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)

Ethanol causes a transient activation of the phosphoinositide-specific phospholipase C in intact hepatocytes and mimics the action of receptor-mediated agonists [Hoek, Thomas, Rubin & Rubin (1987) J. Biol. Chem. 262, 682-691]. Preincubation of the hepatocytes with phorbol esters which activate protein kinase C prevented this effect of ethanol: phorbol ester treatment inhibited the ethanol-induced phosphorylase activation, the increase in intracellular free Ca2+ concentrations measured in quin 2-loaded hepatocytes, and the changes in concentrations of inositol phosphates, phosphoinositides and phosphatidic acid. Several lines of evidence indicate that these effects were mediated by protein kinase C. Phorbol esters acted in a concentration range where they activate protein kinase C; phorbol esters that do not activate protein kinase C were not effective in inhibiting the effects of ethanol. The permeant diacylglycerol oleoyl-acetylglycerol also inhibited the effects of ethanol, but other diacylglycerols were not effective in the intact cells. The inhibition of ethanol-induced Ca2+ mobilization by phorbol esters was prevented by preincubating the cells with the protein kinase C inhibitors 1-(5-isoquinolinesulphonyl)-2-methylpiperazine (H7) and sphingosine. H7 also enhanced the Ca2+ mobilization induced by ethanol in cells that were not pretreated with phorbol esters, indicating that the transient nature of the ethanol-induced Ca2+ mobilization may be due to an activation of protein kinase C caused by the accumulation of diacylglycerol. These data support a model whereby ethanol activates the phosphoinositide-specific phospholipase C, possibly by affecting receptor-G-protein-phospholipase C interactions in the membrane.
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PMID:Ethanol-induced phospholipase C activation is inhibited by phorbol esters in isolated hepatocytes. 313 25

Protein kinase C activity in the particulate fraction of the heart increases two-fold during mid-stage of disease in the cardiomyopathic hamster. No change in the corresponding enzyme activity occurs with aging in healthy control hamsters. In the solubilized particulate fraction of hearts from both myopathic and control animals, Ca++/phospholipid-dependent endogenous phosphorylation of proteins of Mr 26, 31, 45, 53, 69, 98, 105 and 126 kDa are observed. All of these proteins are more highly phosphorylated in the protein kinase C-enriched preparation from the myopathic heart compared to the control. No significant differences between myopathic and control hamsters are observed in the activities of protein kinase C or phosphoinositide-specific phospholipase C from heart cytosol.
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PMID:Heart protein kinase C activity increases during progression of disease in the cardiomyopathic hamster. 320 61

We previously showed that cultured rat aortic vascular smooth muscle cells (VSMC) possess an AT1 angiotensin (Ang) receptor coupled to the activation of a phospholipase D (PLD). AT1 receptors in VSMC are also coupled to the activation of a phosphoinositide-specific phospholipase C (PLC), mobilization of intracellular Ca2+, and activation of protein kinase C (PKC). To determine whether PLD stimulation by Ang II is the result of PLC activation and the subsequent elevation of cytosolic free Ca2+ and PKC activation, we investigated the role of Ca2+ and PKC in the activation of PLD. Chelation of extracellular Ca2+ by EGTA, blockade of voltage-sensitive Ca2+ channels, or chelation of intracellular Ca2+ with BAPTA partially attenuated PLD activation and Ca2+ mobilization in response to Ang II. However, the simultaneous chelation of extracellular Ca2+ with EGTA and intracellular Ca2+ with BAPTA completely attenuated both PLD activation and Ca2+ accumulation. Ca2+ ionophores mimicked Ang II and the combined effects of Ang II and ionophore resulted in no further stimulation of PLD activity above that observed in the presence of either agonist alone. Although the putative PLC inhibitor U73122 blocked the activation of PLD by Ang II, it also may inhibit PLD activation directly, since it attenuated both Ca2+ ionophore and phorbol 12-myristate 13-acetate (PMA)-mediated increases in PLD activity. PMA also activated PLD in VSMC in a dose-dependent manner; however, Ang II and PMA stimulation were additive. Down-regulation of PKC via exposure to phorbol dibutyrate almost completely blocked PMA-induced stimulation of PLD while it had no effect on Ang II- or Ca(2+)-ionophore-mediated increases in PLD activity. The PKC inhibitor staurosporine augmented basal PLD activity and partially inhibited PMA stimulation of PLD while it had little effect on Ang II-induced increases in PLD activity. Thus, optimal Ang II stimulation of PLD is dependent on the availability of both intracellular and extracellular Ca2+ and independent of PMA-mediated effects. Furthermore, these data suggest that Ang II stimulation of PLD may occur subsequent to activation of PLC, since Ang II activates PLC and PLC is shown to be responsible for increases in intracellular Ca2- in response to Ang II.
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PMID:Role of calcium and protein kinase C in the activation of phospholipase D by angiotensin II in vascular smooth muscle cells. 777 8

