EC:2.7.11.13 - FACTA Search

Gene/Protein Disease Symptom Drug Enzyme Compound
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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)

Endotoxin-associated protein (EP) from Salmonella typhi stimulated the release of prostaglandin E2 (PGE2), interleukin-1 (IL-1), and interferon (IFN) activity in macrophages from the lipopolysaccharide (LPS) responder C3H/OuJ mouse strain. However, only PGE2 and IL-1 were stimulated by EP in macrophages from the LPS nonresponder C3H/HeJ mouse strain. LPS stimulated the release of PGE2, IL-1 and IFN activity in C3H/OuJ macrophages, but not in C3H/HeJ macrophages. The protein kinase C (PKC) activator phorbol myristic acid (PMA) stimulated PGE2 production in both strains but not IL-1 production, suggesting that signalling pathways other than PKC may be involved in IL-1 production. The calcium ionophore ionomycin stimulated PGE2 production in C3H/OuJ but not C3H/HeJ macrophages, suggesting a defective calcium-related pathway in the C3H/HeJ macrophages as compared to the C3H/OuJ cells.
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PMID:Differing signal requirements for the activation of macrophages from C3H/HeJ and C3H/OuJ mice. 787 76

The proposal that epidermal growth factor (EGF) activates phospholipase D (PLD) by a mechanism(s) not involving phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2) hydrolysis was examined in Swiss 3T3 fibroblasts. EGF, basic fibroblast growth factor (bFGF), bombesin, and platelet-derived growth factor (PDGF) activated PLD as measured by transphosphatidylation of butanol to phosphatidylbutanol. The increase in inositol phosphates induced by bFGF, EGF, or bombesin was significantly enhanced by Ro-31-8220, an inhibitor of protein kinase C (PKC), suggesting that PtdIns(4,5)P2-hydrolyzing phospholipase is coupled to the receptors for these agonists but that the response is down-regulated by PKC. Activation of PLD by EGF was inhibited dose dependently by the PKC inhibitors bis-indolylmaleimide and Ro-31-8220, which also inhibited the effects of bFGF, bombesin, and PDGF. Down-regulation of PKC by prolonged treatment with 4 beta-phorbol 12-myristate 13-acetate also abolished EGF- and PDGF-stimulated phosphatidylbutanol formation. EGF and bombesin induced biphasic translocations of PKC delta and epsilon to the membrane that were detectable at 15 s. In the presence of Ro-31-8220, translocation of PKC alpha became evident, and membrane association of the delta- and epsilon-isozymes was enhanced and/or sustained in response to the two agonists. The inhibitor also enhanced EGF-stimulated [3H]diacylglycerol formation in cells preincubated with [3H]arachidonic acid, which labeled predominantly phosphatidylinositol, but inhibited [3H]diacylglycerol production in cells preincubated with [3H]myristic acid, which labeled mainly phosphatidylcholine. These data support the conclusion that EGF can stimulate diacylglycerol formation from PtdIns(4,5)P2 and that PKC performs the dual role of down-regulating this response as well as mediating phosphatidylcholine hydrolysis. In summary, all of the results of the study indicate that PLD activation by EGF is downstream of PtdIns(4,5)P2-hydrolyzing phospholipase and is dependent upon subsequent PKC activation.
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PMID:Stimulation of phospholipase D by epidermal growth factor requires protein kinase C activation in Swiss 3T3 cells. 787 45

The involvement of phospholipase D (PLD) in phosphatidylcholine hydrolysis by epidermal (EGF), insulin-like (IGF-I), and basic fibroblast (bFGF) growth factors was investigated in rat pancreatic acini. Acini were prelabeled with [3H]myristic acid which is mostly incorporated into phosphatidylcholine. EGF, IGF-I, and bFGF caused significant and dose-dependent increases in [3H]phosphatidic acid (PA) accumulation in the presence of propranolol, a phosphatidic acid phosphohydrolase inhibitor. The effects of EGF and IGF-I were significant after 5, 15, and 30 min of stimulation, whereas that of bFGF was evident only at 30 min. PA production in response to all three factors was dose dependent with maximal responses to EGF at 25 nM, to IGF-I at 16.5 nM, and to bFGF at 50 pM. Preincubation of acini with staurosporine, a protein kinase C and tyrosine kinase inhibitor, totally inhibited PA production by the three factors. Similarly, acini preincubation with genistein, a specific tyrosine kinase inhibitor, also neutralized the influence of the three factors on PA accumulation. In the presence of 1% ethanol, EGF, IGF-I, and bFGF caused significant phosphatidylethanol production after 20 min of incubation, thus confirming the involvement of PLD in PA production. These data present for the first time the description of a new signaling pathway through which EGF, IGF-I, and bFGF may operate to induce some of their specific effects on the pancreas in association with these growth factor receptors' tyrosine kinase activity.
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PMID:Activation of pancreatic acinar cell phospholipase D by epidermal, insulin-like, and basic fibroblast growth factors involves tyrosine kinase. 789 61

