Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.4.3 (phospholipase C)
18,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Platelets stimulate tissue factor, the initiator of the extrinsic coagulation pathway, and increase fibrinolytic inhibition in fibroblasts grown in vitro. Cellular tissue factor increases an average of 2.8-fold over the control levels after a 6-hr incubation with platelets, and no activity is present in the media. Fibrinolytic inhibition is stimulated in both the fibroblasts and their media in the presence of platelets and accumulates throughout a 24-hr incubation. Neither leukocytes nor erythrocytes stimulate these changes. Both tissue factor and fibrinolytic inhibition increases are dependent on platelet concentration and are blocked by inhibitors of RNA or protein synthesis. Control smooth muscle cells have higher tissue factor and fibrinolytic inhibition than fibroblasts, but their response to the presence of platelets is similar. Confluent monolayers of endothelial cells have very low levels of tissue factor that are not altered by the presence of platelets. However, the ability of endothelial cells to inhibit fibrinolysis is enhanced by the presence of platelets. The fraction that stimulates tissue factor and fibrinolytic inhibition is distinct from platelet-derived growth factor and from the fraction that enhances leukocyte tissue factor. It is associated with an insoluble, nonmitogenic fraction that is not inactivated by phospholipase C, or diisopropylfluorophosphate, nor is it chloroform:methanol extractable. Platelets are a physiologic modulator for both cellular tissue factor and the fibrinolytic system in vitro.
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PMID:Platelet effects on tissue factor and fibrinolytic inhibition of cultured human fibroblasts and vascular cells. 617 62

Addition of biologically active phorbol esters to intact quiescent 3T3 mouse cells stimulates an extremely rapid (detectable within seconds) phosphorylation of a Mr 80,000 cellular protein (termed "80k"). Phorbol 12,13-dibutyrate enhances 80k phosphorylation in a dose-dependent manner; half-maximal effect is obtained at 32 nM. The possibility that this phosphorylation is related to the activation of Ca2+-activated phospholipid-dependent protein kinase is suggested by the fact that phospholipid breakdown induced by exogenous treatment of the cells with phospholipase C from Clostridium perfringens or with platelet-derived growth factor, which is a potent activator of endogenous phospholipase C activity, also causes a rapid enhancement of 80k phosphorylation. Moreover, prolonged pretreatment of the cells with phorbol 12,13-dibutyrate, which leads to a marked decrease in the number of specific phorbol ester binding sites, prevents the phosphorylation of 80k stimulated by phorbol esters, phospholipase C, and platelet-derived growth factor. These findings provide evidence obtained with intact cells that implicate the stimulation of Ca2+-activated phospholipid-dependent protein kinase in the action of phorbol esters and other growth factors.
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PMID:Phorbol esters, phospholipase C, and growth factors rapidly stimulate the phosphorylation of a Mr 80,000 protein in intact quiescent 3T3 cells. 631 49

