results in the dephosphorylation of tyrosine-phosphorylated pp125FAK.
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PMID:Protein-tyrosine-phosphatase SHPTP2 is a required positive effector for insulin downstream signaling. 753 37

The mitogen-activated protein (MAP) kinases and ribosomal S6 protein kinases in the skeletal muscle of insulin-resistant long-term (2 and 6 months' duration) diabetic rats were investigated to understand further the changes in insulin intracellular signaling pathways that accompany diabetes. The effects of insulin-mimetic vanadium compounds on the activity of these kinases were also examined. In the insulin-resistant 2-month diabetic rats, the basal activities of MAP kinases were relatively unchanged, while the basal activities of S6 kinases were significantly increased. Intravenous injection of insulin moderately activated both the 42-kDa MAP kinase (p42mapk) and a 44-kDa MAP kinase (p44erk1) in the 2-month control rats but not in the 2-month diabetic rats. Insulin treatment markedly stimulated the activity of a novel 31-kDa S6 kinase and the previously described 90-kDa ribosomal S6 kinase encoded by one of the rsk genes (p90rsk) in the 2-month control rats, while the effect was substantially reduced in the diabetic rats. In the 6-month diabetic rats, the basal phosphotransferase activities of both MAP kinases were depressed threefold or greater. This correlated with reductions in the amount of immunoreactive p42mapk and p44erk1 proteins in extracts from the diabetic rats. The basal activity of the 31-kDa S6 kinase activity was also reduced fourfold in the 6-month diabetic rats. Treatment of the 2-month diabetic rats with vanadyl sulfate resulted in euglycemia, prevented the increase in the basal activity of S6 kinase, and improved the activation of S6 kinase by insulin.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Skeletal muscle mitogen-activated protein kinases and ribosomal S6 kinases. Suppression in chronic diabetic rats and reversal by vanadium. 755 49

Insulin and epidermal growth factor receptors transmit signals for cell proliferation and gene regulation through formation of active GTP-bound p21ras mediated by the guanine nucleotide exchange factor Sos. Sos is constitutively bound to the adaptor protein Grb2 and growth factor stimulation induces association of the Grb2/Sos complex with Shc and movement of Sos to the plasma membrane location of p21ras. Insulin or epidermal growth factor stimulation induces a rapid increase in p21ras levels, but after several minutes levels decline toward basal despite ongoing hormone stimulation. Here we show that deactivation of p21ras correlates closely with phosphorylation of Sos and dissociation of Sos from Grb2, and that inhibition of mitogen-activated protein (MAP) kinase kinase (also known as extracellular signal-related kinase (ERK) kinase, or MEK) blocks both events, resulting in prolonged p21ras activation. These data suggest that a negative feedback loop exists whereby activation of the Raf/MEK/MAP kinase cascade by p21ras causes Sos phosphorylation and, therefore, Sos/Grb2 dissociation, limiting the duration of p21ras activation by growth factors. A serine/threonine kinase downstream of MEK (probably MAP kinase) mediates this desensitization feedback pathway.
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PMID:Negative feedback regulation and desensitization of insulin- and epidermal growth factor-stimulated p21ras activation. 759 90

