Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.13 (protein kinase C)
 49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Xenopus laevis oocytes are a powerful tool for the characterization of signal transduction pathways leading to the induction of DNA synthesis. Since activation of PLA2, PLC, or PLD has been postulated as a mediator of ras function, we have used the oocyte system to study the putative functional relationship between ras-p21 and these phospholipases. A rapid generation of PA and DAG was observed after ras-p21 microinjection, suggesting the activation of both PLC and PLD enzymes. However, production of DAG was sensitive to inhibition of the PA-hydrolase by propranolol, indicating that PLD is the enzyme responsible for the generation of both PA and DAG. Microinjection of PLD or ras-p21 induced the late production of lysophosphatidylcholine on a p42MAPK-dependent manner, an indication of the activation of a PLA2. Inhibition of this enzyme by quinacrine does not inhibit PLD- or ras-induced GVBD, suggesting that PLA2 activation is not needed for ras or PLD function. Contrary to 3T3 fibroblasts, where ras-p21 is functionally dependent for its mitogenic activity on TPA- and staurosporine-sensitive PKC isoforms, in Xenopus oocytes, induction of GVBD by ras-p21 was independent of PKC, while PLC-induced GVBD was sensitive to PKC inhibition. Thus, our results demonstrate the activation of PLD and PLA2 by ras-p21 proteins, while no effect on PLC was observed.
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PMID:ras-p21 activates phospholipase D and A2, but not phospholipase C or PKC, in Xenopus laevis oocytes. 801 97

Staphylococcus enterotoxins and toxic shock syndrome toxin-1 (TSST-1) are members of the family of staphylococcal exoproteins (SE) which binds specifically to HLA class II molecules and certain V beta T cell receptor phenotypes. These bacterial products have been termed "superantigens" due to their capacity to stimulate a greater proportion of T lymphocytes than peptide antigens without a requirement for antigen processing. The SE stimulate monocytes to secrete IL-1 and TNF-alpha and affect B lymphocyte proliferation in response to anti-human IgM and Ig production by PBMC. The current study concerns the transmission of signals in human B lymphocytes following fixation of TSST-1. Activation of both PLC and PKC are observed while intracellular calcium levels remain unchanged. Levels of HLA class II mRNA were increased suggesting that a pathway leading to activation was triggered. This study therefore identifies some of the second messengers involved after SE fixation on HLA class II molecules and suggests that the signals transmitted via class II antigens as well as those via the TCR may have a role in the physiological responses to bacterial superantigens.
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PMID:Bacterial superantigen signaling via HLA class II on human B lymphocytes. 802 2

We have investigated the mechanism of action by which insulin increases phosphatidate (PA) and diacylglycerol (DAG) levels in cultured rat hepatocytes. Insulin initially stimulated phosphatidylcholine-dependent phospholipase D (PC-PLD) with a significant increase in both PA and intracellular as well as extracellular choline. The involvement of phospholipase D was confirmed by the formation of PC-derived phosphatidylethanol in the presence of ethanol. The DAG increase appeared to be biphasic. Only the early phase of DAG production was inhibited by propranolol, an inhibitor of the phosphatidate phosphatase (PAP) responsible for the conversion of PA into DAG, suggesting that initially the DAG increase is due to the PLD-PAP pathway. The delayed DAG increase was in parallel with increased intracellular and extracellular phosphocholine and probably derived directly from PC-PLC activity. Experiments performed in the presence of 1 microM phorbol 12-myristate 13-acetate (PMA) indicated that protein kinase C (PKC) mediated the insulin effect on PC-PLC, but not on PC-PLD. These findings were confirmed using the PKC inhibitors calphostin, H7 and staurosporine. The dual activation of these phospholipases with a biphasic elevation of DAG levels and activation of specific PKC isoenzymes could be necessary to elicit both early and delayed effects of insulin.
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PMID:Insulin-stimulated hydrolysis of phosphatidylcholine by phospholipase C and phospholipase D in cultured rat hepatocytes. 803 20

