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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)

Mitogen-activated protein kinases (MAP kinases) are active only when phosphorylated. Here we examine whether the activation of Xenopus p42 MAP kinase might involve changes in its association with other proteins as well as changes in its phosphorylation state. We find that when p42 MAP kinase is phosphorylated and active, it is monomeric, and that when p42 MAP kinase is nonphosphorylated and inactive, about half of it is monomeric and half is a component of a 110-kDa complex. We identify Rsk, an 82-kDa protein kinase that can be phosphorylated and partially activated by p42 MAP kinase, as being specifically associated with inactive p42 MAP kinase. It is possible that the complex of inactive p42 MAP kinase and inactive Rsk acts as a single signal reception particle and that the activation of the two kinases may be better described as a fork in a bifurcating signal transduction pathway than as successive levels in a kinase cascade.
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PMID:Evidence that inactive p42 mitogen-activated protein kinase and inactive Rsk exist as a heterodimer in vivo. 820 12

The binding of IL-2 to its specific receptor (IL-2R) triggers various cellular events including the induction of nuclear proto-oncogenes (c-fos, c-jun and c-myc genes) and the proliferation of hemopoietic cells. In the present study, we have established NIH 3T3 fibroblasts in which the three IL-2R subunits, the alpha-chain (IL-2R alpha), the beta-chain (IL-2R beta), and the gamma-chain (IL-2R gamma), are constitutively expressed. The resulting cell lines express high affinity IL-2R on their cell surface at levels comparable with those of IL-2-responsive lymphoid cells. We observed that the high affinity IL-2R in NIH 3T3 fibroblasts can mediate the IL-2-stimulated tyrosine phosphorylation of p42/p44 (mitogen-activated protein kinase) and the induction of the c-fos, c-jun and c-myc genes. In NIH 3T3 fibroblasts the high affinity IL-2R bearing a deletion of a region rich in acidic amino acids (the "acidic" region) in the IL-2R beta-chain failed to induce the tyrosine phosphorylation of MAP kinase as well as the expression of the all three nuclear proto-oncogenes. On the other hand, our previous studies had demonstrated that the high affinity IL-2R bearing the same mutant IL-2R beta-chain retained the ability to induce c-myc gene in response to IL-2 in a murine IL-3-dependent pro-B cell line, BAF/B03. Hence, these results reveal the underlying complexity of signal transduction among different cell types. The inability of the reconstituted high affinity receptor to mediate the IL-2-induced proliferation of NIH 3T3 fibroblasts suggests that induction of the three nuclear proto-oncogenes and the tyrosine phosphorylation of mitogen-activated protein kinase in NIH 3T3 fibroblasts are not sufficient to induce cellular proliferation.
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PMID:Signal transduction mediated by the reconstituted IL-2 receptor. Evidence for a cell type-specific function of IL-2 receptor beta-chain. 820

Naturally occurring human insulin receptor mutants Ser1200 and Thr1134, and a site-directed mutant Arg1030 overexpressed in Chinese hamster ovary (CHO) cells, bind insulin with affinities identical to wildtype receptors but are apparently kinase deficient. Cells expressing the Ser1200 receptor exhibit insulin stimulation of glycogen synthesis similar to these bearing the wildtype receptor, but fail to mediate insulin-responsive DNA synthesis. In contrast, the Thr1134 and Arg1030 mutants exhibit no response to insulin. The activity of Mitogen Activated Protein (MAP) kinase in cells transfected with wildtype receptor is more responsive to insulin than that detected in untransfected parental cells, while cells bearing any of the mutant receptors are less responsive than the parental cells. These differences in the stimulation of MAP kinase activity are paralleled by differences in insulin-dependent phosphorylation of the enzyme. These results suggest that the p42 MAP kinase is not universally required for the metabolic effects of insulin.
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PMID:The stimulation of pp42mapkinase by insulin does not correlate with its metabolic actions in cells overexpressing mutant insulin receptors. 821 4

Myelin basic protein kinase (MBPK) activity of rat adipocytes was measured directly or in gels after purification of p42 microtubule-associated protein kinase (MAPK). Insulin and phorbol esters provoked 2- to 3-fold increases in MBPK/MAPK activity within 5-10 min. Whereas phorbol ester effects were blocked by protein kinase C (PKC) depletion or inhibition, insulin effects were fully intact, indicating that insulin activates MBPK/MAPK independently of PKC. In contrast, PKC depletion or inhibition markedly inhibited insulin effects on [3H]2-deoxyglucose uptake, suggesting that this effect requires PKC, rather than a factor within the ras/MAPK cascade.
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PMID:Insulin activates myelin basic protein (p42 MAP) kinase by a protein kinase C-independent pathway in rat adipocytes. Dissociation from glucose transport. 822 95

