EC:2.7.11.13 - FACTA Search

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Query: EC:2.7.11.13 (protein kinase C)
49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have reported previously that hydrogen peroxide induces arachidonic acid release from prelabeled vascular smooth muscle cells. Here, we studied the effect of hydrogen peroxide on the phosphorylation of cytosolic phospholipase A2 in these cells. Hydrogen peroxide induced a rapid, time-dependent increase in the phosphorylation of cytosolic phospholipase A2. Hydrogen peroxide also increased arachidonic acid release from prelabeled cells in a time-dependent manner similar to that of phosphorylation of cytosolic phospholipase A2. Protein kinase C depletion significantly inhibited the hydrogen peroxide-stimulated cytosolic phospholipase A2 phosphorylation and arachidonic acid release. Hydrogen peroxide caused a time-dependent increase in mitogen activated protein kinase activity. Taken together, these findings suggest that cytosolic phospholipase A2 may, at least in part, contribute to arachidonic acid release induced by hydrogen peroxide and this effect appears to be mediated by protein kinase C and mitogen activated protein kinase.
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PMID:Hydrogen peroxide activation of cytosolic phospholipase A2 in vascular smooth muscle cells. 785 86

The activation of mitogen-activated protein kinase (MAP kinase) in macrophages and the involvement of protein kinase C (PKC) in MAP kinase activation was investigated in macrophages exposed to agents that have previously been shown to activate the 85-kDa cytosolic phospholipase A2 (PLA2) and induce arachidonic acid release. Phorbol 12-myristate 13-acetate (PMA) and zymosan maximally stimulated MAP kinase activity by 5 and 15 min, respectively, whereas the response to okadaic acid was maximal by 60-90 min. MAP kinase activation correlated with tyrosine phosphorylation of p44 MAP kinase in PMA-stimulated cells and p44 and p42 MAP kinases in zymosan- and okadaic acid-stimulated cells. MAP kinase activity was not elevated in A23187-stimulated macrophages. Inhibition of PKC with the inhibitor, bisindolylmaleimide (GF109203X), or by prolonged exposure to PMA suppressed both arachidonic acid release and MAP kinase activation in PMA- and zymosan-stimulated macrophages but not in okadaic acid or A23187-treated cells. However, prolonged exposure to PMA did not suppress the increased cytosolic PLA2 activity in agonist-treated macrophages. This approach was complicated since initial exposure to PMA to down-regulate PKC increased cytosolic PLA2 activity which remained elevated for 16 h. In contrast, GF109203X treatment suppressed the increase in cytosolic PLA2 activity in response to zymosan and PMA but not to okadaic acid or A23187. The results demonstrate that PMA and zymosan trigger PKC activation that leads to the activation of MAP kinase and PLA2, whereas these responses are PKC independent in okadaic acid-treated cells. In addition, the results are consistent with a role for MAP kinase activation in regulating the activation of the 85-kDa PLA2 and arachidonic acid release in PMA-, zymosan-, and okadaic acid-stimulated cells, whereas these responses in A23187-treated cells are MAP kinase-and PKC-independent.
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PMID:Protein kinase C-dependent and -independent pathways of mitogen-activated protein kinase activation in macrophages by stimuli that activate phospholipase A2. 803 17

Both IFN-alpha/beta and IFN-gamma have recently been demonstrated to induce a rapid but transient activation of phospholipase A2 (PLA2) in BALB/c 3T3 fibroblasts and a human neuroblastoma cell line. We report that IFN-gamma induces the synthesis and prolonged activation of cytosolic phospholipase A2 (cPLA2) in a human bronchial epithelial cell line (BEAS 2B). Treatment of the cells with IFN-gamma (300 U/ml) increased the release of [3H]arachidonic acid (AA) from prelabeled cells with a maximal effect at 12 h after stimulation. The increased [3H]AA release was inhibited by the PLA2 inhibitor p-bromophenacyl bromide (10(-5) M). Calcium ionophore A23187 (10(-5) M) further increased the [3H]AA release from the IFN-gamma-treated cells. Subcellular enzyme activity assay revealed that IFN-gamma increased PLA2 activity in both the cytosol and membrane fractions with a translocation of the cPLA2 to cell membranes in a Ca(2+)-free cell lysing buffer. Treatment with IFN-gamma also induced the release of 15-HETE, an arachidonic acid metabolite. Immunoblot showed that IFN-gamma induced the synthesis of cPLA2 protein. Nuclear run-on assay demonstrated that IFN-gamma initiated cPLA2 gene transcription within 15 min, and this effect was sustained at 4 h and returned to near control level at 12 h. The cPLA2 mRNA level was assayed by reverse transcription and PCR. IFN-gamma was found to increase the cPLA2 mRNA after 2-24 h treatment. Furthermore, the IFN-gamma induced cPLA2 mRNA increase was blocked by inhibitors of protein kinase C and calcium/calmodulin-dependent protein kinases, suggesting the involvement of these protein kinases in IFN-gamma-induced gene expression of cPLA2. This study shows that IFN-gamma induces the synthesis and prolonged activation of cPLA2.
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PMID:Interferon-gamma induces the synthesis and activation of cytosolic phospholipase A2. 811 94