Phosphoinositide-specific phospholipase C (PI-PLC) catalyzes the hydrolysis of phosphatidylinositol 4,5-bisphosphate to inositol 1,4,5-trisphosphate (IP3) and diacylglycerol. IP3 induces the release of Ca2+ from intracellular stores, and diacylglycerol acts as the physiological activator of protein kinase C. Several distinct PI-PLC enzymes have been identified from various cells. Based on the primary sequences, PI-PLC isozymes are divided into three families: PLC-beta, PLC-gamma, and PLC-delta. Substantial evidence has strongly suggested that G proteins regulate PI-PLC in various cell-stimulation systems and that there might be two distinct pathways (pertussis toxin-sensitive and pertussis toxin-insensitive). Recently, it has become apparent that beta-type PLC isoforms are activated by the heterotrimeric G protein subfamily Gq. Careful studies using in vitro and in vivo reconstitution systems have further suggested that the alpha-subunits of Gq/11/16 specifically regulate PLC-beta 1 and PLC-beta 3 and that the beta gamma -subunits of the Gi subfamily interact with PLC-beta 2, which are considered to be responsible for the pertussis toxin-insensitive and the pertussis toxin-sensitive pathways, respectively. In this paper, involvement of G proteins in the regulation of phospholipase A2 and phosphatidylcholine-specific PLC and PLD is also discussed.
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PMID:[Phospholipid metabolism regulated by heterotrimeric G proteins]. 803 70

Astrocytes, when appropriately stimulated, produce a variety of cytokines including TNF-alpha. Production of TNF-alpha by astrocytes stimulated with Newcastle disease virus (NDV) is achieved by transcriptional activation and mRNA stabilization. A PKC-dependent pathway is responsible for a 10-fold increase in TNF-alpha mRNA stability by reducing poly(A) tail removal. The present study examined signal pathways induced by NDV in primary rat astrocytes that are responsible for TNF-alpha gene transcription as well as the possible source of kinase activity required for mRNA stabilization. Transcription of TNF-alpha gene in astrocytes stimulated by NDV or LPS and IFN-gamma was inhibited completely by the tyrosine kinase inhibitor herbimycin, and partially by a PKC inhibitor H7, as determined by nuclear run-on assay. HA-1004, a cyclic nucleotide-dependent kinase inhibitor, showed no effect. These results indicated that tyrosine kinase signaling pathways seemed to precede the activation of PKC in induction of TNF-alpha gene. Increase in tyrosine kinase activity in NDV-infected astrocytes was demonstrated by a two- to threefold increase in tyrosine phosphorylation of Pl-PLC gamma 1. Because astrocytes contain minimal Pl-PLC beta, and NDV-induced TNF-alpha mRNA was affected by pertussis toxin only modestly, Pl-PLC gamma 1 is likely the enzyme responsible for DAG generation and the PKC-dependent mRNA stabilization in response to NDV.
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PMID:Tyrosine kinase activation by Newcastle disease virus is required for TNF-alpha gene induction in astrocytes. 808 95

(1) The non-specific protein kinase C inhibitor, staurosporine, inhibited collagen-induced increases in cytosolic free Ca2+ while having no effect on Ca2+ mobilization by other platelet agonists. A more specific inhibitor of protein kinase C, Ro 31-8220, did not inhibit collagen-induced Ca2+ mobilization. Neither drug had an effect on platelet adhesion to collagen. (2) Staurosporine inhibited collagen-stimulated tyrosine phosphorylation, while Ro 31-8220 had no effect. (3) It also inhibited collagen-induced phosphatidic acid formation, inositol trisphosphate formation and arachidonic acid liberation. (4) Ro 31-8220 did not inhibit collagen-stimulated arachidonic acid formation, but it enhanced collagen-stimulated phosphatidic acid and inositol trisphosphate formation. (5) Immunoprecipitation of phospholipase C gamma 2 (PLC gamma 2) with a specific antibody demonstrated that PLC gamma 2 was phosphorylated on tyrosine after stimulation by collagen. (6) The phosphorylation of PLC gamma 2 was inhibited by staurosporine but not by Ro 31-8220. These results provide additional evidence that the mechanism of signal transduction for collagen is different from other platelet agonists and indicate that it involves activation of PLC gamma through a tyrosine kinase-dependent mechanism.
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PMID:Evidence for a role for tyrosine phosphorylation of phospholipase C gamma 2 in collagen-induced platelet cytosolic calcium mobilization. 809 16