Sodium butyrate (SB), a naturally occurring short-chain fatty acid, was investigated for its therapeutic value as an antiproliferative agent for vascular smooth muscle cells (SMCs). At 5-mmol/L concentration, SB had no significant effect on rat SMC proliferation. However, at the same concentration, SB inhibited platelet-derived growth factor (PDGF)-AA-, -AB-, and -BB-induced proliferation of SMCs. Exposure of SMCs to PDGF-BB resulted in activation of receptor intrinsic tyrosine kinase activity and autophosphorylation of beta-PDGF-receptor (beta-PDGFR). The activated beta-PDGFR physically associated and phosphorylated signaling molecules such as ras-GTPase activating protein (GAP) and phospholipase C gamma (PLC gamma). SB, in the absence of PDGF-BB, caused neither beta-PDGFR tyrosine phosphorylation nor phosphorylation and association of GAP and PLC gamma with beta-PDGFR. PDGF-BB-enhanced activation of receptor intrinsic tyrosine kinase activity and autophosphorylation of tyrosine residues of beta-PDGFR were unaffected by SB irrespective of whether SMCs were preincubated with SB before exposure to PDGF-BB plus SB or incubated concomitantly with PDGF-BB plus SB. Likewise, phosphorylation and association of GAP and PLC gamma with PDGF-BB-activated beta-PDGFR were unaffected. In addition, SB did not block PDGF-BB-stimulated, PLC gamma-mediated production of inositol triphosphate. Similarly, PDGF-BB-induced beta-PDGFR degradation was unaffected when SMCs were exposed to PDGF-BB plus SB, and SB by itself had no influence on beta-PDGFR degradation. Unlike beta-PDGFR kinase activity, mitogen-activated protein kinase (MAP-kinase) activity was stimulated by SB by about 2.7-fold. Exposure of SMCs to PDGF-BB caused an approximately 11.4-fold increase in MAP-kinase activity and this increase in activity was not significantly affected when cells were coincubated with PDGF-BB and SB (10.3-fold). However, pretreatment of SMCs with SB for 30 minutes and subsequent incubation in PDGF-BB plus SB abolished most of the PDGF-BB-induced MAP-kinase activity (4.6-fold). Transcription of growth response genes such as c-fos, c-jun, and c-myc were induced by PDGF-BB, and their induction was suppressed, particularly c-myc, by incubating SMCs with PDGF-BB plus SB. Similarly, preincubation of cells with SB for 30 minutes and subsequent incubation in PDGF-BB plus SB diminished PDGF-BB-induced transcription of c-fos, c-jun, and c-myc. However, SB by itself had no significant effect on c-fos, c-jun, and c-myc transcription.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Sodium butyrate inhibits platelet-derived growth factor-induced proliferation of vascular smooth muscle cells. 748 53

We have previously reported that c-met protooncogene, a member of a new class of receptor tyrosine-kinase gene family, is transforming when overexpressed in NIH-3T3 cells. In this paper, we report that the c-met protooncogene-transformed cells proliferate in a serum- and growth factor-free medium and exhibit constitutive tyrosine phosphorylation of several cellular proteins including the met protooncogene-encoded p145 and p185. Further investigations revealed platelet-derived growth factor (PDGF)-independent phosphorylation of PDGF-beta receptors in the transformed cells. Phosphoamino acid analysis revealed phosphorylation of PDGF receptors at tyrosine and serine residues. The PDGF receptor phosphorylation is unlikely to occur via autocrine production of PDGF since we could not detect PDGF activity both at the RNA level and at a functional protein level. Additionally, phospholipase C-gamma (PLC-gamma) a substrate of activated PDGF receptors, was found to be physically associated with PDGF receptors in the absence of PDGF stimulation in transformed cells. Furthermore, PDGF receptors coimmunoprecipitated along with PLC-gamma. Taken together, our results demonstrate a PDGF-independent phosphorylation and activation of PDGF-beta receptor in NIH-3T3 cells transformed by c-met protooncogene.
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PMID:PDGF-independent activation of PDGF-beta receptors in NIH-3T3 cells transformed by c-met protooncogene. 751 39

Thrombin elicits multiple biological effects on a variety of cells. We have previously shown that thrombin is a potent mitogen for human glomerular mesangial cells. This mitogenic effect of thrombin is associated with activation of phospholipase C (PLC) and induction of platelet-derived growth factor (PDGF) gene expression. The thrombin receptor, which belongs to the guanine nucleotide binding protein (G protein)-coupled receptor family, has recently been shown to induce rapid tyrosine phosphorylation of cellular proteins. In the present study, we investigated the role of protein-tyrosine phosphorylation in mediating the cellular responses elicited by thrombin in human glomerular mesangial cells. Amino acid labeling followed by immunoprecipitation with phosphotyrosine antibodies demonstrate that thrombin stimulates tyrosine phosphorylation of a set of cellular proteins. Treatment of mesangial cells with thrombin followed by immunoblotting with phosphotyrosine antibodies showed three major bands of tyrosine-phosphorylated proteins approximately 130, 70, and 44-42 kDa. Phosphorylation of these proteins was inhibited by two tyrosine kinase inhibitors, herbimycin A and genistein. Both compounds inhibited DNA synthesis and PDGF B-chain gene expression but had no effect on inositol phosphates production or increases in cytosolic calcium in response to thrombin. These data demonstrate that protein-tyrosine phosphorylation is not required for thrombin-induced PLC activation with inositol phosphate formation and subsequent intracellular calcium release, but it is an absolute requirement for thrombin-induced DNA synthesis and PDGF B-chain gene expression.
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PMID:Mitogenic signaling of thrombin in mesangial cells: role of tyrosine phosphorylation. 752 56

