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)

alpha-Thrombin, a G-protein-coupled receptor agonist, is mitogenic for neonatal vascular smooth muscle (VSM) cells, but it also causes secretion of the tyrosine kinase-coupled receptor agonist platelet-derived growth factor (PDGF). In order to determine the role of growth factors with tyrosine kinase-coupled receptors in thrombin's mitogenic signal transduction cascade, the synergistic effect of basic fibroblast growth factor (bFGF) in this system was examined. While bFGF itself is a growth factor for VSM cells, it causes a 1.7-fold synergistic effect when added together with thrombin. Herbimycin A, a specific tyrosine kinase inhibitor, both decreases thrombin-induced mitogenesis by greater than 90% and abolishes tyrosine phosphorylation of phospholipase C (PLC)-gamma-1. The magnitude and time course of the increase in intracellular free calcium concentration in response to thrombin is comparable in both the presence and absence of herbimycin A. These results provide evidence that herbimycin A specifically inhibits PLC-gamma-1 tyrosine phosphorylation without affecting VSM cell viability or calcium release. Furthermore, tyrosine phosphorylation is a necessary step in thrombin's mitogenic signal transduction cascade, but it is not essential for thrombin-induced release of calcium from intracellular stores. These data suggest that a tyrosine kinase, possibly supplied by the bFGF receptor, plays an essential role in thrombin-induced mitogenesis.
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PMID:Inhibition of tyrosine phosphorylation prevents thrombin-induced mitogenesis, but not intracellular free calcium release, in vascular smooth muscle cells. 154 34

Cross-linking the antigen receptor on B cells results in a rapid increase in protein tyrosine kinase activity as detected by increased phosphorylation on tyrosine residues of multiple proteins. Although the identity of most of this substrates remains unknown, some have been proposed. One possible substrate of the antigen receptor-associated kinase is phospholipase C (PLC). Since multiple isoforms of PLC have been identified, we have studied which isoforms are targets of the antigen receptor. PLC-gamma 1 and PLC-gamma 2 but not PLC-beta 1 or PLC-delta 1 were detected in human B cells. Immunoprecipitation with antibodies against PLC-gamma 1 or PLC-gamma 2 and subsequent Western blotting with anti-phosphotyrosine antibodies revealed that both PLC-gamma 1 and PLC-gamma 2 are tyrosine phosphorylated in stimulated but not in resting B cells. This was confirmed by experiments whereby B cell lysates were immunoprecipitated with anti-phosphotyrosine antibody and subsequently blotted with antibodies against PLC-gamma 1 or PLC-gamma 2. Further, the specific protein tyrosine kinase inhibitors, tyrphostins, which block phospholipase-C activation and proliferation of B cells also inhibited tyrosine phosphorylation on both PLC-gamma 1 and PLC-gamma 2. We conclude that both isoforms PLC-gamma 1 and PLC-gamma 2 are targets of the antigen receptor-associated protein tyrosine kinase.
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PMID:Phospholipase C-gamma 1 and phospholipase C-gamma 2 are substrates of the B cell antigen receptor associated protein tyrosine kinase. 155 May 50

The lipid mediator platelet-activating factor (1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine, AGEPC) has been shown to elicit several important biochemical signaling responses in mammalian cells, including polyphosphoinositide hydrolysis, arachidonic acid release/eicosanoid production, and protein tyrosine phosphorylation. In the present study, the roles of Ca2+ and protein kinase C (PKC), two signaling components of the phospholipase C pathway, in AGEPC-stimulated eicosanoid production and protein tyrosine phosphorylation, were investigated in cultured rat Kupffer cells. AGEPC at nanomolar concentrations induced an increase in intracellular calcium concentration ([Ca2+]i), stimulated membrane PKC activity, and resulted in protein tyrosine phosphorylation. The maximal increase in [Ca2+]i and membrane PKC activity in response to AGEPC were observed within 30-50 s, whereas the AGEPC-induced protein tyrosine phosphorylation reached maximal levels within 2-5 min. [Ethylenebis(oxyethylenenitrilo)]tetraacetic acid (EGTA) but not 8-(N,N-diethylamino)-octyl-3,4,5-trimethoxybenzoate hydrochloride (TMB-8), an inhibitor of calcium release from intracellular compartments, nearly abolished the AGEPC-induced increase in [Ca2+]i suggesting involvement of extracellular calcium influx in this event. Both EGTA and TMB-8 abolished or inhibited AGEPC-stimulated protein tyrosine phosphorylation and eicosanoid formation, respectively. The calcium ionophore A23187 alone stimulated eicosanoid production and protein tyrosine phosphorylation with an identical pattern to that of AGEPC. Phorbol myristate acetate (PMA), an activator of PKC, which did not affect [Ca2+]i, mimicked the actions of AGEPC, stimulating eicosanoid production and promoting tyrosine phosphorylation of a set of proteins similar to those phosphorylated following AGEPC stimulation. AGEPC-enhanced tyrosine phosphorylation of some of the protein substrates and eicosanoid production were inhibited in cells "down-regulated" for PKC. Furthermore, both PMA- and AGEPC-stimulated eicosanoid production and protein tyrosine phosphorylation were attenuated or abolished by at least one of the PKC inhibitors, staurosporine, and calphostin C. Taken together, these results are consistent with the conclusions that: (a) AGEPC stimulates the phospholipase-mediated arachidonic acid release/eicosanoid synthesis cascade and protein tyrosine phosphorylation through extracellular Ca(2+)-dependent and PKC-dependent and -independent mechanism(s) and (b) the Ca(2+)-PKC interaction determines the efficacy of the AGEPC-stimulated cellular events.
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PMID:Platelet-activating factor-stimulated protein tyrosine phosphorylation and eicosanoid synthesis in rat Kupffer cells. Evidence for calcium-dependent and protein kinase C-dependent and -independent pathways. 155 80