To investigate the efficacy and mechanism of action of sodium metavanadate as an oral hypoglycemic agent, five insulin-dependent diabetes mellitus (IDDM) and five noninsulin-dependent diabetes mellitus (NIDDM) patients were studied before and after 2 weeks of oral sodium metavanadate (NaVO3; 125 mg/day). Glucose metabolism measured during a two-step euglycemic insulin clamp was not significantly increased by vanadate therapy in patients with IDDM, but was improved by 29% during the low dose (0.5 mU/kg.min) insulin infusion and 39% during the high dose (1.0 mU/kg.min) in patients with NIDDM. The changes in glucose metabolism were largely accounted for by an increase in nonoxidative glucose disposal, as measured by indirect calorimetry. Basal hepatic glucose production and suppression of hepatic glucose production by insulin were unchanged by vanadate therapy. There was a significant decrease in insulin requirements in the patients with IDDM (39.1 +/- 6.6 to 33.8 +/- 4.7 U/day; P < 0.05). Cholesterol levels significantly decreased in both IDDM (4.53 +/- 0.16 vs. 4.27 +/- 0.22 mmol/L; P = 0.06) and NIDDM (6.92 +/- 0.75 vs. 5.28 +/- 0.46 mmol/L; P < 0.05). After NaVO3 therapy, there was a 1.7- to 3.9-fold increase in basal mitogen-activated protein and S6 kinase activities in mononuclear cells from patients with IDDM and NIDDM that mimicked the effect of insulin stimulation in controls. The most common adverse effect of oral NaVO3 was mild gastrointestinal intolerance. These data suggest that vanadate or related agents may have a potential role as adjunctive therapy in patients with diabetes mellitus.
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PMID:Metabolic effects of sodium metavanadate in humans with insulin-dependent and noninsulin-dependent diabetes mellitus in vivo and in vitro studies. 759 44

Hepatic metabolism and gene expression are among the factors controlled by the cellular hydration state, which changes within minutes in response to aniso-osmotic environments, cumulative substrate uptake, oxidative stress and under the influence of hormones such as insulin. The signalling events coupling cell-volume changes to altered cell function were studied in H4IIE rat hepatoma cells. Hypo-osmotic cell swelling resulted within 1 min in a tyrosine kinase-mediated activation of the extracellular signal-regulated protein kinases Erk-1 and Erk-2, which was independent of protein kinase C and cytosolic calcium. Activation of mitogen-activated protein kinases was followed by an increased phosphorylation of c-Jun, which may explain our recently reported finding of an about 5-fold increase in c-jun mRNA level in response to cell swelling. Pretreatment of cells with pertussis or cholera toxin abolished the swelling-induced activation of Erk-1 and Erk-2, suggesting the involvement of G-proteins. Thus, a signal-transduction pathway resembling growth factor signalling is activated already by osmotic water shifts across the plasma membrane, thereby providing a new perspective for adaption of cell function to alterations of the environment.
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PMID:Activation of extracellular signal-regulated kinases Erk-1 and Erk-2 by cell swelling in H4IIE hepatoma cells. 761 47

The receptors for insulin-like growth factor 1 (IGF1) and insulin are related heterotetrameric proteins which, like the epidermal growth factor (EGF) receptor, possess intrinsic ligand-stimulated tyrosine protein kinase activity. In Rat 1 fibroblasts, stimulation of mitogen-activated protein (MAP) kinase via the IGF1 receptor and the Gi-coupled receptor for lysophosphatidic acid (LPA), but not via the EGF receptor, is sensitive both to pertussis toxin treatment and to cellular expression of a specific G beta gamma subunit-binding peptide. The IGF1, LPA, and EGF receptor-mediated signals are all sensitive to inhibitors of tyrosine protein kinases, require p21ras activation, and are independent of protein kinase C. These data suggest that some tyrosine kinase growth factor receptors (e.g. IGF1 receptor) and classical G protein-coupled receptors (e.g. LPA receptor) employ a similar mechanism for mitogenic signaling that involves both tyrosine phosphorylation and G beta gamma subunits derived from pertussis toxin-sensitive G proteins.
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PMID:G beta gamma subunits mediate mitogen-activated protein kinase activation by the tyrosine kinase insulin-like growth factor 1 receptor. 762 49