The alpha 2-adrenergic receptors are linked to inhibition of adenylylcyclase and, under certain circumstances, to stimulation of phospholipid hydrolysis via pertussis toxin-sensitive G proteins. Here we show that alpha 2-adrenergic receptors can couple to an alternative signaling pathway. When expressed in Rat-1 cells, stimulation of the alpha 2A receptor, which couples to Gi2 and Gi3, causes rapid, transient activation of the protooncogene product p21ras as measured by an increase in the amount of bound GTP. Furthermore, alpha 2A receptor stimulation causes rapid phosphorylation of the p42 mitogen-activated protein (MAP) kinase. Pertussis toxin completely inhibits both p21ras activation and MAP kinase phosphorylation, but both responses appear to be independent of adenylylcyclase inhibition or phospholipase stimulation. Thus, alpha 2-adrenergic receptors can couple to the p21ras-MAP kinase pathway via Gi, which may explain the mitogenic potential of alpha 2 agonists in certain cell types; together with previous results, these findings further suggest that activation of this pivotal signaling pathway may be a common event in the action of Gi-coupled receptors.
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PMID:Gi-mediated activation of the p21ras-mitogen-activated protein kinase pathway by alpha 2-adrenergic receptors expressed in fibroblasts. 822 27

Arginine vasopressin (AVP) has been shown to stimulate tyrosine phosphorylation and activation of p42 mitogen-activated protein (MAP) kinase (p42MAPK) in vascular smooth muscle cells (VSMC). In VSMC, AVP increases free intracellular Ca2+ concentration ([Ca2+]i) and activates protein kinase C (PKC) through activation of phospholipase C. The contribution of PKC and [Ca2+]i in p42MAPK regulation was therefore determined. Activation of PKC by phorbol 12-myristate 13-acetate (PMA) stimulated tyrosine phosphorylation and activation of p42MAPK to the same extent as AVP. Inhibition of PKC by staurosporine or downregulation of PKC by PMA pretreatment abolished AVP-induced stimulation of p42MAPK. When [Ca2+]i was elevated to the same level as with AVP, using either ionomycin (0.1 microM) or thapsigargin (0.1 microM), MAP kinase was only partially activated. Elevation of [Ca2+]i to supraphysiological levels by 1 microM ionomycin stimulated MAP kinase activity to the same extent as AVP. This effect was blocked by downregulation of PKC. The intracellular Ca2+ chelator BAPTA [1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid] blocked AVP-induced [Ca2+]i increase but did not affect AVP stimulation of p42MAPK. Thus AVP-induced activation of p42MAPK requires only the activation of PKC but not an increase in [Ca2+]i.
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PMID:AVP-induced activation of MAP kinase in vascular smooth muscle cells is mediated through protein kinase C. 823 19

Lysophosphatidic acid (LPA) is a platelet-derived phospholipid that serves as a mitogen for fibroblasts. LPA activates its own G protein-coupled receptor(s) leading to stimulation of phospholipase C and inhibition of adenylate cyclase. Furthermore, LPA rapidly activates p21ras through a pertussis toxin-sensitive pathway. In this study, we have examined LPA-induced protein tyrosine phosphorylation in Rat-1 fibroblasts. LPA action was compared with that of endothelin, which is a stronger activator of phospholipase C than LPA but fails to activate p21ras and to stimulate DNA synthesis in these cells. LPA and, more effectively, endothelin rapidly stimulate tyrosine phosphorylation of proteins of 110-130, 95, and 65-75 kDa. The effect of LPA is dose- and time-dependent, being half-maximal at 3-30 nM and peaking after 2-5 min. Among the 110-130-kDa group of phosphotyrosyl proteins is the 125-kDa "focal adhesion kinase" (p125FAK) but not the 120-kDa p21ras GTPase-activating protein. Furthermore, LPA, like epidermal growth factor, causes tyrosine phosphorylation and activation of the p42/p44 mitogen-activated protein (MAP) kinases, paralleling p21ras activation. In contrast, endothelin fails to phosphorylate MAP kinase. Treatment of the cells with pertussis toxin blocks LPA-induced MAP kinase phosphorylation without affecting the other tyrosine phosphorylations. The kinase inhibitor staurosporine (1 microM) blocks LPA-induced, but not epidermal growth factor-induced, activation of p21ras and MAP kinase, consistent with an intermediate protein kinase linking the LPA receptor to p21ras activation. The results support a model in which LPA-induced phosphorylation of MAP kinase is mediated by p21ras, and tyrosine phosphorylation of the other substrates, including p125FAK, is associated with phospholipase C activation.
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PMID:Protein tyrosine phosphorylation induced by lysophosphatidic acid in Rat-1 fibroblasts. Evidence that phosphorylation of map kinase is mediated by the Gi-p21ras pathway. 827 65