We have shown previously that phosphatidic acid esterified to polyunsaturated fatty acids is mitogenic for primary cultures of mouse mammary epithelial cells embedded within collagen gels. We hypothesized that this mitogenic competence resulted from the ability of this phospholipid to activate multiple signal transduction pathways in mammary epithelium. A closer examination of this hypothesis was undertaken by examining the effect of exogenous phosphatidic acid on phosphoinositide (PI) hydrolysis and its intracellular metabolism to diglyceride, an activator of protein kinase C. For assays of phosphoinositide-specific phospholipase C activation, mammary epithelial cells from virgin Balb/c mice were isolated by collagenase dissociation of mammary glands and cultured on the surface of Type I collagen-coated culture dishes. Phosphatidic acid (PA) stimulated a sustained increase in inositol phosphates and caused inositol phospholipid depletion when added to cells in which inositol phospholipids were prelabeled with 3H-myoinositol. This effect was specific for PA among phospholipids tested. Neither lineoleic acid, that can be released from PA, nor prostaglandin E2 affected PI hydrolysis. When mammary epithelial cells were cultured inside collagen gels in the presence of exogenous PA or phosphatidylcholine (PC) radiolabeled with 3H-glycerol, PA was found to persist intracellularly and be dephosphorylated to diglyceride (an activator of protein kinase C) to a greater extent than PC, a nonmitogenic phospholipid. In contrast to PA, epidermal growth factor (EGF) only slightly stimulated PI hydrolysis, showing that these two different growth-promoting factors do not actively couple to the same signal transduction pathways in mammary epithelial cells. These results show that PA may activate multiple pathways in mammary epithelial cells either directly or via its metabolism to diglyceride.
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PMID:Multifunctional phosphatidic acid signaling in mammary epithelial cells: stimulation of phosphoinositide hydrolysis and conversion to diglyceride. 777 98

Agonist-stimulated phospholipid turnover can generate diacylglycerol (DAG), an intracellular second messenger that activates protein kinase C (PKC). DAG can be produced from the hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2) by a phosphoinositide-specific phospholipase C and by the degradation of phosphatidylcholine (PC) by a phospholipase C or the concerted actions of phospholipase D and phosphatidate phosphohydrolase. In vascular smooth muscle, agonist-stimulated DAG accumulation is biphasic; PIP2 hydrolysis produces a transient increase in DAG, which is followed by a sustained phase of DAG accumulation from PC degradation. Metabolism of DAG attenuates PKC activation and thus results in signal termination. The metabolic fates for DAG include 1) ATP-dependent phosphorylation to form phosphatidic acid (DAG kinase), 2) hydrolysis to release fatty acids and glycerol (DAG and monoacylglycerol lipases), 3) synthesis of triacylglycerol (DAG acyltransferase), and 4) synthesis of PC (choline phosphotransferase). Hydrolysis through the lipase pathway is the predominant metabolic fate of DAG in vascular smooth muscle. Activation of PKC in vascular smooth muscle modulates agonist-stimulated phospholipid turnover, produces an increase in contractile force, and regulates cell growth and proliferation. Further research is required to investigate cross talk between signal transduction mechanisms involving lipid second messengers. In addition, spatial considerations such as nuclear PKC activation and the influence of diradylglycerol generation on the duration of PKC activation are important issues.
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PMID:Signal transduction in vascular smooth muscle: diacylglycerol second messengers and PKC action. 794 96