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

Tyrosine phosphorylation plays a critical role in Fc gamma RIIA signaling. In a mouse macrophage cell line transfected with human Fc gamma RIIA, cross-linking Fc gamma RIIA led to the transient generation of inositol 1, 4, 5-trisphosphate (IP3), [Ca2+]i flux, and rapid tyrosine phosphorylation of cellular substrates, including Shc, PLC-gamma 1, and a tyrosine kinase p72syk. In addition, tyrosine phosphorylated Fc gamma RIIA was co-precipitated with activated PLC-gamma 1. In contrast, no tyrosine phosphorylation of Shc or PLC-gamma 1 was detected in cells transfected with mutant receptors that failed to trigger [Ca2+]i flux. PMA inhibits both tyrosine phosphorylation of Shc and IP3 production leading to [Ca2+]i flux. However, PMA does not affect tyrosine phosphorylation of PLC-gamma 1 and p72syk. These results suggest that tyrosine phosphorylation of Shc and PLC-gamma 1 is important for the initiation of [Ca2+]i flux, and that activation of protein kinase C may modulate the activity of PLC-gamma 1 through serine/threonine phosphorylation.
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PMID:Correlations among tyrosine phosphorylation of Shc, p72syk, PLC-gamma 1, and [Ca2+]i flux in Fc gamma RIIA signaling. 814

PC hydrolysis by PLA2, PLC or PLD is a widespread response elicited by most growth factors, cytokines, neurotransmitters, hormones and other extracellular signals. The mechanisms can involve G-proteins, PKC, Ca2+ and tyrosine kinase activities. Although an agonist-responsive cytosolic PLA2 has been purified, cloned and sequenced, the agonist-responsive form(s) of PC-PLC has not been identified and no form of PC-PLD has been purified or cloned. Regulation of PLA2 by Ca2+ and MAPK is well established and involves membrane translocation and phosphorylation, respectively. PKC regulation of the enzyme in intact cells is probably mediated by MAPK. The question of G-protein control of PLA2 remains controversial since the nature of the G-protein is unknown and it is not established that its interaction with the enzyme is direct or not. Growth factor regulation of PLA2 involves tyrosine kinase activity, but not necessarily PKC. It may be mediated by MAPK. The physiological significance of PLA2 activation is undoubtedly related to the release of AA for eicosanoid production, but the LPC formed may have actions also. There is much evidence that PKC regulates PC-PLC and PC-PLD and this is probably a major mechanism by which agonists that promote PI hydrolysis secondarily activate PC hydrolysis. Since no agonist-responsive forms of either phospholipase have been isolated, it is not clear that PKC exerts its effects directly on the enzymes. Although it is assumed that a phosphorylation mechanism is involved, this may not be the case, and regulation may be by protein-protein interactions. G-protein control of PC-PLD is well-established, although, again, it has not been demonstrated that this is direct, and the nature of the G-protein(s) involved is unknown. In some cell types, there is evidence of the participation of a soluble protein, which may be a low Mr GTP-binding protein. What role this plays in the activation of PC-PLD is obscure. Agonist activation of PC hydrolysis in cells is usually Ca(2+)-dependent, but the step at which Ca2+ is involved is unclear, since PC-PLD and PC-PLC per se are not influenced by physiological concentrations of the ion. Most growth factors promote PC hydrolysis and this is mainly due to activation of PKC as a result of PI breakdown. However, in some cases, PC breakdown occurs in the absence of PI hydrolysis, implying another mechanism that does not involve PI-derived DAG.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Phosphatidylcholine breakdown and signal transduction. 815 24

The activation of human platelets is inhibited by two intracellular pathways regulated by either cGMP- or cAMP-elevating agents. There is considerable evidence that the inhibitory effects of cGMP and cAMP are mediated by the cGMP-PK and cAMP-PK, respectively, in human platelets. The cGI-PDE is an additional target for cGMP, and the cGMP-mediated elevation of cAMP levels contributes to the well known synergism between cAMP- and cGMP-elevating platelet inhibitors. Stimulation of both cAMP-PK and cGMP-PK prevents the agonist-induced activation of MLCK and PKC and inhibits the agonist-induced calcium mobilization from intracellular stores without any major effect on the ADP-regulated cation channel. These studies suggest that the inhibition of an early event of platelet activation, e.g. activation of PLC, is an effect common to both cGMP-PK and cAMP-PK stimulation. A common substrate of both cGMP-PK and cAMP-PK, the 46/50 kDa protein VASP, has been recently identified as a novel microfilament- and focal contact-associated protein whose phosphorylation correlates very well with platelet inhibition. Future investigations will have to identify the precise molecular mechanism of cyclic nucleotide inhibition of Ca2+ discharge from intracellular stores and whether cGMP-PK- and cAMP-PK-mediated VASP phosphorylation is an important component of this effect of cyclic nucleotides in human platelets.
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PMID:Role of cyclic nucleotide-dependent protein kinases and their common substrate VASP in the regulation of human platelets. 820 91


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