A hydrophilic enzyme, lysozyme, was myristoylated in vitro by the N-hydroxysuccinimide ester of myristic acid and three monomyristoylated lysozymes modified at a distinct position (at Lys-13, Lys-33, Lys-97) were isolated by two-step column chromatography. The relationship between membrane binding and phosphorylation by protein kinase C of these monomyristoylated lysozymes were examined using phospholipid vesicles. These three lysozymes bound to phospholipid vesicles to the same extent, whereas the binding of nonmyristoylated native lysozyme was negligible. When native and three monomyristoylated lysozymes were reacted with protein kinase C in a phosphatidylserine (PS)-containing vesicle system, phosphorylation was observed with the myristoylated lysozymes, whereas that of native lysozyme was negligible. However, a remarkable (more than sixfold) difference in the extent of phosphorylation by protein kinase C was observed among three monomyristoylated lysozymes with a different myristoylated position. These results suggest that the membrane binding of substrate protein is not sufficient for the phosphorylation by protein kinase C and the topology of the substrate protein on the membrane play a crucial role in the recognition of substrate protein by protein kinase C. These results further indicate that protein myristoylation can modulate the topology of the membrane-bound protein.
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PMID:Myristoylation of protein at a distinct position allows its phosphorylation by protein kinase C. 808 Feb 81

Intercellular adhesion molecule 1 (ICAM-1) is a major adhesion receptor of the immune system. Its cell surface expression on a wide variety of cells including cancer cells regulated by various proinflammatory cytokines. Incubation of the human glioma cell line HS 683 and the neuroblastoma cell line SK-N-SH with 12-phorbol 13-myristic acid (PMA), retinoic acid, or gamma-interferon (IFN-gamma) strongly stimulates ICAM-1 expression. In the present study, we investigated the role of the protein kinase C (PKC)-mediated signal transduction pathway in this process. We found that IFN-gamma, but not retinoic acid, was able to induce activation and translocation of PKC after 60 min in a dose-dependent fashion, contrasting with the very rapid activation and translocation induced by PMA which occurred at 15 min. The PKC inhibitors 1-(5-isoquinolinesulfonyl)-2-methyl-piperazine dihydrochloride and staurosporine, as well as depletion of PKC by a 24-h treatment with 100 nM PMA, decreased the PMA-mediated stimulation but not the retinoic acid- or the IFN-gamma-mediated stimulation of ICAM-1 expression. On the contrary, they rather stimulated ICAM-1 expression. Furthermore, this stimulation was additive with retinoic acid and IFN-gamma. A 24-h incubation in the presence of retinoic acid or IFN-gamma strongly inhibited activation and translocation of PKC by PMA. These results suggest that although PMA-induced ICAM-1 expression is PKC dependent on HS 683 and SK-N-SH cells, the stimulation of ICAM-1 expression by retinoic acid and by IFN-gamma may be due to PKC inactivation at longer time points (24 h), as mimicked by 1-(5-isoquinolinesulfonyl)-2-methylpiperazine dihydrochloride, staurosporine, or PKC depletion by high doses of PMA.
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PMID:Transduction of retinoic acid and gamma-interferon signal for intercellular adhesion molecule-1 expression on human tumor cell lines: evidence for the late-acting involvement of protein kinase C inactivation. 809 32

