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)

In human platelets a proline-directed kinase distinct from the ERK MAP kinases is stimulated by both thrombin and the thrombin receptor agonist peptide SFLLRN and may be involved in the activation of Ca(2+)-dependent cytosolic phospholipase A2 (Kramer, R. M., Roberts, E. F., Hyslop, P. A., Utterback, B. G., Hui, K. Y., and Jakubowski, J.A. (1995) J. Biol. Chem. 270, 14816-14823). Here we show that this kinase is identical with or closely related to p38 (the mammalian homolog of HOG1 from yeast), a recently discovered protein kinase typically activated by inflammatory cytokines and environmental stress. Further, we demonstrate that activation of this kinase by thrombin is transient (with maximal stimulation at 1 min), is accompanied by tyrosine phosphorylation, and precedes the activation of the ERK kinases. This is the first report to show that p38 kinase is activated by thrombin and to suggest a role for this MAP kinase in the thrombin-mediated signaling events during platelet activation.
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PMID:Thrombin induces activation of p38 MAP kinase in human platelets. 749 91

Stimulation of the mast cell line, RBL-2H3, with antigen via the tetrameric (alpha beta gamma 2) immunoglobulin E receptor (Fc epsilon R1) leads to the activation of cytosolic phospholipase A2 and the release of arachidonic acid. This pathway is dependent on the activation of the mitogen-activated protein (MAP) kinase. In this paper, we show that the MAP kinase/cytosolic phospholipase A2 pathway is linked to Fc epsilon R1 via the cytosolic tyrosine kinase, Syk, and that the GDP/GTP exchange factor, Vav, might be one candidate for accomplishing this link. Cross-linking of transmembrane chimeras containing the Fc epsilon R1 gamma motif, which is known to activate Syk, results in the tyrosine phosphorylation of Vav, activation of MAP kinase, and release of arachidonic acid. Cross-linking of chimeras containing the Fc epsilon R1 beta motif does not cause these events. Furthermore, stimulation of these events by antigen is enhanced by transient overexpression of a wild-type form of Syk and blocked by overexpression of a dominant negative form of Syk. By contrast, stimulation via the transfected, G protein-coupled, muscarinic m1 receptor is not influenced by either form of Syk and does not result in tyrosine phosphorylation of Vav. These data establish unequivocally that the two types of receptor are independently linked to the two types of receptor are independently linked to the MAP kinase/cytosolic phospholipase A2 pathway and demonstrate the existence of the Fc epsilon R1-Syk-MAP kinase pathway.
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PMID:A requirement for Syk in the activation of the microtubule-associated protein kinase/phospholipase A2 pathway by Fc epsilon R1 is not shared by a G protein-coupled receptor. 753 41

Hepatocyte growth factor (HGF) and epidermal growth factor (EGF)-stimulated DNA synthesis in primary cultured rat hepatocytes. HGF-induced DNA synthesis was concentration-dependently inhibited by a cyclooxygenase inhibitor, indomethacin. BW755C, a dual inhibitor for cyclooxygenase and lipoxygenase activities, also inhibited hepatocyte growth. Prostaglandin E1 (PGE1), PGE2, and PGF2 alpha induced DNA synthesis even at such a low concentration as 5 nmol/L and potentiated [3H]thymidine incorporation induced by HGF in an additive manner. HGF caused arachidonic acid (AA) release and eicosanoid production. These events were detectable within 10 minutes after stimulation and lasted for at least 60 minutes. Furthermore, two proteins with approximately 40 kd were tyrosine phosphorylated by HGF. These proteins were identified as p42/p44 mitogen-activated protein (MAP) kinases by anti-MAP kinase immunoblots, which were known to activate cytosolic phospholipase A2 (cPLA2), a key enzyme in AA release. Activation of MAP kinases was detectable within 5 minutes after stimulation with HGF and lasted for at least 60 minutes. EGF-mediated DNA synthesis was also inhibited by the above cyclooxygenase inhibitors. EGF caused AA release and tyrosine phosphorylation of MAP kinases. These results suggest that HGF as well as EGF causes AA release, probably through activation of cPLA2 mediated by MAP kinases, and that PGs, metabolites of AA, might play a pivotal role in hepatocyte proliferation in an autocrine mechanism.
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PMID:Roles of prostaglandin production and mitogen-activated protein kinase activation in hepatocyte growth factor-mediated rat hepatocyte proliferation. 753 96

