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)

1. Phospholipase D (PLD) is the key enzyme in a signal transduction pathway leading to the formation of the second messengers phosphatidic acid and diacylglycerol. In order to define the pharmacological profile of PLD-coupled metabotropic glutamate receptors (mGluRs), PLD activity was measured in slices of adult rat brain in the presence of mGluR agonists or antagonists. Activation of the phospholipase C (PLC) pathway by the same agents was also examined. 2. The mGluR-selective agonist (1S,3R)-l-aminocyclopentane-1,3-dicarboxylic acid [(1S,3R)-ACPD] induced a concentration-dependent (10-300 microM) activation of PLD in the hippocampus, neocortex, and striatum, but not in the cerebellum. The effect was particularly evident in hippocampal slices, which were thus used for all subsequent experiments. 3. The rank order of potencies for agonists stimulating the PLD response was: quisqualate > ibotenate > (2S,3S,4S)-alpha-(carboxycyclopropyl)-glycine > (1S,3R)-ACPD > L-cysteine sulphinic acid > L-aspartate > L-glutamate. L-(+)-2-Amino-4-phosphonobutyric acid and the ionotropic glutamate receptor agonists N-methyl-D-aspartate, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, and kainate failed to activate PLD. (RS)-3,5-dihydroxyphenylglycine (100300 microM), an agonist of mGluRs of the first group, stimulated PLC but inhibited the PLD response elicited by 100 microM (1S,3R)-ACPD. 4. (+)-alpha-Methyl-4-carboxyphenylglycine (0.1-1 mM), a competitive antagonist of mGluRs of the first and second group, elicited a significant PLD response. L-(+)-2-Amino-3-phosphonopropionic acid (1 mM), an antagonist of mGluRs of the first group, inhibited the 100 microM (1S,3R)-ACPD-induced PLC response but produced a robust stimulation of PLD. 5. 12-O-Tetradecanoylphorbol 13-acetic acid and phorbol 12,13-dibutyrate (PDBu), activators of protein kinase C, at 1 microM had a stimulatory effect on mGluRs linked to PLD but depressed (1S,3R)-ACPD-induced phosphoinositide hydrolysis. The protein kinase C inhibitor, staurosporine (1 and 10 microM) reduced PLD activation induced by 1 microM PDBu but not by 100 microM (1S,3R)-ACPD. 6. Our results suggest that PLD-linked mGluRs in rat hippocampus may be distinct from any known mGluR subtype coupled to PLC or adenylyl cyclase. Moreover, they indicate that independent mGluRs coupled to the PLC and PLD pathways exist and that mGluR agonists can stimulate PLD through a PKC-independent mechanism.
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PMID:Pharmacological characterization of metabotropic glutamate receptors coupled to phospholipase D in the rat hippocampus. 879 79

Western blot analysis shows the presence of protein kinase C (PKC) alpha, beta1, beta2, delta, epsilon, zeta isozymes in rat basophilic leukemia (RBL-2H3) cells. Antigen stimulation caused preferential translocation of protein kinase C (PKC) delta and epsilon to membranes. On the other hand, when the cells were stimulated by phorbol 12-myristate 13-acetate (PMA) or ionophore (A23187), PKCalpha and beta were predominantly translocated. Phospholipase D (PLD) was activated by three stimulants in order: A23187 > PMA >> antigen. Therefore, PKCalpha and beta seem to be involved in the activation of PLD in RBL cells. The translocation of all PKC isozymes in A23187 stimulation was weak. Therefore, PLD activation in A23187 stimulation may require some other factors than PKC which are associated with the increase of Ca2+ in the cells. The cells stimulated by antigen secreted serotonin to the same level as the cells stimulated by A23187. In both stimulation, PKCalpha and epsilon were translocated to almost similar level, suggesting that PKCalpha and epsilon are involved in the secretion. All PKC isozymes except zeta were markedly translocated in PMA stimulation, but secretion did not occur. These results indicate that translocation of PKC alpha and beta may be associated with PLD activation and also that both translocation of PKCalpha and epsilon and intracellular calcium increase are required for serotonin secretion in RBL cells.
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PMID:[The involvement of protein kinase C isozymes in activation of phospholipase D and secretion of serotonin in rat basophilic leukemia cells]. 887 Dec 96