A cDNA encoding a guinea pig histamine H1 receptor was stably expressed in Chinese hamster ovary (CHO) cells. In one resulting clone, named CHO(H1), the H1 receptor was found to be coupled to several major signal transduction pathways. In each case the involvement of a Gi/Go protein with pertussis toxin (PTX) was assessed, as well as the influence of extracellular Ca2+ and of protein kinase C activation by phorbol 12-myristate 13-acetate (PMA). Histamine induced, in a PTX- and PMA-insensitive manner, a biphasic increase in the intracellular Ca2+ level of which only the second sustained phase was dependent on the extracellular Ca2+ level. Histamine also caused a threefold elevation of inositol phosphate production, which was PTX-insensitive, but slightly inhibited by PMA and reduced by 75% in the absence of extracellular Ca2+. Histamine also caused a massive release of arachidonic acid, which occurred in a Ca(2+)- and PMA-sensitive manner, probably through the activation of a cytosolic phospholipase A2, which partly involves coupling to a PTX-sensitive G protein. In comparison, in HeLa cells endowed with a native H1 receptor, the histamine-induced arachidonic acid release was also Ca(2+)- and PMA-sensitive, but totally PTX-insensitive. Finally, in CHO(H1) cells, histamine in very low concentrations potentiated the cyclic AMP accumulation induced by forskolin. This response appeared to be insensitive to PTX, extracellular Ca2+, and PMA.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Guinea pig histamine H1 receptor. II. Stable expression in Chinese hamster ovary cells reveals the interaction with three major signal transduction pathways. 829 14

In the mouse keratinocyte line HEL-30 the epidermal mitogen transforming growth factor-alpha (TGF-alpha) stimulated the rapid release of arachidonic acid in a dose- and time-dependent manner. The liberation of arachidonic acid was due to the activation of a Ca(2+)-dependent cytosolic phospholipase A2 (cPLA2). The activation mechanism critically depended on a functionally active epidermal growth factor receptor tyrosine kinase and occurred independently of phospholipase C-mediated increases in cellular diacylglycerol and inositol 1,4,5-trisphosphate concentrations and protein kinase C activation. The activation included an increase in cytosolic PLA2 (cPLA2) activity and an association of the enzyme with the membrane fraction. Both activation steps apparently occurred in the presence of basal cytoplasmic Ca2+ concentrations. Moreover, cPLA2 or a closely associated protein was found to be phosphorylated on tyrosine upon TGF-alpha challenge of the cells. The data suggest that tyrosine phosphorylation is involved in the TGF-alpha-induced activation of cPLA2.
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PMID:Activation of cytosolic phospholipase A2 by transforming growth factor-alpha in HEL-30 keratinocytes. 834 57

The abilities of platelet-derived growth factor (PDGF) and insulin-like growth factor (IGF-I) to regulate cAMP metabolism and mitogen-activated protein kinase (MAP kinase) activity were compared in human arterial smooth muscle cells (hSMC). PDGF-BB stimulated cAMP accumulation up to 150-fold in a concentration-dependent manner (EC50 approximately 0.7 nM). The peak of cAMP formation and cAMP-dependent protein kinase (PKA) activity occurred approximately 5 min after the addition of PDGF and rapidly declined thereafter. Incubating cells with PDGF and 3-isobutyl-1-methylxanthine (IBMX, a phosphodiesterase inhibitor) enhanced the accumulation of cAMP and PKA activity by an additional 2.5-3-fold, whereas IBMX alone was essentially without effect. The PDGF-stimulated increase in cAMP was prevented by addition of the cyclooxygenase inhibitor indomethacin, consistent with release of prostaglandins stimulating cAMP. PDGF, but not IGF-I, stimulated MAPK activity, cytosolic phospholipase A2 (cPLA2) phosphorylation, and cAMP synthesis which indicated a key role for MAP kinase in the activation of cPLA2. Further, PDGF stimulated the rapid release of arachidonic acid and synthesis of prostaglandin E2 (PGE2) which could be inhibited by a cPLA2 inhibitor (AACOCF3). Calcium mobilization was required for PDGF-induced arachidonic acid release and PGE2 synthesis but not for MAPK activation, whereas PKC was required for PGE2-mediated activation of PKA. In summary, these results demonstrated that PDGF increases cAMP formation and PKA activity through a MAP kinase-mediated activation of cPLA2, arachidonic acid release, and PGE2 synthesis in human arterial smooth muscle cells.
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PMID:Platelet-derived growth factor stimulates protein kinase A through a mitogen-activated protein kinase-dependent pathway in human arterial smooth muscle cells. 855 Jun 11