When membrane Ig (mIg) on the surface of B lymphocytes is cross-linked using anti-Ig antibodies, the enzyme phospholipase C (PLC) is activated to cleave inositol phospholipids. Tyrosine kinase inhibitors have been reported to inhibit this event. Therefore, we investigated the effect of cross-linking of mIg on the state of tyrosine phosphorylation of PLC activity in two murine B cell lines and in normal resting mouse B cells. Proteins from lysates of stimulated or unstimulated cells were immunoprecipitated with an antiphosphotyrosine antibody and subsequently assayed for PLC activity. Treatment of the B cell line WEHI-231 with anti-IgM led within 15 to 30 s to a 10- to 20-fold increase in tyrosine-phosphorylated PLC activity. Inositol trisphosphate generation by WEHI-231 cells stimulated under the same conditions demonstrated similar kinetics. Normal resting B cells treated with anti-IgM or anti-IgD demonstrated 2.5- and 4-fold increases, respectively, of tyrosine-phosphorylated PLC activity. To identify the isozyme of PLC that was phosphorylated, we immunoprecipitated PLC-gamma 1 or PLC-gamma 2 with specific antibodies and assessed the amount of tyrosine phosphorylation of these proteins by antiphosphotyrosine immunoblotting. Treatment of WEHI-231 or Bal17 cells with anti-IgM induced an increase in PLC-gamma 2 tyrosine phosphorylation over background levels. There was no detectable tyrosine phosphorylation of PLC-gamma 1 in treated or untreated WEHI-231 cells, whereas anti-IgM-treated Bal17 cells did exhibit low but detectable levels of tyrosine phosphorylation of PLC-gamma 1. In normal resting mouse B cells, there was no detectable PLC-gamma 1, but PLC-gamma 2 was abundant. These observations suggest that PLC-gamma 2 is a significant substrate for the mIg-activated protein tyrosine kinase and may be responsible for mediating mIg stimulation of inositol phospholipid hydrolysis in murine B cells.
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PMID:Tyrosine phosphorylation of phospholipase C-gamma 2 upon cross-linking of membrane Ig on murine B lymphocytes. 157 27

Chronic injections of epidermal growth factor (EGF) or the beta-adrenergic receptor agonist isoprenaline resulted in rat parotid gland hypertrophy and hyperplasia. Introduction of a polyclonal antibody to EGF or the EGF-receptor (EGF-R) caused a specific retardation of acinar cell proliferation when injected along with the growth factor. Meanwhile, only the antibody to EGF-R caused a dose-dependent retardation of proliferation on co-administration with isoprenaline both in vivo and in vitro. The antibody injected alone had no effect on cell growth. When cells were incubated in the presence of EGF, plasma membranes from isoprenaline-treated and control animals showed phosphorylation of the EGF-R tyrosine moieties and transient increases in membrane-associated phospholipase C gamma. Isoprenaline did not stimulate phosphorylation of the EGF-R in isolated plasma membranes. However, activation of the phosphotyrosine-signalling pathway could be duplicated by incubating isoprenaline-treated acinar cells, but not control cells, with bovine galactosyltransferase. Immunopurified EGF-R demonstrated variations in reactivity with two different lectins after treatment of the cells with the beta-agonist as well as increased galactosyltransferase substrate capacity in vitro. In addition, incubation of intact acinar cells and isolated plasma-membrane fractions from isoprenaline-treated rats with UDP-[14C]galactose resulted in an increased incorporation of label into the EGF-R. The results suggest that the carbohydrate moiety of the EGF-R has been altered in isoprenaline-treated animals allowing galactosyltransferase now to recognize this receptor. This interaction may in part mediate proliferation of parotid acinar cells. Indeed, we have previously shown that an antibody to galactosyltransferase is capable of blocking isoprenaline-mediated acinar cell proliferation in vivo [Humphreys-Beher, Schneyer, Kidd & Marchase (1987) J. Biol. Chem. 262, 11706-11713].
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PMID:A novel mechanism for isoprenaline-stimulated proliferation of rat parotid acinar cells involving the epidermal growth factor receptor and cell surface galactosyltransferase. 162 94