Lysophosphatidylcholine (lyso PC) mediates multiple potentially atherogenic effects on endothelial cells, although the cellular mechanism of these effects remains unclear. Phospholipase D (PLD) has been recognized as a novel second-messenger system that may regulate cellular function. The purpose of this study was to determine the effect of lyso PC on PLD activity in human coronary artery endothelial cells (HCAEC) by measuring [3H]phosphatidylethanol production in cells labeled with [3H]myristic acid. After incubation with lyso PC (20 microM) for 40 min, PLD activity was markedly stimulated from five- to sixfold. Stimulation of PLD activity by lyso PC was concentration dependent (half-maximum effective concentration of 7.6 microM) and was not mimicked by phosphatidylcholine (20 microM). Because PLD can be regulated by protein kinases, the effect of several protein kinase inhibitors on lyso PC-stimulated PLD activity was tested. The protein kinase A inhibitor H-89 (300 nM) and the tyrosine kinase inhibitors genistein (30 microM) and tyrphostin A25 (100 microM) had no effect on the stimulation of PLD by lyso PC (20 microM). The protein kinase C (PKC) inhibitor calphostin C (10-300 nM) affected neither lyso PC (20 microM)-nor 4 beta-phorbol 12,13-dibutyrate (PDBu, 300 nM)-stimulated PLD activity, suggesting that this agent may not inhibit PKC in these cells. In contrast, the selective PKC inhibitors GF-109203X (0.3-10 microM) and chelerythrine (1-30 microM) concentration dependently inhibited lyso PC (20 microM)-stimulated PLD activity and blocked PDBu (300 nM)-stimulated PLD activity. Together, these data document that lyso PC stimulated PLD in human endothelial cells, possibly by a PKC-dependent mechanism, and provide evidence that PLD activation in human endothelium is a novel and important mechanism by which lyso PC mediates its cellular and possibly atherogenic effects.
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PMID:Lysophosphatidylcholine stimulates phospholipase D in human coronary endothelial cells: role of PKC. 889 67

Intracellular mediators regulating the initiation of parturition are not fully understood. This study was designed to determine the possible mechanism of oxytocin-induced uterine contractility during labour. In-vitro isometric contraction studies were performed with longitudinal strips of human pregnant myometrium in the presence and absence of the protein kinase C inhibitors, staurosporine and RO 31-8220, and the tyrosine kinase inhibitor, genistein. Phospholipase D activity was measured by employing the transphosphatidylation reaction. Staurosporine significantly reduced oxytocin-stimulated contractile activity with mean activity reduced by > 50% following the addition of 10(-6) M staurosporine (P < 0.01), while addition of 10(-5) M resulted in a measured mean contractile activity of approximately 10% of the control (P < 0.001, n = 5). Similarly, uterine activity was minimal with oxytocin application following incubation with RO 31-8220, mean contractile activity being reduced by approximately 40% by the addition of 10(-7) M RO 31-8220 (P < 0.05) and by approximately 87% by the addition of either 10(-6) or 10(-5) M (P < 0.01, n = 3). Conversely, addition of genistein (10(-7) and 10(-6) M) had little effect on oxytocin-induced contractions, although at a higher concentration (10(-5) M) a significant reduction in oxytocin-induced contractile activity was observed (P < 0.01). Oxytocin evoked phospholipase D activation in a concentration- and time-dependent manner in cultured human pregnant myometrial cells (n = 4). These results indicate that activation of protein kinase C and tyrosine kinase are involved in the regulation of oxytocin-mediated myometrial contractile activity and that a coupled phospholipase D/phosphatidate phosphohydrolase pathway may play a role in the sustained stimulation of myometrial activity during labour.
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PMID:Activation of protein kinase C is required for oxytocin-induced contractility in human pregnant myometrium. 894 42