Phosphorylated tyrosine residues in receptor tyrosine kinases serve as binding sites for signal transduction molecules. We have identified two autophosphorylation sites, Tyr-988 and Tyr-1018, in the platelet-derived growth factor (PDGF) alpha-receptor carboxyl-terminal tail, which are involved in binding of phospholipase C-gamma (PLC-gamma). The capacities of the Y988F and Y1018F mutant PDGF alpha-receptors, expressed in porcine aortic endothelial cells, to bind PLC-gamma are 60 and 5% of that of the wild-type receptor, respectively. Phosphorylated but not unphosphorylated peptides containing Tyr-1018 are able to compete with the intact receptor for binding to immobilized PLC-gamma SH2 domains; a phosphorylated Tyr-988 peptide competes 10 times less efficiently. The complex between PLC-gamma and the PDGF alpha-receptor is more stable than that of PLC-gamma and the PDGF beta-receptor. However, PDGF stimulation results in a smaller fraction of tyrosine-phosphorylated PLC-gamma and a smaller accumulation of inositol trisphosphate in cells expressing the alpha-receptor as compared with cells expressing the beta-receptor. We conclude that phosphorylated Tyr-988 and Tyr-1018 in the PDGF alpha-receptor carboxyl-terminal tail bind PLC-gamma, but this association leads to only a relatively low level of tyrosine phosphorylation and activation of PLC-gamma.
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PMID:Demonstration of functionally different interactions between phospholipase C-gamma and the two types of platelet-derived growth factor receptors. 753 78

Mitogenic stimulation of Swiss 3T3 fibroblasts with bombesin results in receptor-mediated activation of a complex array of effectors, including phospholipase C beta and mitogen-activated protein (MAP) kinase. Incubation of Swiss 3T3 fibroblasts with the 11-amino acid [D-Arg1,D-Phe5,D-Trp7,9,Leu11]substance P peptide inhibited bombesin-stimulated cell proliferation and phospholipase C beta activation even at high bombesin concentrations. The peptide did not inhibit the activation of phospholipase C beta by a GTPase-deficient form of the Gq-like protein, G16, indicating that the peptide does not inhibit phospholipase C beta and is acting at a point upstream of the activated form of the G protein alpha subunit. The peptide inhibited MAP kinase activation at low bombesin concentrations, but unlike phospholipase C beta, this inhibition could be overcome with 30 nM bombesin. In control Swiss 3T3 cells, bombesin did not measurably activate Ras or Raf-1 above basal levels. Following incubation of the cells with the [D-Arg1,D-Phe5,D-Trp7,9,Leu11]substance P peptide, 50 nM bombesin activated Raf-1 4-6-fold over basal levels. Platelet-derived growth factor-stimulated activities of PLC, Ras, Raf-1, and MAP kinase were unaltered after incubation of Swiss 3T3 cells with the [D-Arg1,D-Phe5,D-Trp7,9,Leu11]substance P peptide, as was platelet-derived growth factor-stimulated growth of the Swiss 3T3 cells. Thus, the peptide behaves as an antagonist that differentially inhibited phospholipase C beta and MAP kinase signal transduction pathways. The growth arrest observed with the peptide indicates that the bombesin-stimulated activation of MAP kinase is not sufficient to support mitogenesis in Swiss 3T3 cells.
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PMID:Differential modulation of bombesin-stimulated phospholipase C beta and mitogen-activated protein kinase activity by [D-Arg1,D-Phe5,D-Trp7,9,Leu11]substance P. 753 38

