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)

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

NIH 3T3 cells stably transfected with the gene encoding phosphatidylcholine-hydrolyzing phospholipase C (PC-PLC) from Bacillus cereus display a chronic elevation of intracellular diacylglycerol levels and a transformed phenotype. We have used such PC-PLC-transformed cells to evaluate the roles of the cytoplasmic serine/threonine kinases Raf-1, zeta protein kinase C (zeta PKC) and protein kinase A (PKA) in oncogenesis and mitogenic signal transduction elicited by phosphatidylcholine hydrolysis. We demonstrate here that stable expression of dominant negative mutants of both zeta PKC and Raf-1 lead to reversion of PC-PLC-transformed cells. Interestingly, expression of kinase defective zeta PKC also reverted NIH 3T3 cells transformed by the v-Ha-ras oncogene. Activation of PKA in response to elevation of cAMP levels also lead to reversion of PC-PLC-induced transformation, implicating PKA as a negative regulator acting downstream of PC-PLC. On the other hand, inhibition or depletion of phorbol ester responsive PKCs attenuated but did not block the ability of PC-PLC-transformed cells to induce DNA synthesis in the absence of growth factors. These results clearly implicate both Raf-1 and zeta PKC as necessary downstream components for transduction of the mitogenic/oncogenic signal generated by PLC-mediated hydrolysis of phosphatidylcholine and suggest, together with other recent evidence, a bifurcation in the signaling pathway downstream of PC-PLC.
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PMID:Evidence for a bifurcation of the mitogenic signaling pathway activated by Ras and phosphatidylcholine-hydrolyzing phospholipase C. 767 65

The transforming protein of simian sarcoma virus is homologous to the platelet-derived growth factor (PDGF) B-chain. Fibroblasts transformed with simian sarcoma virus constitutively produce a growth factor that stimulates the endogenous tyrosine kinase of PDGF receptors in an autocrine manner. Autophosphorylation of PDGF receptors upon ligand stimulation provides binding sites for Src homology 2 domains of intracellular signaling molecules, which thereby become activated. We have characterized the PDGF receptor-mediated signal transduction in NIH 3T3 cells transformed with a PDGF B-chain cDNA (Sis 3T3 cells) in the absence and presence of suramin, a polyanionic compound that quenches PDGF-induced mitogenicity and reverts the transformed phenotype of the Sis 3T3 cells. Our data show that in the presence of suramin the general level of tyrosine phosphorylation was decreased. Nevertheless, autophosphorylated receptors complexed with substrates persisted in the cells. Suramin had no effect on activation of phosphatidylinositol 3'-kinase or on tyrosine phosphorylation of phospholipase C-gamma and GTPase-activating protein of Ras. On the other hand, kinase activation of Src and Raf-1, phosphorylation of protein-tyrosine phosphatase 1D/Syp and Shc, and complex formation with Grb2 were greatly diminished by suramin. A possible explanation for our findings is that different PDGF receptor-coupled signaling pathways are active in different structural or functional compartments in the cell. Those pathways that are not affected by suramin might elicit distinct cellular responses, which are not sufficient for growth and transformation.
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PMID:Compartmentalization of autocrine signal transduction pathways in Sis-transformed NIH 3T3 cells. 773 Mar 19

Mitogen-activated protein kinases (MAPKs) are activated upon a variety of extracellular stimuli in different cells. In macrophages, colony-stimulating factor 1 (CSF-1) stimulates proliferation, while bacterial lipopolysaccharide (LPS) inhibits cell growth and causes differentiation and activation. Both CSF-1 and LPS rapidly activate the MAPK network and induce the phosphorylation of two distinct ternary complex factors (TCFs), TCF/Elk and TCF/SAP. CSF-1, but not LPS, stimulated the formation of p21ras. GTP complexes. Expression of a dominant negative ras mutant reduced, but did not abolish, CSF-1-mediated stimulation of MEK and MAPK. In contrast, activation of the MEK kinase Raf-1 was Ras independent. Treatment with the phosphatidylcholine-specific phospholipase C inhibitor D609 suppressed LPS-mediated, but not CSF-1-mediated, activation of Raf-1, MEK, and MAPK. Similarly, down-regulation or inhibition of protein kinase C blocked MEK and MAPK induction by LPS but not that by CSF-1. Phorbol 12-myristate 13-acetate pretreatment led to the sustained activation of the Raf-1 kinase but not that of MEK and MAPK. Thus, activated Raf-1 alone does not support MEK/MAPK activation in macrophages. Phosphorylation of TCF/Elk but not that of TCF/SAP was blocked by all treatments that interfered with MAPK activation, implying that TCF/SAP was targeted by a MAPK-independent pathway. Therefore, CSF-1 and LPS target the MAPK network by two alternative pathways, both of which induce Raf-1 activation. The mitogenic pathway depends on Ras activity, while the differentiation signal relies on protein kinase C and phosphatidylcholine-specific phospholipase C activation.
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PMID:Ras-dependent and -independent pathways target the mitogen-activated protein kinase network in macrophages. 779 56