In [3H]myristic acid-labelled osteoblast-like MC3T3-E1 cells, prostaglandin F2 alpha (PGF2 alpha)-induced PLD activity was assessed by measuring the [3H]phosphatidylethanol (PEt) formation in the presence of ethanol. Inhibition of the increase in intracellular Ca2+ concentration ([Ca2+]i) by U73122, an inhibitor of phosphoinositide-specific phospholipase C (PI-PLC), or chelation of extracellular Ca2+ with EGTA or of intracellular Ca2+ with BAPTA, suppressed PGF2 alpha-induced phospholipase D (PLD) activation. Neither protein kinase C (PKC) inhibitors nor PKC down-regulation with phorbol 12-myristate 13-acetate affected PGF2 alpha-induced [3H]PEt formation. In permeabilized cells, guanosine 5'-[gamma-thio]triphosphate enhanced PGF2 alpha 's potency in [3H]PEt formation in the presence of Ca2+. The pretreatment of intact cells with pertussis toxin failed to inhibit PGF2 alpha-induced [3H]PEt formation. PGF2 alpha caused a biphasic production of [3H]1,2-diacylglycerol ([3H]1,2-DAG) in [3H]glycerol-labelled cells. The initial transient phase was decreased by U73122, whereas the late sustained phase was decreased by ethanol and the phosphatidic acid phosphohydrolase inhibitor, propranolol. From these results, it was suggested that PGF2 alpha-induced PLD activation was mediated by the dual control of the [Ca2+]i increase due to PI-PLC activation and activation of pertussis-toxin-insensitive G-protein, but not mediated by PKC, and also that PLD activation was involved in the late sustained 1,2-DAG generation in MC3T3-E1 cells.
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PMID:Prostaglandin F2 alpha-stimulated phospholipase D activation in osteoblast-like MC3T3-E1 cells: involvement in sustained 1,2-diacylglycerol production. 813 58

We have investigated the regulation of phospholipase D (PLD) by guanine nucleotides and AlF4- in bovine corneal epithelial cells (BCEC) prelabeled with [3H]myristic acid. In the presence of ethanol, AlF4- increased the production of [3H]PA and [3H]PET indicating activation of PLD in these cells. The effects of AlF4- were time- and dose-dependent. Addition of guanosine 5[gamma-thio]triphosphate (GTP gamma S), to streptolysin O-permeabilized cells also resulted in increased accumulation of [3H]PA and [3H]PEt. Other guanine and adenine nucleotides were ineffective, and guanosine thiodiphosphate inhibited the GTP gamma S-induced activation of PLD. Direct addition of GTP gamma S to microsomal fraction prepared from [3H]myristate-labeled BCEC resulted in increased formation of [3H]PEt in a time- and dose-dependent manner. The activation of PLD by GTP gamma S in the microsomal fraction was absolutely dependent on the presence of Ca2+ > 0.5 microM. Addition of Ca2+ (10-100 microM) alone dose-dependently stimulated the PLD activity. Treatment of the microsomal fraction with phorbol esters had no effect on the ability of GTP gamma S to stimulate PLD. Addition of isoproterenol to BCEC resulted in several-fold stimulation of cAMP, but it had no effect on basal or PDBu-induced stimulation of PLD. Taken together, the data suggest that a GTP-binding protein is involved in regulation of PLD in BCEC, and that maximal stimulation of PLD probably results from an interaction between Ca2+, PKC and G-protein in BCEC.
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PMID:Activation of phospholipase D by guanosine 5'[gamma-thio]triphosphate and AlF4- in bovine corneal epithelial cells. 819 72

We have examined the activation of phospholipase D (PLD) in bovine pulmonary artery endothelial cells (BPAEC) treated with 4-hydroxynonenal (4-HNE). Treatment of BPAEC labelled with [32P] orthophosphate (5 h for minimal phospholipid labelling) and [3H] myristic acid (24 h) with 4-HNE in the presence of 0.5% ethanol resulted in the formation of [3H] phosphatidylethanol (PEt) and [3H] phosphatidic acid (PA) with very little accumulation of [32P] PEt. The formation of [3H] PEt, as opposed to [32P] PEt, suggests that PEt synthesis was not through de novo pathway but rather through the PLD mechanism. 4-Hydroxynonenal-induced PLD activation was dose and time dependent, and was not associated with cytotoxicity as determined by [3H] deoxyglucose release. The formation of PEt was not affected by chelation of either extracellular Ca2+ with EGTA (5 mM, 30 min) or intracellular Ca2+ with BAPTA-AM (25 microM, 30 min). Treatment of BPAEC with either staurosporine (10 microM, 15 min), a protein kinase C (PKC) inhibitor, or down regulation of PKC by chronic 12-0-tetradecanoylphorbol-13-acetate (TPA) treatment (100 nM, 18 h) had no effect on 4-HNE-induced PLD activation. These results indicate that PLD activation by 4-HNE is independent of PKC activity. We also examined the specificity of nonylaldehyde derivatives and hydroxyalkenals on PLD activation. In addition to 4-HNE, 4-hydroxyoctenal and 4-hydroxyhexenal also stimulated [32P] PEt formation. Among the various nonylaldehydes examined, only trans-2-nonenal and trans-2-cis 6-nonadienal exhibited PLD activation, suggesting the requirement of a trans double bond at carbon 2 and a hydroxyl group at carbon 4. However, in contrast to 4-HNE-induced PLD activation of BPAEC monolayers, treatment of 105,000 x g membranes with 4-HNE had no effect on PLD catalyzed hydrolysis of [2-14C] oleoyl phosphatidylcholine. These data provide evidence that 4-HNE, a metabolite of membrane lipid peroxidation, may be involved in endothelial cell signal transduction, through the activation of phospholipase D and the generation of second messengers like phosphatidic acid and diacylglycerol.
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PMID:4-Hydroxynonenal, a metabolite of lipid peroxidation, activates phospholipase D in vascular endothelial cells. 822 18