This review examines the functional role of phospholipase D in the neutrophil. Phospholipase D is emerging as an important component in the signal transduction pathways leading to granulocyte activation. Through the second messenger it produces, phosphatidic acid, phospholipase D plays an active role in the regulation of granulocyte NADPH oxidase activation and granular secretion. Many factors from both the cytosol and the membrane are necessary for maximal phospholipase D activation. This paper will focus on the regulation of phospholipase D by low molecular weight GTP-binding proteins, tyrosine kinases, and protein kinase C.
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PMID:Small GTPase-regulated phospholipase D in granulocytes. 896 Mar 52

Phospholipase D (PLD) is activated by a variety of stimuli, including mitogenic stimulation by growth factors and oncogene transformation. Activation of PLD by growth factors requires protein kinase C (PKC) since depletion of the enzyme by down-regulation or direct inhibition by specific drugs completely abrogates this effect. Transformation by the ras and src oncogenes is also associated with an increase in basal PLD activity. However, this effect is not dependent on PKC, suggesting that growth factors and oncogenes may activate PLD by two independent mechanisms. Here we demonstrate that activation of PLD by phorbol esters is greatly enhanced in ras-transformed cells, suggesting synergistic activation of PLD by ras oncogenes and PKC. Also, ras-transformed cells showed a dramatic attenuation of the PLD activation induced by growth factors, although receptor function was still detectable. This attenuation paralleled the specific uncoupling of the phosphatidylinositol-specific phospholipase C (PI-PLC) pathway, indicating that activation of PLD by growth factors may be mediated by PI-PLC and PKC activation. Attenuation of PLD activation by platelet-derived growth factor was also observed in several oncogene-transformed cells, as well as the uncoupling of the PI-PLC pathway. Neither the co-operation with PKC activation nor the attenuation of the PLD response to growth factors in ras-transformed cells was a general consequence of cell transformation, since cells transformed by other oncogenes showed a normal response to either treatment. These results support the existence of at least two alternative signalling routes for the activation of PLD, one mediated by the PI-PLC/diacylglycerol/PKC pathway and a second one mediated by several oncogenes, independent of the PKC pathway, which synergizes with the PI-PLC/PKC-dependent pathway.
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PMID:Activation of phospholipase D by growth factors and oncogenes in murine fibroblasts follow alternative but cross-talking pathways. 906 72

Phospholipase D exists in various forms that differ in their regulation but predominantly hydrolyze phosphatidylcholine. The Ca(2+)-dependent isozymes of protein kinase C regulate phospholipase D in vitro and play a major role in its control by growth factors and G protein-linked agonists in vivo. Recent studies have demonstrated that small G proteins of the ADP-ribosylation factor (ARF) and Rho families activate the enzyme in vitro, and evidence is accumulating that they also are involved in its control in vivo. Both types of G protein play important roles in cellular function, and the possible mechanisms by which they are activated by agonists are discussed. There is also emerging evidence of the control of phospholipase D and Rho proteins by soluble tyrosine kinases and novel serine/threonine kinases. The possible role of these kinases in agonist regulation of phospholipase D is discussed. The function of phospholipase D in cells is still poorly defined. Postulated roles of phosphatidic acid produced by phospholipase D action include the activation of Ca(2+)-independent isoforms of protein kinase C, the regulation of growth and the cytoskeleton in fibroblasts, and control of the respiratory burst in neutrophils. Another important function of phosphatidic acid is to act as a substrate for a specific phospholipase A2 to generate lysophosphatidic acid, which is becoming increasingly recognized as a major intercellular messenger. Finally, it is possible that the phospholipid changes induced in various cellular membranes by phospholipase D may per se play an important role in vesicle trafficking and other membrane-associated events.
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PMID:Phospholipase D: enzymology, mechanisms of regulation, and function. 911 16