CONTENTS. T-cell activation--Structure of the T-cell antigen receptor--Modular organisation of the T-cell antigen receptor--T-cell antigen receptor-coupled signaling pathways: Activation of protein-tyrosine kinase by the T-cell antigen receptor; Signal transduction in lymphoid cells involves several protein-tyrosine kinases in parallel; Regulation of T-cell antigen receptor signaling by the phosphoprotein phosphatase CD45--Consequences of T-cell antigen receptor-induced tyrosine phosphorylation: Activation of phosphoinositol-lipid-turnover pathways--Activation of phospholipase C-gamma-1: p59fyn or p56lck?--G-protein motif of CD3-gamma: relevance for signal transduction--Association of lipid kinase with the T-cell antigen receptor--Intracellular signaling by phospholipid metabolites and calcium: activation of protein kinase C--Protein kinase C isoenzymes--Heterogenity of protein kinase C and mode of activation--Phospholipid-derived mediators in activation of protein kinase C in T-cells--Role of phospholipase D metabolites in activation of protein kinase C--Polyunsaturated fatty acids and lysophosphatidylcholine as activators of protein kinase C--Potein kinase C and p21ras function in interdependent and distinct signaling pathways during T-cell activation--Raf-1 kinase: regulator or target of protein kinase C?--Summary and perspectives.
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PMID:T-cell antigen receptor-induced signal-transduction pathways--activation and function of protein kinases C in T lymphocytes. 788 88

The serine-threonine protein kinase Raf-1 is an important signal transducer in mitogenesis, phosphorylating and activating mitogen-activated protein (MAP) kinase kinase. Raf-1 activation in vivo is dependent on Ras, but the mechanism of Raf activation is unknown. The ability of preparations of plasma membranes to activate exogenous (His)6-Raf-1 was studied. Plasma membranes of v-Ras-transformed NIH 3T3 cells, but not parental cells, enhanced MAP kinase kinase kinase (MAPKKK) activity dependent on addition of (His)6-Raf-1 and ATP/Mg. Treatment of membranes with concentrations of Bacillus cereus phosphatidylcholine-specific phospholipase C that activated Raf-1 in vivo failed to enhance MAPKKK activity in vitro. Activation of (His)6-Raf-1 in vitro by membranes was dependent on binding to Ras. Membranes from v-Src-transformed cells also activated (His)6-Raf-1 and synergized with v-Ras membranes. Serum-treatment of NIH 3T3 cells stimulated the ability of membranes to activate (His)6-Raf-1. Activated (His)6-Raf-1 could be recovered on Ni(2+)-agarose, and this methodology was used to demonstrate that activation by membranes was ATP dependent. These findings demonstrate Ras- and ATP-dependent step(s) for Raf-1 activation by plasma membranes in vitro.
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PMID:Activation of (His)6-Raf-1 in vitro by partially purified plasma membranes from v-Ras-transformed and serum-stimulated fibroblasts. 793 2

Expression of the GTPase-deficient G alpha 16 polypeptide G alpha 16Q212L, a member of the Gq family of heterotrimeric G proteins, constitutively activated phospholipase C beta activity in Swiss 3T3 cells. Expression of G alpha 16Q212L appears to persistently stimulte a low level of protein kinase C activity which also increases protein kinase A activity in Swiss 3T3 cells. Growth of G alpha 16Q212L expressing cells was significantly inhibited relative to wild-type Swiss 3T3 cells. Bombesin-stimulated DNA synthesis was completely inhibited in G alpha 16Q212L expressing clones, whereas the growth responses to platelet-derived growth factor (PDGF) and serum were inhibited 50-80% relative to wild-type cells. In addition to the inhibition of cell growth, G alpha 16Q212L expression significantly inhibited the stimulation of protein kinase C, Raf-1, MEK, mitogen-activated protein kinase, phospholipase A2 activity, and Ca2+ mobilization in response to PDGF. In contrast, PDGF receptor activation of phospholipase C gamma, phosphatidylinositol 3-kinase, and Ras GTP loading was similar in wild-type and G alpha 16Q212L expressing clones. PDGF regulation of membrane ruffling and actin fiber assembly, responses mediated in part by phosphatidylinositol 3-kinase, were unaffected in G alpha 16Q212L expressing clones. The growth inhibitory action of G alpha 16Q212L expression in Swiss 3T3 cells is downstream of the initial SH2 domain-encoded signal transduction proteins regulated in response to PDGF receptor autophosphorylation. The findings demonstrate that constitutively activated G alpha 16Q212L persistently activates phospholipase C activity and effectively inhibits a subset of cytoplasmic signal transduction pathways involved in growth factor tyrosine kinase receptor stimulation of cell growth. G16/Gq-regulated signal transduction can acutely stimulate specific response pathways involved in mitogenesis; but persistent activation of G16/Gq-regulated effectors, including phospholipase C beta, inhibit tyrosine kinase-initiated mitogenesis. One role for G16/Gq response systems may be to modulate growth factor receptor signaling.
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PMID:Expression of GTPase-deficient G alpha 16 inhibits Swiss 3T3 cell growth. 802 Dec 43