Phospholipase A2 (PLA2) activity has been suggested to mediate some of the tumor necrosis factor (TNF) induced cellular responses including cytotoxicity. We evaluated the induction of both the 85-kDa cytosolic phospholipase A2 (cPLA2) and non-pancreatic group II PLA2 gene expression by TNF-alpha in a human bronchial epithelial cell line (BEAS 2B cell). TNF-alpha (20 ng/ml) induced a significantly increased release of prelabeled [3H]arachidonic acid (AA) following 4-24 h incubation. Calcium ionophore A23187 (10(-5) M) further increased the [3H]AA release from the TNF-alpha-treated cells. In vitro activity assay revealed that TNF-alpha increased the dithiothreitol (DTT)-resistant PLA2 activity which was blocked by the cPLA2 inhibitor AACOCF3. Treatment with TNF-alpha for 4-24 h increased the cPLA2 protein and mRNA levels which were blocked by the broad inhibitor of protein kinases staurosporine, the protein kinase C (PKC) inhibitor calphostin C, and to a lesser extent the calcium/calmodulin-dependent protein kinase inhibitor W-7. Reverse transcription and polymerase chain reaction amplification of the group II PLA2 mRNA showed that it is expressed in human lung but not in the bronchial epithelial cell line. TNF-alpha failed to induce the expression of group II PLA2 in the BEAS 2B cells. These results demonstrate that the cPLA2 gene expression is up-regulated by TNF-alpha and this effect may contribute to the TNF-alpha stimulated AA release in airway epithelial cells.
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PMID:Tumor necrosis factor-alpha induces the 85-kDa cytosolic phospholipase A2 gene expression in human bronchial epithelial cells. 861 31

Mitogen-activated protein kinases (MAPKs), a family of protein serine/threonine kinases regulating cell growth and differentiation, are activated by a dual-specificity kinase through phosphorylation at threonine and tyrosine. We used a recently described selective inhibitor of the p42/p44mapk-activating enzyme, PD 98059 [2-(2'-amino-3'-methoxyphenyl)-oxanaphthalen-4-one], to investigate the role of the p42/p44mapk pathway in human platelets. PD 98059 inhibited p42/p44mapk activation in thrombin-, collagen- and phorbol esterstimulated platelets, as determined from in-gel renaturation kinase assays, with an IC50 of approx. 5 microM (thrombin stimulation). It also prevented activation of MAPK kinase, which was measured in whole-cell lysates with glutathione S-transferase/p42mapk fusion protein (GST-MAPK) as substrate. Inhibition of p42/p44mapk did not affect platelet responses to thrombin or collagen such as aggregation, 5-hydroxytryptamine release and protein kinase C activation. In addition, PD 98059 did not interfere with release of arachidonic acid, a response mediated by cytosolic phospholipase A2 (cPLA2), or with cPLA2 phosphorylation. This suggests that platelet cPLA2 is not regulated by p42/p44mapk after stimulation with physiological agonists. In contrast, phorbol ester-induced phosphorylation of cPLA2 and potentiation of arachidonic acid release stimulated by Ca2+ ionophore A23187 were inhibited by PD 98059, indicating that p42/p44mapk phosphorylates cPLA2 after activation of protein kinase C by the non-physiological tumour promoter.
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PMID:Inhibition of mitogen-activated protein kinase kinase does not impair primary activation of human platelets. 876 73

