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)

Several lines of evidence implicate a regulatory tyrosine phosphorylation in the activation of phospholipase C (PLC) by the T cell antigen receptor (TCR). These include studies using inhibitors of protein tyrosine kinases (PTKs). In Jurkat T cells expressing the heterologous human muscarinic receptor (HM1), PLC activity can be induced by either the TCR or HM1. HM1 activates PLC via a guanine nucleotide binding protein. We have studied the selectivity of the effects of the PTK inhibitors, herbimycin A and genistein, in this system. The results indicate that these inhibitors have different mechanisms of action, and suggest that herbimycin A, but not genistein, is a specific inhibitor of PTKs in T cells. Herbimycin A markedly inhibited both the resting and induced levels of phosphotyrosine-containing proteins, including the gamma 1 isozyme of PLC and the zeta chain of the TCR, and prevented activation of PLC by anti-TCR mAb. Herbimycin A did not inhibit activation of PLC by HM1. Genistein had a much less pronounced effect than herbimycin A on the appearance of tyrosine phosphoproteins. Moreover, genistein inhibited activation of PLC by both the TCR and HM1, and inhibition was only partial. Genistein was cytotoxic and markedly inhibited protein synthesis in both Jurkat cells and human peripheral lymphocytes. Herbimycin A was not cytotoxic. These findings confirm the role of a regulatory tyrosine phosphorylation in activation of PLC by the TCR. Herbimycin A was a selective inhibitor of a subclass of PTKs in Jurkat cells. In contrast, inhibition of signal transduction and later events in T cells by genistein may be due to effects other than direct inhibition of PTK activity.
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PMID:The protein tyrosine kinase inhibitor herbimycin A, but not genistein, specifically inhibits signal transduction by the T cell antigen receptor. 147 73

The effects of the expression of the protein tyrosine kinase pp60v-src on endothelin- and thrombin-stimulated inositol 1,4,5-trisphosphate (Ins(1,4,5)P3) production and calcium responses were investigated in Rat-1 fibroblasts. The ability of endothelin-1 to induce the accumulation of these second messengers was dramatically amplified by v-src transformation, with 6- and 3-fold enhancements of the peak Ins(1,4,5)P3 and peak calcium responses, respectively. In contrast, thrombin-dependent responses were slightly reduced following v-src transformation, demonstrating that the augmentation of endothelin-stimulated signal transduction is a selective effect. The magnitude of the stimulated accumulation of Ins(1,4,5)P3 presumably depends upon both the functional activation of phospholipase C to produce Ins(1,4,5)P3, and the activity of the enzymes that metabolize Ins(1,4,5)P3. Although the metabolism of Ins(1,4,5)P3 was strikingly altered by expression of pp60v-src, with a bias towards the production of higher inositol polyphosphates that is consistent with an activated Ins(1,4,5)P3 3-kinase, this change could not account for the marked increase in endothelin-stimulated signaling induced by v-src transformation. This suggests that an effect of pp60v-src is expressed at the level of the plasma membrane, through an interaction with one or more components in the receptor/guanine nucleotide binding protein (G protein)/phospholipase C system that transduces the endothelin signal into Ins(1,4,5)P3 production. Preparation of membranes from normal and v-src-transformed cells showed that, while there was no change in the number of high-affinity endothelin binding sites, the release of Ins(1,4,5)P3 in response to guanine nucleotides and endothelin-1 was significantly increased following v-src transformation. In contrast, the Ins(1,4,5)P3 responses to thrombin and high Ca2+ concentrations were unaffected by transformation. Thus the selective interactions within the G protein system that couples the endothelin receptor to phospholipase C are potential sites at which the v-src transformation process may act to amplify endothelin-dependent Ins(1,4,5)P3 production.
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PMID:Selective amplification of endothelin-stimulated inositol 1,4,5-trisphosphate and calcium signaling by v-src transformation of rat-1 fibroblasts. 155 85