In this study we have verified the existence of a cytosolic phospholipase A2 (cPLA2) in rat-liver macrophages. Stimulation of these cells with phorbol 12-myristate 13-acetate (PMA), zymosan and lipopolysaccharide (LPS), but not with the Ca(2+)-ionophore A23187, leads to phosphorylation of cPLA2 and activation of mitogen-activated protein (MAP) kinase, supporting the hypothesis that MAP kinase is involved in cPLA2 phosphorylation. We show furthermore, that the tyrosine kinase inhibitor genistein prevents the LPS- but not the PMA- or zymosan-induced phosphorylation of cPLA2 and activation of MAP kinase, indicating that tyrosine kinases participate in LPS- but not in PMA- and zymosan-induced cPLA2 phosphorylation and MAP kinase activation. Phosphorylation of cPLA2 does not strongly correlate with stimulation of the arachidonic acid (AA) cascade: (1) A23187, a potent stimulator of AA release, fails to induce cPLA2 phosphorylation; (2) withdrawal of extracellular Ca2+, which inhibits PMA-stimulated AA release (Dieter, Schulze-Specking and Decker (1988) Eur. J. Biochem. 177, 61-67), has no effect on PMA-induced phosphorylation of cPLA2; (3) LPS induces cPLA2 phosphorylation within minutes, whereas increased AA release upon treatment with LPS is detectable for the first time after 4 h; and (4) genistein, which prevents LPS-induced cPLA2 phosphorylation, does not inhibit AA release in response to LPS. From these data we suggest that a rise in intracellular Ca2+, but not phosphorylation of cPLA2, is essential for activation of the AA cascade in rat-liver macrophages.
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PMID:Role of cytosolic phospholipase A2 in arachidonic acid release of rat-liver macrophages: regulation by Ca2+ and phosphorylation. 757 53

Human platelets pretreated with indomethacin release arachidonic acid predominantly through the activity of cytosolic phospholipase A2 (cPLA2), an 85-kDa protein. This enzyme is regulated by an increase in intracellular Ca2+, a necessary condition of for arachidonic acid liberation, and by phosphorylation. Phosphorylation of cPLA2 enhanced the Ca(2+)-induced arachidonic acid release in platelets stimulated by the ionophore A23187 and phorbol ester (phorbol 12,13-dibutyrate (PDBu)). In thrombin-stimulated platelets, however, phosphorylation appeared not to be necessary for arachidonic acid release since the latter response was not impaired in the presence of staurosporine, which inhibited phosphorylation. Collagen, thrombin, and PDBu induced phosphorylation of platelet cPLA2 as well as activation of mitogen-activated protein kinase (MAPK; p42mapk and p44mapk). cPLA2 activation was not dependent on protein kinase C (PKC) in thrombin- and collagen-stimulated platelets, as preincubation with the PKC inhibitor Ro 31-8220 neither interfered with cPLA2 phosphorylation nor reduced arachidonic acid release. However, collagen- and thrombin-induced activation of MAPK was inhibited by Ro 31-8220, indicating that PKC is necessary for MAPK stimulation in platelets. Although MAPK may underlie phosphorylation of cPLA2 in PDBu-activated human platelets, our results provide evidence for PKC- and MAPK-independent phosphorylation of cPLA2 in platelets stimulated by the physiological activators collagen and thrombin.
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PMID:Cytosolic phospholipase A2 is phosphorylated in collagen- and thrombin-stimulated human platelets independent of protein kinase C and mitogen-activated protein kinase. 759 75