Phospholipase D is believed to play an important role in cell proliferation and tumorigenesis. One of its major functions is to cause a sustained activation of protein kinase C through the primary production of phosphatidic acid from phosphatidylcholine by the enzyme, followed by dephosphorylation forming diacylglycerol. Protein kinase C is known to be activated or translocated in some tumors including breast tumors. In order to examine phospholipase D activity in breast tumors, surgical specimens of human breast tumors were obtained by mastectomy or wide excision, and their phospholipase D activities were assayed by determining the formation of phosphatidylethanol from phosphatidylcholine and ethanol. Phospholipase D activity was predominantly localized in the microsomal fraction of the tumor tissue and markedly stimulated by oleic acid. We observed a significant increase in phospholipase D activity in 17 out of 19 spontaneous human breast tumors as compared to adjacent histologically normal breast tissue. The mean specific activity in the tumors was 52.9 +/- 41.8 (SD) pmol min-1 mg protein-1 whereas the value for the normal breast tissue was 34.0 +/- 36.2 (SD) pmol min-1 mg protein-1 (P < 0.01; paired Wilcoxon's rank-sum test). The mean tumor/normal activity ratio was 2.37. Among prognostic factors, the nuclear grade, evaluated according to Schnitt et al., was found to be correlated with the activity ratio. Our results suggest a role for phospholipase D in human breast tumors. An elevation in phospholipase D activity is useful as a potential marker for malignant disease in the breast.
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PMID:Increased phospholipase D activity in human breast cancer. 920 Dec 51

This review focuses on two phospholipase activities involved in eukaryotic signal transduction. The action of the phosphatidylinositol-specific phospholipase C enzymes produces two well-characterized second messengers, inositol 1,4,5-trisphosphate and diacylglycerol. This discussion emphasizes recent advances in elucidation of the mechanisms of regulation and catalysis of the various isoforms of these enzymes. These are especially related to structural information now available for a phospholipase C delta isozyme. Phospholipase D hydrolyzes phospholipids to produce phosphatidic acid and the respective head group. A perspective of selected past studies is related to emerging molecular characterization of purified and cloned phospholipases D. Evidence for various stimulatory agents (two small G protein families, protein kinase C, and phosphoinositides) suggests complex regulatory mechanisms, and some studies suggest a role for this enzyme activity in intracellular membrane traffic.
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PMID:Regulation of eukaryotic phosphatidylinositol-specific phospholipase C and phospholipase D. 924 15

Phospholipase D (PLD) activity in human embryonic kidney (HEK) cells is stimulated by phorbol-ester-activated protein kinase C (PKC) and by membrane receptors, the latter apparently acting via the GTP-binding proteins, ADP-ribosylation factor (ARF) and Rho. In the present study, performed in cell-free preparations, we have characterized and compared the regulation of HEK cell PLD activity by the stable GTP analogue, guanosine 5'-O-[gamma-thio]triphosphate (GTP[S]), and the phorbol ester, phorbol 12-myristate 13-acetate (PMA). In digitonin-permeabilized HEK cells, prelabeled with [3H]oleic acid, GTP[S] and PMA caused an approximately threefold concentration-dependent increase in the formation of [3H]phosphatidylethanol, measured in the presence of ethanol. Neomycin, which is known to complex with the PLD cofactor, phosphatidylinositol 4,5-bisphosphate, decreased basal and GTP[S]- or PMA-stimulated PLD activities with similar sensitivity. GDP and its analogue, guanosine 5'-O-[beta-thio]diphosphate, inhibited the stimulatory effect of GTP[S], whereas the PMA response was prevented by the nonselective PKC inhibitor, staurosporine, but not vice versa. PLD stimulation by GTP[S], but not by PMA, was markedly reduced upon cytosol depletion and reconstituted by purified recombinant ARF1. In HEK cell membranes, addition of purified recombinant ARNO, a guanine-nucleotide-exchange factor for ARF1. potentiated the GTP[S]-stimulated PLD activity. PLD stimulation by PMA in HEK cell membranes required MgATP and was largely prevented by the selective PKC inhibitors Goe 6976 and bisindolylmaleimide I. Immunoblot analysis demonstrated that both conventional PKC (alpha, beta, gamma) and atypical PKC isozymes (zeta, tau) were present in HEK cell membranes. The results indicate that phorbol ester stimulation of PLD activity in HEK cells apparently occurs by a phosphorylation-dependent mechanism involving membrane-associated PKC isozymes but not ARF proteins, the major targets of GTP[S]' action.
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PMID:Characteristics of protein-kinase-C- and ADP-ribosylation-factor-stimulated phospholipase D activities in human embryonic kidney cells. 934 96


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