Thioredoxin (Trx) catalyzes thiol-disulfide oxidoreductions. We and others recently showed that human Trx could function as an autocrine growth factor for human lymphoid cells immortalized by the human T-lymphotrophic virus type I or the Epstein-Barr virus. Here we report that reduced Trx from Escherichia coli generated by NADPH and thioredoxin reductase increases the proliferation of an Epstein-barr virus(+)-B cell line 1G8, which constitutively produces low amounts of human Trx. This proliferative effect involved the activation of protein kinase C through its translocation to the membrane. Staurosporin and calphostin C, two inhibitors of protein kinase C, but not of H8, a protein kinase A inhibitor, were able to block Trx-dependent proliferation. The addition of Trx to 1G8 cells resulted in the formation of inositol 1,4,5-triphosphate and sn-1,2-diacylglycerol by a phosphoinositide-specific phospholipase C, as well as increased free calcium concentration. Diacylglycerol showed a biphasic increase; the first phase, corresponding to an early peak (30 s) of inositol 1,4,5-triphosphate and a second larger, prolonged phase. The second phase was inhibited by propranolol, a specific inhibitor of phosphohydrolase, indicating that it is most likely derived from phosphatidylcholine hydrolysis by the sequential action of phospholipase D and phosphatidic acid phosphohydrolase. Our data suggest that enhanced phosphoinositide-specific phospholipase C activity induced by the dithiol form of Trx in 1G8 cells is associated to protein kinase C activation, and thus plays a role in the permanent growth of Epstein-Barr virus-infected B cells.
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PMID:Thioredoxin increases the proliferation of human B-cell lines through a protein kinase C-dependent mechanism. 796 46

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

The effects of bradykinin (BK) and angiotensin II (ANG II) were compared in cultured rat mesenteric arterial smooth muscle cells. BK and ANG II activated a phosphoinositide-specific phospholipase C, leading to the rapid release of [3H]inositol phosphates, an increase in intracellular calcium, and formation of sn-1,2-diacylglycerol (DAG). DAG formation was biphasic with a transient peak at 5 s followed by a sustained increase from 60 to 600 s. The BK-mediated increases in inositol triphosphate and DAG were dose dependent with half-maximal increases at concentrations of 5 and 2 nM, respectively. Both hormones were found to activate protein kinase C (PKC) as assessed by phosphorylation of the 68- to 72-kDa intracellular PKC substrate myristoylated alanine-rich C kinase substrate. However, despite similar phosphorylation of this substrate, only ANG II produced a significant increase in membrane-bound PKC activity. The mechanism accounting for the inability of BK to increase membrane-bound PKC activity is unclear. Our studies excluded differential translocation of PKC to the nuclear membrane, production of an inhibitor of membrane-bound PKC activity, and expression of BK and ANG II receptors on different cells as the mechanism. Vascular smooth muscle cells were found to express at least four different PKC isozymes: alpha, delta, zeta, and a faint band for epsilon. All of the isozymes except zeta-PKC were translocated by treatment with the phorbol ester 4 beta-phorbol 12-myristate 13-acetate. However, neither ANG II nor BK produced significant translocation of any measured isozyme; therefore, we could not exclude the possibility that ANG II and BK activate different isozymes of PKC. Both hormones were found to have a similar small and inconsistent effect in stimulating [3H]thymidine incorporation. These observations demonstrate that BK and ANG II have similar biochemical effects on vascular smooth muscle cells and imply that, in selected vessels, the vasodilatory effects of BK mediated by the endothelium may be partially counterbalanced by a vasoconstrictor effect on the underlying vascular smooth muscle cells.
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PMID:Bradykinin and angiotensin II: activation of protein kinase C in arterial smooth muscle. 820 4