The presence of a novel 38 kDa protein that is tyrosine phosphorylated in human neutrophils, a terminally differentiated cell, upon stimulation of these cells with low concentrations of lipopolysaccharide (LPS) in combination with serum has been demonstrated. This 38 kDa protein was identified as the mammalian homologue of HOG1 in yeast, the p38 mitogen-activated protein (MAP) kinase. This conclusion is based on the experimental findings that anti-phosphotyrosine (anti-PY) antibody immunoprecipitates a 38 kDa protein that is recognized by anti-p38 MAP kinase antibody, and conversely, anti-p38 MAP kinase antibody immunoprecipitates a 38 kDa protein that can be recognized by anti-PY antibody. Moreover, this tyrosine phosphorylated protein is found associated entirely with the cytosol. It was also found that this p38 MAP kinase is activated following stimulation of these cells with low concentrations of LPS in combination with serum. This conclusion is based on three experimental findings. First, soluble fractions isolated from LPS-stimulated cells phosphorylate heat shock protein 27 (hsp27) in an in vitro assay, and this effect is not inhibited by protein kinase C and protein kinase A inhibitor peptides. This effect is similar to the effect produced by the commercially available phosphorylated and activated MAPKAP kinase-2 (MAP kinase activated protein kinase-2). Secondly, a 27 kDa protein that aligns with a protein recognized by anti-hsp27 antibody is phosphorylated upon LPS stimulation of intact human neutrophils prelabelled with radioactive phosphate. Lastly, immune complex protein kinase assays, using [gamma-32P]ATP and activating transcription factor 2 (ATF2) as substrates, showed increased p38 MAP kinase activity from LPS-stimulated human neutrophils. The phosphorylation and activation of this p38 MAP kinase can be affected by both G-protein-coupled receptors such as platelet-activating factor (PAF) and non-G-protein-coupled receptors such as the cytokine-coupled receptors for granulocyte-macrophage colony-stimulating factor (GM-CSF) and tumour necrosis factor alpha (TNF-alpha). The effect of low concentrations of PAF is greatly increased in cells pretreated with LPS. The tyrosine phosphorylation of the p38 MAP kinase is not restricted to stimuli that mediate their actions through membrane-associated receptors, but it can be affected by agents that bypass membrane-associated receptors such as the protein translation blocker anisomycin. While anisomycin is known to increase the tyrosine phosphorylation of the 54 kDa SAPK (stress-activated protein kinase), this is the first report that shows that anisomycin also tyrosine phosphorylates the p38 MAP kinase. Cytokine receptors that increase the tyrosine phosphorylation and activation of the erk1 and erk2 MAP kinases have less effect on this p38 MAP kinase than those that do not affect the erk1 and erk2 MAP kinases. The possible role of the p38 MAP kinase in the phosphorylation of cytosolic phospholipase A2 is discussed.
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PMID:Tyrosine phosphorylation and activation of a new mitogen-activated protein (MAP)-kinase cascade in human neutrophils stimulated with various agonists. 876 79

The expression of cytokine-induced neutrophil chemoattractants (CINC-1 and CINC-2) mRNA was studied in rat peritoneal cells stimulated with insoluble IgG/ovalbumin immune complexes. A dose- and time-dependent induction was observed in adherent cells, which was more prominent than that induced by the lipid mediator platelet-activating factor (PAF), comparable to that observed in response to 10 micrograms endotoxin in the absence of lipopolysaccharide (LPS)-binding protein, but lower than that produced by 1 mM dibutyryl cyclic AMP, a compound which stabilized transiently expressed genes containing AU-rich sequences in the 3' untranslated region. Analysis of CINC-1 protein by specific enzyme-linked immunosorbent assay confirmed the presence of CINC-1 in the supernatants at concentrations of approximately 4 nM, 4 h after addition of 100 micrograms/ml immune complexes. CINC-2 beta protein was detectable at a lower concentration (approximately 0.3 nM) under the same conditions. Attempts to relate CINC-1 induction with the pathways for cytoplasmic signaling showed a dissociation of Ca2+ mobilization and protein kinase C activation as judged from the small effect of thapsigargin and the lack of effect of phorbol ester. In contrast, these agents produced a marked mobilization of arachidonate linked to the MAP kinase-dependent activation of cytosolic phospholipase A2. The possible dependence of CINC-1 induction on the autocrine generation of lipid mediators was ruled out by a set of experiments including the use of the PAF receptor antagonist BB823, and the analysis of the effect of free arachidonate and leukotriene B4 on CINC-1 induction. Surprisingly, the inhibitor of leukotriene synthesis MK-886 in the range of concentration 1-10 microM inhibited CINC-1 induction by a mechanism that appears to be independent of its effect on eicosanoid production. Interestingly, CINC-1 induction appeared to be related to protein tyrosine phosphorylation reactions on the basis of both the appearance of several tyrosine-phosphorylated protein bands in lysates from adherent peritoneal cells treated with immune complexes and the complete blockade of CINC-1 induction by treatment with 1 microM herbimycin A, an inhibitor of src protein tyrosine kinases.
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PMID:The expression of cytokine-induced neutrophil chemoattractants (CINC-1 and CINC-2) in rat peritoneal macrophages is triggered by Fc gamma receptor activation: study of the signaling mechanism. 881 63

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