Chemoattractants bind to seven transmembrane-spanning, G-protein-linked receptors on polymorphonuclear leukocytes (neutrophils) and induce a variety of functional responses, including activation of microtubule-associated protein (MAP) kinase. Although the pathways by which MAP kinases are activated in neutrophils are unknown, we hypothesized that activation of the Ras/Raf pathway leading to activation of MAP/ERK kinase (MEK) would be induced by the chemoattractant f-met-leu-phe. Human neutrophils exposed to 10 nM FMLP for 30 s exhibited an MAP kinase kinase activity coeluting with MEK-1. Immunoprecipitation of Raf-1 kinase after stimulation with FMLP revealed an activity that phosphorylated MEK, was detectable at 30 s, and peaked at 2-3 min. Immunoprecipitation of Ras from both intact neutrophils labeled with [32P]orthophosphate and electropermeabilized neutrophils incubated with [32P]GTP was used to determine that FMLP treatment was associated with activation of Ras. Activation of both Ras and Raf was inhibited by treatment of neutrophils with pertussis toxin, indicating predominant linkage to the Gi2 protein. Although phorbol esters activated Raf, activation induced by FMLP appeared independent of protein kinase C, further suggesting that Gi2 was linked to Ras and Raf independent of phospholipase C and protein kinase C. Dibutyryl cAMP, which inhibits many neutrophil functional responses, blocked the activation of Raf by FMLP, suggesting that interruption of the Raf/MAP kinase pathway influences neutrophil responses to chemoattractants. These data suggest that Gi2-mediated receptor regulation of the Ras/Raf/MAP kinase pathway is a primary response to chemoattractants.
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PMID:FMLP activates Ras and Raf in human neutrophils. Potential role in activation of MAP kinase. 804 Feb 99

PDGF heterodimer of A and B chains, a complete mitogen for 3T3 mouse fibroblasts, exemplifies those growth factors interacting with membrane associated tyrosine kinase receptors. Its binding to the PDGF-receptors results in receptor dimerization and subsequent activation of tyrosine kinase activity in the cytoplasmic protein domain, autophosphorylation of the receptor being the first event in the transduction cascade. Before the ligand-receptor complex is internalized and degraded, receptor stimulation is transmitted to the general transduction network, in which several tyrosine kinase substrates are activated by phosphorylation and changes the cytoplasmic biochemistry. These changes include cytoplasmic alkalinization, increases in the intracellular concentration of cyclic-AMP and Ca2+ and activation of protein kinase C through the degradation of phosphoinositides. The known substrates recruited by the PDGF-receptor association are phosphatidylinositol-3'-kinase, ras-GTPase-activating protein, phospholipase C-gamma, serine-threonine kinase Raf-1 and src and src-related tyrosine kinases. Upon binding of PDGF to its receptor, transactivation of transcriptional and nuclear factors such as c-fos and c-myc genes and dephosphorylation of c-jun occurs, V-sis, the oncogen of the simian sarcoma virus (SSV), is highly homologous to the c-sis/PDGF-B gene that encodes the homodimer of the B-chain of the PDGF receptor. Cells transformed by SSV have been studied as a model system for the autocrine stimulation of the PDGF receptor.
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PMID:Platelet derived growth factor/tyrosine kinase receptor mediated proliferation. 822 Jan 10

We have investigated the relationship between hydrolysis of phosphatidylcholine (PC) and activation of the Raf-1 protein kinase in Ras-mediated transduction of mitogenic signals. As previously reported, cotransfection of a PC-specific phospholipase C (PC-PLC) expression plasmid bypassed the block to cell proliferation resulting from expression of the dominant inhibitory mutant Ras N-17. In contrast, PC-PLC failed to bypass the inhibitory effect of dominant negative Raf mutants, suggesting that PC-PLC functions downstream of Ras but upstream of Raf. Consistent with this hypothesis, treatment of quiescent cells with exogenous PC-PLC induced Raf activation, even when normal Ras function was blocked by Ras N-17 expression. Further, activation of Raf in response to mitogenic growth factors was blocked by inhibition of endogenous PC-PLC. Taken together, these results indicate that hydrolysis of PC mediates Raf activation in response to mitogenic growth factors.
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PMID:Hydrolysis of phosphatidylcholine couples Ras to activation of Raf protein kinase during mitogenic signal transduction. 824 81


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