Human platelet thromboxane A2/prostaglandin H2 (TXA2/PGH2) receptors are linked to phosphoinositide-specific phospholipase C (PI-PLC) via a G protein tentatively identified as a member of the Gq class. In contrast, platelet thrombin receptors appear to activate PI-PLC via other unidentified G proteins. Platelets from most dogs are TXA2 insensitive (TXA2-); i.e., they do not aggregate irreversibly or secrete although they bind TXA2, but they respond normally to thrombin. In contrast, a minority of dogs have TXA2-sensitive (TXA2+) platelets that are responsive to TXA2. To determine the mechanism responsible for TXA2- platelets, we evaluated receptor activation of PI-PLC. Equilibrium binding of TXA2/PGH2 receptor agonists, [125I]BOP and [3H]U46619, and antagonist, [3H]SQ29,548, revealed comparable high-affinity binding to TXA2-, TXA2+, and human platelets. U46619-induced PI-PLC activation was impaired in TXA2- platelets as evidenced by reduced (a) phosphorylation of the 47-kD substrate of protein kinase C, (b) phosphatidic acid (PA) formation, (c) rise in cytosolic calcium concentration, and (d) inositol 1,4,5 trisphosphate (IP3) formation, while thrombin-induced PI-PLC activation was not impaired. GTPase activity stimulated by U46619, but not by thrombin, was markedly reduced in TXA2- platelets. Antisera to Gq class alpha subunits abolished U46619-induced GTPase activity in TXA2-, TXA2+, and human platelets. Direct G protein stimulation by GTP gamma S yielded significantly less PA and IP3 in TXA2- platelets. Immunotransfer blotting revealed comparable quantities of Gq class alpha-subunits in all three platelet types. Thus, TXA2- dog platelets have impaired PI-PLC activation in response to TXA2/PGH2 receptor agonists secondary to G protein dysfunction, presumably involving a member of the Gq class.
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PMID:Thromboxane-insensitive dog platelets have impaired activation of phospholipase C due to receptor-linked G protein dysfunction. 822 62

Surfactant phospholipid secretion can be stimulated by a variety of agonists acting via a number of signal-transduction mechanisms. To determine whether phospholipase D has a role in surfactant secretion, we examined phosphatidylethanol formation in response to surfactant secretagogues in primary cultures of rat type II cells. Phosphatidylethanol formation was stimulated by ATP, 12-O-tetradecanoylphorbol-13 acetate (TPA), and dioctanoylglycerol, surfactant secretagogues that also activate protein kinase C. Surfactant secretagogues that act via other signaling mechanisms had no effect on phosphatidylethanol formation. The effect of ATP on phosphatidylethanol formation was dependent on time, with the maximum stimulation being achieved in approximately 10 min. It was also dependent on ATP concentration. The ATP concentration eliciting 50% of the maximum effect (EC50) was 2.45 x 10(-6) M. This was similar to the EC50 reported for ATP stimulation of surfactant secretion. ATP analogues also stimulated phosphatidylethanol formation with a potency order generally similar to that reported for surfactant secretion. The effects of ATP, TPA, and dioctanoylglycerol were antagonized by protein kinase C inhibitors. We speculate that activation of protein kinase C either directly by TPA and dioctanoylglycerol or indirectly subsequent to phosphoinositide-specific phospholipase C activation by ATP leads to initial stimulation of surfactant secretion as well as activation of phospholipase D. The action of phospholipase D on cellular phospholipids then leads to further generation of diacylglycerols, continued activation of protein kinase C, and sustained surfactant secretion.
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PMID:Activation of phospholipase D in rat type II pneumocytes by ATP and other surfactant secretagogues. 844 26

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