Neurotransmitters and growth factors can trigger activation of a newly described family of mitogen-activated protein kinases. To help define the role of this kinase family in signal transduction in the nervous system, we have conducted immunohistochemical studies to localize p42 mitogen-activated protein kinase in rat brain sections. Light-microscopic studies revealed staining in neuronal cell bodies and dendrites that is particularly prominent in superficial layers of the neocortex, the hippocampal CA3 region and dentate gyrus, as well as cerebellar Purkinje cells. Discrete staining of oligodendrocytes was also apparent in fiber tracts, indicating expression of p42 mitogen-activated protein kinase in both neuronal and glial cell types. Electron-microscopic studies demonstrated that staining in dendrites is closely associated with microtubules. In the cell bodies, prominent staining was associated with the Golgi apparatus. In contrast, immunolabeling of synaptic terminals was not detected. Previous studies have demonstrated that p42 mitogen-activated protein kinase responds to neuronal stimulation. Immunohistochemical studies presented in this paper demonstrate prominent staining for this kinase in neuronal cell bodies and dendrites. Therefore, this kinase is likely to play a key role in postsynaptic signal transduction. As both p42 mitogen-activated protein kinase and microtubule-associated protein 2, an in vitro substrate of p42 mitogen-activated kinase, are associated with dendritic microtubules, this kinase may mediate effects of growth factors or neurotransmitters on the dendritic cytoskeleton.
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PMID:p42 mitogen-activated protein kinase in brain: prominent localization in neuronal cell bodies and dendrites. 837 38

Phospholipase A2 (PLA2) is the enzyme regulating the release of arachidonic acid in most cell types. A high molecular mass, 85-kDa soluble form of PLA2 (cPLA2) has recently been identified, the activity of which is stably increased by stimulation of cells with hormones and growth factors. Growth factor stimulation of cells has been reported to result in increased phosphorylation of cPLA2 on serine residues, but the kinases mediating this effect have not been identified. We report here that human cPLA2 is phosphorylated in vitro by two growth factor-stimulated serine/threonine-specific kinases, p42 MAP kinase and protein kinase C (PKC). Phosphorylation of the cPLA2 enzyme by either kinase results in an increase in catalytic cPLA2-specific activity. Domains of the cPLA2 molecule have been expressed in Escherichia coli, and the fusion proteins purified. PKC and p42 MAP kinase give different patterns of phosphorylation of the recombinantly expressed cPLA2 fragments. p42 MAP kinase selectively phosphorylates the domain of cPLA2 containing a MAP kinase consensus sequence, whereas PKC phosphorylates sites in all three recombinantly expressed domains of the enzyme. Peptide mapping indicates that the site phosphorylated by p42 MAP kinase is different from those phosphorylated by PKC. The combined action of both of these kinases is likely to mediate the effects of growth factor stimulation on arachidonic acid release through the activation of cPLA2.
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PMID:Phosphorylation and activation of a high molecular weight form of phospholipase A2 by p42 microtubule-associated protein 2 kinase and protein kinase C. 838 May 83

ET-1 stimulated MBP kinase activity in cultured cardiomyocytes. Maximal activation (3.5-fold) was at 5 min. EC50 was 0.2 nM. PMA or PE also increased MBP kinase (4- or 2.5-fold, respectively). Pre-treatment with PMA down-regulated the subsequent response to ET-1 or PMA. ET-1- or PMA-stimulated MBP kinase was resolved into 2 major (peaks II and IV) and 2 minor peaks by FPLC on Mono Q. Peaks II and IV were inactivated by either LAR or PP2A. Renatured MBP kinase activities following SDS-PAGE in MBP-containing gels and immunoblot analysis showed that peak II was a p42 MAP kinase and peak IV was a p44 MAP kinase.
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PMID:Endothelin-1, phorbol esters and phenylephrine stimulate MAP kinase activities in ventricular cardiomyocytes. 838 Oct 95


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