The relationship between intracellular calcium concentration ([Ca2+]i), the release of arachidonic acid and the synthesis of leukotriene B4 (LTB4) was investigated using Ca(2+)-depleted human polymorphonuclear leucocytes (PMNs) in which [Ca2+]i can be manipulated by varying the concentration of exogenous Ca2+ added with agonists. In this model, Ca2+, platelet-activating factor (PAF) and N-formyl-Met-Leu-Phe (FMLP), added alone, were unable to induce arachidonic acid release or LTB4 synthesis, as assessed by measurements of the products by MS and HPLC, respectively. However, the simultaneous addition of Ca2+ and either PAF or FMLP to these Ca(2+)-depleted PMNs resulted in an influx of Ca2+ proportional to the extracellular concentration of Ca2+ and caused a substantial release of arachidonic acid and synthesis of LTB4. The [Ca2+]i values for threshold and maximal arachidonic acid release were found to be 150 nM and 350 nM respectively, suggesting the involvement of cytosolic phospholipase A2 (cPLA2). Under stimulatory conditions resulting in similar [Ca2+]i, Ca(2+)-depleted PMNs released significant amounts of arachidonic acid but normal (Ca(2+)-repleted) PMNs did not, indicating that Ca2+ depletion of PMNs altered the normal regulation of arachidonic acid release and facilitated the release of the fatty acid upon stimulation with agonists. cPLA2 and mitogen-activated protein kinase (MAP kinase) phosphorylation, as assessed by changes of electrophoretic mobility, occurred in both Ca(2+)-depleted and Ca(2+)-depleted PMNs upon addition of agonist. These data demonstrate that in Ca(2+)-depleted PMNs stimulated with agonists, arachidonic acid release and LTB4 synthesis correlated with extracellular Ca2+ influx.
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PMID:Leukotriene synthesis in calcium-depleted human neutrophils: arachidonic acid release correlates with calcium influx. 765 11

The regulation of the lysophospholipase activity of the 85-kDa cytosolic phospholipase A2 (PLA2) was studied in vitro and in stimulated macrophages. Bovine serum albumin was found to inhibit lysophospholipase activity of the recombinant 85-kDa PLA2 when assayed at a relatively low substrate concentration. Inhibition could be reversed if the substrate concentration was increased or if Ca2+ was present in the assay. Incubation of recombinant enzyme with macrophage membranes and lipid extracts from macrophage membranes resulted in the release of arachidonic acid, as well as, stearic acid, which is enriched at the sn-1 position of macrophage phospholipids. This suggests that with a bilayer substrate the PLA2 can sequentially deacylate the sn-2 then sn-1 acyl groups. This was verified by demonstrating that the phospholipids, phosphatidylcholine and phosphatidylinositol, were hydrolyzed to glycerophosphocholine and glycerophosphoinositol by incubation with recombinant 85-kDa PLA2. The 85-kDa enzyme was identified as the main lysophospholipase activity in mouse peritoneal macrophage cytosols. Addition of Ca2+ to the assay enhanced activity, but this effect decreased as the substrate concentration was increased. Incubation of macrophages with zymosan increased the lysophospholipase activity of the 85-kDa PLA2 in cytosols. Phosphorylation of recombinant PLA2 with mitogen-activated protein kinase resulted in an increase in lysophospholipase, as well as, PLA2 activity. In macrophages stimulated with zymosan release of stearic acid (18:0) and palmitic acid (16:0) was observed in addition to arachidonic acid (20:4). These results are consistent with a role of the 85-kDa PLA2 in regulating lysophospholipid levels in macrophages during zymosan stimulation.
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PMID:Regulation of lysophospholipase activity of the 85-kDa phospholipase A2 and activation in mouse peritoneal macrophages. 765 19