The effect of bradykinin on the activation production of inositol 1,4,5-trisphosphate and prostaglandin E2 (PGE2) was examined in the murine osteoblastic cell line, MC3T3-E1. Bradykinin, at concentrations ranging from 1 to 1000 nM, stimulated the production of inositol 1,4,5-trisphosphate 2.5- to 3-fold within 10 s, and elevated cytosolic-free Ca2+, even in the absence of external Ca2+. This process is mediated through the activation of phospholipase C. Bradykinin at the same concentration also stimulated the production of PGE2 and caused a release of 3H radioactivity from the cells prelabeled with [3H]arachidonic acid, probably via the activation of phospholipase A2. Pretreatment of the cells with pertussis toxin inhibited the stimulation of PGE2 production and 3H radioactivity release, while the elevation in cytosolic Ca2+ and the production of inositol 1,4,5-trisphosphate were not altered by toxin-pretreatment. The addition of an unhydrolyzable analog of GTP, guanosine 5'-[gamma-thio]triphosphate (GTP gamma S) to the beta-escin-permeabilized cells prelabeled with [3H]arachidonic acid enhanced the release of 3H radioactivity. The simultaneous presence of bradykinin with GTP gamma S further activated the 3H radioactivity release in the beta-escin-permeabilized cells. These results provide evidence that receptors for bradykinin in the MC3T3-E1 couple stimulating arachidonate release, probably via the activation of phospholipase A2, through a guanine nucleotide binding protein sensitive to pertussis toxin.
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PMID:Evidence for coupling of bradykinin receptors to a guanine-nucleotide binding protein to stimulate arachidonate liberation in the osteoblast-like cell line, MC3T3-E1. 165 14

In a variety of cells and tissues, platelet activating factor (PAF) stimulates phospholipase C catalyzed breakdown of phosphoinositides. This results in the generation of the second messengers, inositol trisphosphate and diglyceride. This process occurs independently of extracellular Ca2+. A number of PAF structural analogues, receptor antagonists and drugs have been utilized to pharmacologically probe the activation of phospholipase C. PAF stimulation of the phosphoinositide turnover was shown to be sensitive to pertussis toxin in some systems, but not in others. The involvement of guanine nucleotide binding protein(s) and tyrosine kinase(s) in this process have also been postulated. These developments give new insights into PAF-receptor function at the molecular level, and also provide leads towards a better understanding of the cellular responses to PAF.
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PMID:Inositol phospholipid turnover in PAF transmembrane signalling. 166 2

Stimulation of the T-cell antigen receptor (TCR), which itself is not a protein-tyrosine kinase (PTK), activates a PTK and phospholipase C (PLC). Using the human T-cell leukemic line Jurkat and normal peripheral blood lymphocytes, we demonstrate that stimulation of the TCR specifically induces the recovery of PLC activity in eluates from anti-phosphotyrosine immunoprecipitates. Stimulation of the human muscarinic receptor, subtype 1, when expressed in Jurkat activates PLC through a guanine nucleotide binding protein but does not induce the recovery of PLC activity in eluates from anti-phosphotyrosine immunoprecipitates. Western blot analysis reveals that PLC-gamma 1 is tyrosine-phosphorylated in response to TCR stimulation. Nearly all of the PLC activity recovered in eluates from anti-phosphotyrosine immunoprecipitates was depleted by anti-PLC-gamma 1 antibodies. Stimulation of the TCR on mutants derived from Jurkat that are defective in TCR-induced PLC activation results in markedly reduced, if any, PLC activity recovered in phosphotyrosine immunoprecipitates and in no detectable PLC-gamma 1 tyrosine phosphorylation. Thus, the TCR functions like PTK growth factor receptors, but through an indirect interaction, to induce tyrosine phosphorylation of PLC-gamma 1. Since other studies have implicated two members of the src family of PTKs in TCR-mediated signal transduction, our findings suggest that the induction of tyrosine phosphorylation of PLC-gamma 1 by a mechanism involving a src-like kinase may be the means by which the TCR regulates PLC activity in T cells.
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PMID:Functional activation of the T-cell antigen receptor induces tyrosine phosphorylation of phospholipase C-gamma 1. 171 1