1. We have studied whether a nucleotide receptor mediates the effects of extracellular ATP and UTP on phosphatidylcholine metabolism in rat cultured glomerular mesangial cells. 2. ATP and UTP stimulated a biphasic 1,2-diacylglycerol (DAG) formation in [3H]-arachidonic acid-labelled mesangial cells. In contrast, in cells labelled with [3H]-myristic acid, a tracer that preferentially marks phosphatidylcholine, both nucleotides induced a delayed monophasic production of DAG with a concomitant increase in phosphatidic acid and choline formation. 3. A phospholipase D-mediated phosphatidylcholine hydrolysis was further suggested by the observation that ATP and UTP stimulate the accumulation of phosphatidylethanol, when ethanol was added to mesangial cells. 4. The rank order of potency of a series of nucleotide analogues for stimulation of phosphatidylethanol formation was UTP = ATP > ITP > ATP gamma S > beta gamma-imido-ATP = ADP > 2-methylthio-ATP = beta gamma-methylene-ATP = ADP beta S, while AMP, adenosine, CTP and GTP were inactive, indicating the presence of a nucleotide receptor. 5. Elevation of cytosolic free Ca2+ by the calcium ionophore A23187 (1 microM) or the Ca(2+)-ATPase inhibitor, thapsigargin (200 nM) slightly increased phosphatidylethanol formation. However, chelation of cytosolic Ca2+ with high concentrations of Quin 2 did not attenuate ATP- and UTP-induced phosphatidylethanol production, thus suggesting that Ca2+ is not crucially involved in agonist-stimulated phospholipase D activation. 6. The protein kinase C (PKC) activator, phorbol 12-myristate 13-acetate (PMA), but not the biologically inactive 4 alpha-phorbol 12,13-didecanoate, increased phospholipase D activity in mesangial cells, suggesting that PKC may mediate nucleotide-induced phosphatidylcholine hydrolysis. 7. Down-regulation of PKC-alpha and -delta isoenzymes by 8 h PMA treatment still resulted in full phospholipase D activation. In contrast, a 24 h treatment of mesangial cells with PMA, a regimen that also causes depletion of PKC-epsilon, markedly attenuated nucleotide-evoked phosphatidylethanol formation. In addition, the selective PKC inhibitor, calphostin C attenuated ATP- and UTP-induced phosphatidylethanol production.8. In summary, these data suggest that extracellular ATP and UTP use a common nucleotide receptor to activate phospholipase D-mediated phosphatidylcholine hydrolysis. Stimulation of phospholipase D appears to involve the PKC-epsilon isoenzyme, activated by DAG derived from phosphoinositide hydrolysis by phospholipase C.
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PMID:Extracellular ATP and UTP activation of phospholipase D is mediated by protein kinase C-epsilon in rat renal mesangial cells. 824 60

Phospholipase D (PLD) activation by vasopressin (VP) was compared to activation by TPA in REF52 cells prelabeled with [3H]glycerol and [14C]myristic acid. Upon VP-treatment, the formation of [3H] and [14C]phosphatidic acid (PA) and phosphatidylethanol (PEt) was accompanied by the loss of radioactivity from PC and PI. However, upon TPA-treatment, radioactivity was lost from PC only. No significant changes of phosphatidylethanolamine and phosphatidylserine were detected in the same samples. The inclusion of 5 microM staurosporine for 10 min diminished the production of [3H]PEt and [14C]PEt by 27% and 53% in VP-treated cells, and by 100% and 75% in TPA-treated cells, respectively. Adding 1 mM EGTA to chelate extracellular Ca2+ inhibited [3H]PEt by approximately 31% and [14C]PEt by 17% after VP-stimulation. In contrast, EGTA had no effect on TPA-stimulation. The data suggest that REF52 cells contain dual PLD activities. The first is stimulated only by VP, requires Ca2+ and hydrolyzes PI. The second is stimulated by both TPA and VP, activated by protein kinase C and hydrolyzes PC.
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PMID:Comparison of phospholipase D activity in vasopressin- and phorbol ester-stimulated fibroblasts. 845 47

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