Although tumor necrosis factor (TNF)-alpha stimulation of human neutrophils does not result in a significant release of arachidonic acid, it primes the cell for arachidonic acid release when cells are further stimulated by agents that induce an intracellular calcium increase. We demonstrate that TNF-alpha stimulation of neutrophils induces the phosphorylation of cytosolic phospholipase A2 (cPLA2) and also increases its activity. These results indicate that although TNF-alpha, by itself, does not cause the release of arachidonic acid in intact cells, it increases the phosphorylation and activation of the enzyme cPLA2. Since we recently found that TNF-alpha stimulation of neutrophils does not increase the tyrosine phosphorylation or activation of the p42erk2 and p44erk1 mitogen-activated protein kinases (MAPKs), the present studies demonstrate the involvement of a MAPK independent pathway in the phosphorylation and activation of cPLA2.
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PMID:A mitogen-activated protein kinase independent pathway involved in the phosphorylation and activation of cytosolic phospholipase A2 in human neutrophils stimulated with tumor necrosis factor-alpha. 772 46

The role of mitogen-activated protein (MAP) kinase in the release of arachidonic acid was examined in a mutated mast cell (RBL-2H3(m1)) line that expressed both native Fc epsilon R1 and the G protein-coupled muscarinic m1 receptor. Stimulation of these cells with Ag, carbachol, Ca(2+)-ionophore, or thapsigargin resulted in the phosphorylation of Raf1, MEK1, p42mapk MAP kinase, and the recently cloned cytosolic phospholipase A2 (PLA2) and increased activities of both MAP kinase and PLA2, as well as release of arachidonic acid. Because this cascade of reactions was inhibited by guanosine 5'-(2-thiodiphosphate), it appeared to be dependent on a GTP-binding protein(s). These reactions, however, were not dependent on protein kinase C; the cascade was totally resistant to the actions of a selective protein kinase C inhibitor, Ro31-7549, whereas release of the secretory granule marker, hexosaminidase, was blocked by this agent. Differences between the stimulatory pathways for release of arachidonic acid and hexosaminidase were evident also from the effects of the kinase inhibitor, quercetin. The above cascade of reactions, including release of arachidonic acid, was inhibited by 50% with approximately 5 microM quercetin, whereas secretion was inhibited only at higher concentrations of inhibitor. Moreover, inhibition of the activation of MAP kinase and release of arachidonic acid were closely correlated. This and previous findings suggested that release of arachidonic acid was attributable to the regulation of cytosolic PLA2 by MAP kinase (for activation of PLA2) and Ca2+ (for association of PLA2 with the membrane), whereas release of hexosaminidase was regulated primarily by Ca2+ and protein kinase C.
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PMID:Activation of the mitogen-activated protein kinase/cytosolic phospholipase A2 pathway in a rat mast cell line. Indications of different pathways for release of arachidonic acid and secretory granules. 773 Jun 40

We examined the mechanism of arachidonate release induced by somatostatin-14 (SS14) in CHO-K1 cells overexpressing rat hippocampal somatostatin receptor SSTR4. SSTR4 couples to pertussis toxin (PTX)-sensitive G-protein in CHO cells and does not lead to phosphoinositides breakdown or intracellular calcium ([Ca2+]i) mobilization (Bito et al.: J. Biol. Chem. 269, 12722-12730, 1994). SSTR4 activated mitogen-activated protein (MAP) kinase and induced the phosphorylation of 85kDa cytosolic phospholipase A2 (cPLA2), in a PTX-sensitive manner. Furthermore, activations of both MAP kinase and cPLA2 were inhibited by treatment with wortmannin, at almost identical IC50 values. Thus, SSTR4 appears to stimulate MAP kinase and cPLA2 in a Gi-dependent, and through a wortmannin-sensitive pathway. We also showed that stimulation with SS14, in combination with calcium-ionophore, strongly enhanced arachidonate release from these cells.
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PMID:On the mechanism of cytosolic phospholipase A2 activation in CHO cells carrying somatostatin receptor: wortmannin-sensitive pathway to activate mitogen-activated protein kinase. 799 20


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