The blood coagulation factor, human thrombin has been shown to have chemotactic and mitogenic effects on mononuclear phagocytic inflammatory cells. In the present study, we have used the U937 human monocytic cell line to explore the signal transduction mechanisms utilised by thrombin in these cells. In U937 cells differentiated into a macrophage-like phenotype, thrombin stimulated the formation of inositol trisphosphate (IP3) and the mobilisation of intracellular Ca2+ [( Ca2+]i) via a mechanism which was partially sensitive to pertussis toxin. Thrombin failed, however, to evoke thromboxane (Tx) B2 synthesis in the differentiated cells. In contrast, the chemotactic peptide N-formyl-L-methionylleucyl-L-phenylalanine (FMLP) stimulated TxB2 synthesis under conditions where it evoked increases in IP3 formation and [Ca2+]i mobilisation, via a pertussis toxin-sensitive mechanism, comparable in extent to those mediated by thrombin. Thrombin also failed to cause inhibitory guanine nucleotide binding protein (Gi)-mediated inhibition of adenylate cyclase activity in U937 cell membranes. These results indicate that U937 cells express receptors for thrombin which are in part coupled via a pertussis toxin-sensitive guanine nucleotide binding protein to phospholipase C activation, the formation of IP3 and the mobilisation of [Ca2+]i. However, the failure of thrombin to stimulate TxB2 synthesis or cause Gi-mediated inhibition of adenylate cyclase in U937 cells contrasts with its effects in human platelets and other thrombin-responsive cells. These results suggest that the thrombin receptor or receptor-effector coupling mechanism(s) in mononuclear cells is functionally distinct from the thrombin receptor or receptor-effector coupling mechanism(s) present in other thrombin-responsive cells.
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PMID:Thrombin signalling in U937 human monocytic cells is coupled to inositol phosphate formation but not to thromboxane B2 synthesis nor to inhibition of adenylate cyclase: distinct differences in thrombin signalling between U937 cells and platelets. 180 Jan 26

The influence of acute and chronic ethanol exposures on the coupling of neurotensin and bradykinin receptors to phospholipase C was determined in intact N1E-115 cells. Phospholipase C was monitored by the formation of total [3H]inositol phosphates in the presence of lithium in cells prelabeled with [3H]inositol. Acute exposure to ethanol over a range of 50 to 200 mM inhibited the stimulation of [3H]inositol phosphate formation elicited by neurotensin and bradykinin. In cells chronically exposed to 100 mM ethanol for 7 days, neither basal- nor neurotensin-stimulated [3H]inositol phosphate formation differed significantly from those of control (untreated) cells. In contrast, the [3H]inositol response to bradykinin was significantly inhibited in cells chronically exposed to ethanol. Because chronic ethanol exposure had no parallel effects on either the specific binding of [3H]bradykinin or the stimulation of [3H]inositol phosphate formation by the stable GTP analog, guanine 5'-(y-thiotriphosphate), it is suggested that chronic ethanol impairs the ability of bradykinin receptors to activate the guanine nucleotide binding protein associated with phospholipase C. In addition, because chronic ethanol had no effect on the inositol phosphate response to neurotensin, it is proposed that certain types of receptor-guanine nucleotide binding protein interactions are more vulnerable than are others to disruption by chronic ethanol treatment.
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PMID:Selective effects of acute and chronic ethanol exposure on neuropeptide and guanine nucleotide stimulated phospholipase C activity in intact N1E-115 neuroblastoma. 190 59