In rabbit aortic vascular smooth muscle cells (VSMC) platelet-derived growth factor BB (PDGF-BB) stimulated the tyrosine phosphorylation of phospholipase C-gamma, p120 GTPase-activating protein, and the p85 alpha subunit of phosphatidylinositol 3'-kinase only at high concentrations (5-25 ng/ml). In contrast, PDGF-BB induced a rapid and concentration-dependent increase in p125 focal adhesion kinase (p125FAK) tyrosine phosphorylation, which was half-maximal and maximum at 1 and 2.5 ng/ml, respectively. Saliently, stimulation of p125FAK tyrosine phosphorylation was sustained at up to 100 ng/ml PDGF-BB and for prolonged times of treatment. With similar concentration dependence, PDGF-BB stimulated the tyrosine phosphorylation of the 68-kDa focal adhesion-associated protein, paxillin. PDGF-BB also induced p125FAK and paxillin tyrosine phosphorylation in human aortic VSMC. PDGF-BB caused no detectable disruption of the actin cytoskeleton in VSMC. PDGF-BB stimulated rabbit VSMC migration with a very similar concentration dependence to that for p125FAK and paxillin tyrosine phosphorylation. PDGF-BB was equally effective in stimulating p125FAK and paxillin tyrosine phosphorylation under conditions similar to those used for cell migration. In Swiss 3T3 fibroblasts, PDGF-BB and -AA stimulated p125FAK tyrosine phosphorylation and cell migration only at low concentrations, and stimulation was abolished at 10-25 ng/ml. PDGF-AA failed to stimulate tyrosine phosphorylation, mitogenesis, and chemotaxis in rabbit VSMC, and immunoblot analysis showed that rabbit VSMC expressed PDGF beta-receptors but no alpha-receptors. These results implicate p125FAK in the chemotactic response to PDGF-BB and suggest that the ability of PDGF-BB to trigger the p125FAK pathway may be dependent both upon cell type and receptor isotype expression.
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PMID:Differential effects of platelet-derived growth factor BB on p125 focal adhesion kinase and paxillin tyrosine phosphorylation and on cell migration in rabbit aortic vascular smooth muscle cells and Swiss 3T3 fibroblasts. 753 14

When expressed in PC12 cells, the platelet-derived growth factor beta receptor (beta PDGF-R) mediates cell differentiation. Mutational analysis of the beta PDGF-R indicated that persistent receptor stimulation of the Ras/Raf/mitogen-activated protein (MAP) kinase pathway alone was insufficient to sustain PC12 cell differentiation. PDGF receptor activation of signal pathways involving p60c-src or the persistent regulation of phospholipase C gamma was required for PC12 cell differentiation. beta PDGF-R regulation of phosphatidylinositol 3-kinase, the GTPase-activating protein of Ras, and the tyrosine phosphatase, Syp, was not required for PC12 cell differentiation. In contrast to overexpression of oncoproteins involved in regulating the MAP kinase pathway, growth factor receptor-mediated differentiation of PC12 cells requires the integration of other signals with the Ras/Raf/MAP kinase pathway.
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PMID:Mitogen-activated protein kinase activation is insufficient for growth factor receptor-mediated PC12 cell differentiation. 754 Jul 18

Thrombin is a potent mitogen for mesangial cells and stimulates PDGF B-chain gene expression in these cells. It also activates phospholipase C (PLC) resulting in an increase in cytosolic Ca2+ and diacylglycerol (DAG) that are the physiological activators of protein kinase C (PKC). Immunoprecipitation of specific PKC isotypes from thrombin-stimulated mesangial cells with subsequent measurement of their enzymatic activity shows activation of Ca(2+)-dependent PKC alpha and Ca(2+)-independent PKC zeta in a time dependent manner. Optimum activation of both of these isozymes was obtained at 60 minutes. PKC alpha activity increased 83% over basal while activity of PKC zeta increased 104%. Prolonged exposure of mesangial cells to phorbol myristate acetic acid (PMA) inhibited the enzymatic activity of PKC alpha but not PKC zeta. This inhibition of PKC alpha had no effect on thrombin-induced DNA synthesis but abolished PDGF B-chain gene expression induced by thrombin. These data provide the first evidence that PKC alpha activation is necessary for thrombin-induced PDGF B-chain gene expression but not for thrombin-induced DNA synthesis.
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PMID:PKC alpha regulates thrombin-induced PDGF-B chain gene expression in mesangial cells. 758 54


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