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Query: UNIPROT:P51812 (mitogen-activated protein)
 10,636 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The metabolic and mitogenic actions of insulin have been proposed to be mediated by cellular serine/threonine kinases such as the ribosomal protein S6 kinases pp70-S6 (pp70-S6 kinase) and pp90rsk and the erk-encoded mitogen-activated protein kinases (pp42mapk and pp44mapk). Rapamycin completely blocked activation of pp70-S6 kinase by insulin in 3T3-L1 adipocytes, but did not inhibit insulin-stimulated glucose transport, translocation of GLUT4 to the cell surface, or activation of pp90rsk or pp44mapk by insulin. Concordant with the inhibition of kinase activity, rapamycin prevented the insulin-induced decrease in mobility of pp70-S6 kinase visualized by SDS-polyacrylamide gel electrophoresis, reflecting a reduction in the hormone-stimulated phosphorylation of the enzyme. The structurally related macrolide, FK506, had no effect on pp70-S6 kinase or hexose uptake. These data demonstrate that rapamycin blocks insulin activation of pp70-S6 kinase in 3T3-L1 adipocytes and that pp70-S6 kinase is not required in the signaling pathway leading to insulin-stimulated glucose transport.
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PMID:Dissociation of pp70 ribosomal protein S6 kinase from insulin-stimulated glucose transport in 3T3-L1 adipocytes. 767 6

Insulin exerts diverse effects on mitogenesis, metabolism, gene expression, and protein synthesis depending on the target cell type. A variety of extracellular serine/threonine kinases, including the ribosomal protein S6 kinases pp70-ribosomal S6 kinase (pp70-S6K) and pp90-ribosomal S6 kinase (pp90rsk) and the erk-encoded mitogen-activated protein (MAP) kinases pp44mapk/ERK-1 and pp42mapk/ERK-2, have been postulated as mediators of insulin action. In this study, we have investigated the role of the MAP kinase/pp90rsk signaling pathway in insulin-stimulated glucose transport in 3T3-L1 adipocytes. Differentiation of 3T3-L1 fibroblasts into adipocyte-like cells was accompanied by a marked increase in the capacity of insulin to activate pp90rsk and pp44mapk. Whereas the maximal insulin-stimulated pp90rsk and pp44mapk activities were only approximately 30% of the serum-stimulated activities in preadipocytes, the insulin-stimulated kinase activities in adipocytes were equal to or greater than the serum-stimulated activities. The increase in hormone receptor number accompanying differentiation accounted for the greater sensitivity, as overexpression of human insulin receptors in NIH-3T3 cells also conferred insulin-stimulatable kinase activity. In 3T3-L1 adipocytes, the stimulation of pp90rsk and pp44mapk activities was sufficiently rapid and hormone sensitive to convey a signal for increased hexose uptake. However, epidermal growth factor and fetal bovine serum were equipotent with insulin in stimulating pp90rsk and pp44mapk activities in adipocytes, but were without effect on hexose uptake. These data indicate that activation of these enzymes is not sufficient for the acute stimulation of glucose transport.
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PMID:Characterization of the mitogen-activated protein kinase/90-kilodalton ribosomal protein S6 kinase signaling pathway in 3T3-L1 adipocytes and its role in insulin-stimulated glucose transport. 829 68

The insulin-regulated glucose transporter GLUT4 is a key modulator of whole body glucose homeostasis, and its selective loss in adipose tissue or skeletal muscle causes insulin resistance and diabetes. Here we report an RNA interference-based screen of protein kinases expressed in adipocytes and identify four negative regulators of insulin-responsive glucose transport: the protein kinases PCTAIRE-1 (PCTK1), PFTAIRE-1 (PFTK1), IkappaB kinase alpha, and MAP4K4/NIK. Integrin-linked protein kinase was identified as a positive regulator of this process. We characterized one of these hits, MAP4K4/NIK, and found that it is unique among mitogen-activated protein (MAP) kinases expressed in cultured adipocytes in attenuating hexose transport. Remarkably, MAP4K4/NIK suppresses expression of the adipogenic transcription factors C/EBPalpha, C/EBPbeta, and PPARgamma and of GLUT4 itself in these cells. RNA interference-mediated depletion of MAP4K4/NIK early in differentiation enhances adipogenesis and triglyceride deposition, and even in fully differentiated adipocytes its loss up-regulates GLUT4. Conversely, conditions that inhibit adipogenesis such as TNF-alpha treatment or depletion of PPARgamma markedly up-regulate MAP4K4/NIK expression in cultured adipocytes. Furthermore, TNF-alpha signaling to down-regulate GLUT4 is impaired in the absence of MAP4K4/NIK, indicating that MAP4K4 expression is required for optimal TNF-alpha action. These results reveal a MAP4K4/NIK-dependent signaling pathway that potently inhibits PPARgamma-responsive gene expression, adipogenesis, and insulin-stimulated glucose transport.
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PMID:An RNA interference-based screen identifies MAP4K4/NIK as a negative regulator of PPARgamma, adipogenesis, and insulin-responsive hexose transport. 1646 67