PHAS-I levels increased 8-fold as 3T3-L1 fibroblasts differentiated into adipocytes and acquired sensitivity to insulin. Insulin increased PHAS-I protein (3.3-fold after 2 days), the rate of PHAS-I synthesis (3-fold after 1 h), and the half-life of the protein (from 1.5 to 2.5 days). Insulin also increased the phosphorylation of PHAS-I and promoted dissociation of the PHAS-I eukaryotic initiation factor-4E (eIF-4E) complex, effects that were maximal within 10 min. With recombinant [H6]PHAS-I as substrate, mitogen-activated protein (MAP) kinase was the only insulin-stimulated PHAS-I kinase detected after fractionation of extracts by Mono Q chromatography; however, MAP kinase did not readily phosphorylate [H6]PHAS-I when the [H6]PHAS-I.eIF-4E complex was the substrate. Thus, while MAP kinase may phosphorylate free PHAS-I, it is not sufficient to dissociate the complex. Moreover, rapamycin attenuated the stimulation of PHAS-I phosphorylation by insulin and markedly inhibited dissociation of PHAS-I.eIF-4E, without decreasing MAP kinase activity. Rapamycin abolished the effects of insulin on increasing phosphorylation of ribosomal protein S6 and on activating p70S6K. The MAP kinase kinase inhibitor, PD 098059, markedly decreased MAP kinase activation by insulin, but it did not change PHAS-I phosphorylation or the association of PHAS-I with eIF-4E. In summary, insulin increases the expression of PHAS-I and promotes phosphorylation of multiple sites in the protein via multiple transduction pathways, one of which is rapamycin-sensitive and independent of MAP kinase. Rapamycin may inhibit translation initiation by increasing PHAS-I binding to eIF-4E.
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PMID:Control of PHAS-I by insulin in 3T3-L1 adipocytes. Synthesis, degradation, and phosphorylation by a rapamycin-sensitive and mitogen-activated protein kinase-independent pathway. 762 82

We examined the effects of the bronchoconstrictor agonists serotonin (5-hydroxytryptamine; 5-HT) and histamine on mitogen-activated protein (MAP) kinase activation in cultured bovine tracheal myocytes. Kinase renaturation assays demonstrated activation of the 42- and 44-kDa MAP kinases within 2 min of 5-HT exposure. MAP kinase activation was mimicked by alpha-methyl-5-HT and reduced by pretreatment with either phorbol 12,13-dibutyrate or forskolin, suggesting activation of the 5-HT2 receptor, protein kinase C, and Raf-1, respectively. Raf-1 activation was confirmed by measurement of Raf-1 activity, and the requirement of Raf-1 for 5-HT-induced MAP kinase activation was demonstrated by transient transfection of cells with a dominant-negative allele of Raf-1. Histamine pretreatment significantly inhibited 5-HT and insulin-derived growth factor-1-induced MAP kinase activation. Attenuation of MAP kinase activation was reversed by cimetidine, mimicked by forskolin, and accompanied by cAMP accumulation and inhibition of Raf-1, suggesting activation of the H2 receptor and cAMP-dependent protein kinase A. However, histamine treatment inhibited Raf-1 but not MAP kinase activation following treatment with either platelet-derived growth factor or epidermal growth factor, implying a Raf-1-independent MAP kinase activation pathway. In summary, our data suggest a model whereby 5-HT activates MAP kinase via a protein kinase C/Raf-1 pathway, and histamine attenuates MAP kinase activation by serotonin via activation of cAMP-dependent protein kinase A and inhibition of Raf-1.
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PMID:Histamine antagonizes serotonin and growth factor-induced mitogen-activated protein kinase activation in bovine tracheal smooth muscle cells. 765 5

The precise role of the protein tyrosine phosphatase Syp in insulin signaling is not well understood. We previously reported that expression of catalytically inactive Syp phosphatase blocked stimulation of mitogen-activated protein (MAP) kinase by insulin. In this study, we investigated the effect of dominant negative Syp on the intermediates in MAP kinase pathway. The expression of dominant negative Syp blocked the activation of MEK and raf-1 kinase in response to insulin and had no detectable effect on insulin-induced activation of p21ras. These data suggest that the target of the Syp phosphatase may reside in proteins immediately downstream of p21ras.
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PMID:Expression of a catalytically inert Syp blocks activation of MAP kinase pathway downstream of p21ras. 767 89


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