The potential for cross-talk between the adenyl cyclase and phosphoinositide (PPI) lipid second messenger system was investigated in astrocytes cultured from neonatal rat brain. Glutamate-stimulated PPI turnover, measured by the formation of total inositol phosphates from myo-[3H]inositol-labeled lipids, was inhibited in a concentration-dependent manner by the elevation of intracellular cyclic AMP levels produced either by stimulation of the isoproterenol receptor linked to adenyl cyclase or by its direct activation by forskolin. N6,2'-O-Dibutyryl cyclic AMP, an analogue that can also activate cyclic AMP-dependent kinase, inhibited glutamate-stimulated PPI turnover in a concentration-dependent manner as well, a result suggesting that cyclic AMP-dependent kinase is involved in mediating the inhibition. Inclusion of an inhibitor of cyclic AMP-dependent kinase, 1-(5-isoquinolinesulfonyl)-2 methylpiperazine dihydrochloride or N-(2-guanidinoethyl)-5-isoquinolinesulfonamide hydrochloride, blocked the cyclic AMP-mediated inhibition in a concentration-dependent manner, a finding further supporting this hypothesis. The site of inhibition of the phosphoinositol lipid pathway by cyclic AMP was probed using a digitonin-permeabilized cell system. Guanosine 5'-O-(3-thiotriphosphate), a nonhydrolyzable analogue of GTP, stimulated PPI turnover and potentiated glutamate-stimulated PPI turnover, and guanosine 5'-O-(3-thiodiphosphate) inhibited glutamate-stimulated PPI turnover in these cells, results providing evidence that glutamate receptors are coupled to phospholipase C by a guanine nucleotide binding protein in astrocytes.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Glutamate-stimulated, guanine nucleotide-mediated phosphoinositide turnover in astrocytes is inhibited by cyclic AMP. 197 58

Cholera toxin (CT) inhibited the in vitro growth of three of four human small-cell lung carcinoma (SCLC) cell lines with a 50% inhibitory concentration of 27-242 ng/ml. Loss of surface membrane ruffling and the capacity of [Tyr4]-bombesin, vasopressin, and fetal calf serum to stimulate increases in intracellular free calcium clearly preceded effects on cellular metabolic activity and cell growth. 125I-[Tyr4]-bombesin binding was unaffected by CT treatment but [Tyr4]-bombesin stimulated phospholipase C activity was decreased in membranes from CT-treated SCLC cells. CT stimulated a rapid but transient increase in intracellular cyclic AMP ([cAMP]i) in SCLC. The effects of CT on susceptible SCLC were not reproduced by elevations of [cAMP]i induced by forskolin or cyclic AMP analogues. GM1 ganglioside, the cellular binding site for CT, was highly expressed in the CT-sensitive but not the CT-resistant SCLC cell lines. In contrast, expression of guanine nucleotide binding protein substrates for ADP-ribosylation by CT was similar. These data demonstrate the existence of a CT-sensitive growth inhibitory pathway in SCLC-bearing GM1 ganglioside. Addition of CT results in decreased responsiveness to several mitogenic stimuli. These results suggest novel therapeutic approaches to human SCLC.
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PMID:Cholera toxin inhibits signal transduction by several mitogens and the in vitro growth of human small-cell lung cancer. 217 11

Membranes prepared from clone D1 of Madin-Darby canine kidney (MDCK) cells contain activity that can be attributed to Gp, a guanine nucleotide binding protein linked to phosphatidylinositol 4,5-bisphosphate dependent phospholipase C. Polyphosphoinositides are produced by addition of GTP, nonhydrolyzable GTP analogs, or fluoroaluminate. This production is inhibited by guanosine 5'-(beta-thiodiphosphate). While Ca2+ at 1 microM or more can generate high yields of inositol phosphates, guanine nucleotide activation of Gp can potentiate this Ca2(+)-dependent yield at resting levels of the cation. Membranes from cells expressing large amounts of ras-p21 exhibit small differences in guanine nucleotide induced polyphosphoinositide quantities. The greatest difference between normal and ras membranes was seen with AlF4- incubation. Of the three inositol phosphates measured, only the inositol bisphosphate yield was greatly increased in ras membranes compared with membranes from both parental and the D-1 clone of MDCK cells. From these data, we conclude that the presence of ras-p21 may affect production of polyphosphoinositides in MDCK cell membranes by some means other than direct participation in phospholipase C activation.
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PMID:G-protein linked polyphosphoinositide phospholipase C activity in cell membranes from clonally derived and ras-transformed Madin-Darby canine kidney cells. 217


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