Prolonged treatment of quiescent Swiss 3T3 cells with vasopressin induced heterologous desensitization of specific early signals stimulated by platelet-derived growth factor (PDGF). PDGF caused a striking dose-dependent release of [3H]arachidonic acid (EC50 = 2 ng/ml) and prostaglandin E2 (EC50 = 5 ng/ml). These responses are severely attenuated (greater than 85%) by prior exposure to vasopressin in a dose-dependent manner (IC50 = 1.5 nM). Maximal loss of responsiveness occurred after 40 h of vasopressin treatment with a half-maximal desensitization after 11-13 h. The desensitization is dependent upon binding to the V1 receptor, since it can be prevented by the antagonist [Pmp1,O-Me-Tyr2,Arg8]vasopressin. In contrast, stimulation of inositol phosphate accumulation and production of diacylglycerol and phosphatidic acid by PDGF are unchanged. Thus, the observed heterologous desensitization cannot be attributed to an inability to activate phospholipase C. Furthermore, prior exposure to vasopressin did not affect the ability of PDGF to evoke tyrosine phosphorylation of cellular substrates, demonstrating that vasopressin-induced heterologous desensitization causes a block at a point distal to activation of receptor tyrosine kinase activity. Other downstream responses including transient induction of c-fos expression and stimulation of DNA synthesis were attenuated by vasopressin pretreatment. The findings demonstrate a novel mechanism of heterologous cellular desensitization namely, persistent occupancy of a guanine nucleotide-binding protein-coupled receptor, like the V1 type vasopressin receptor, attenuates responsiveness to a polypeptide growth factor like PDGF that initiates responses through a tyrosine kinase receptor.
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PMID:Heterologous desensitization of platelet-derived growth factor-mediated arachidonic acid release and prostaglandin synthesis. 163 51

Studies were performed to identify the receptor that mediates AVP-stimulated phosphoinositide (PI) hydrolysis in cultured rat inner medullary collecting tubule (RIMCT) cells. While the selective V1 receptor agonist [Ho1, Phe2, Orn8] VT has no effect on inositol trisphosphate (IP3) production over the range of 10(-13)-10(-7) M, the selective V2 receptor agonist VDAVP stimulates IP3 production in dose-dependent fashion. Oxytocin stimulates IP3 production in dose-dependent fashion as well. AVP-stimulated phospholipase C activity is not inhibited by the V1 receptor antagonist d(CH2)5Tyr(Me)AVP(10(-7) M) but is eliminated by the V2 receptor antagonist d(CH2)5DTyr(Et)VAVP (10(-7) M). Similarly, the response to oxytocin is eliminated by the V2 receptor antagonist. The selective oxytocin receptor agonist [Thr4, Gly7] oxytocin does not stimulate cAMP production in RIMCT cells but does promote PI hydrolysis. The selective oxytocin receptor antagonist desGlyNH2d(CH2)5[Tyr(Me)-Thr4]OVT (10(-7) M) does not inhibit AVP-stimulated cAMP production but eliminates IP3 production in response to AVP or the V2 receptor agonist VDAVP. These studies demonstrate that AVP or a V2 receptor agonist stimulate PI hydrolysis in cultured RIMCT cells via occupancy of the oxytocin receptor.
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PMID:Vasopressin-stimulated phosphoinositide hydrolysis in cultured rat inner medullary collecting duct cells is mediated by the oxytocin receptor. 164 53

A phosphatidylinositol-3 (PI-3) kinase activity of unknown biological function associates with tyrosine kinase-containing proteins, including a number of growth factor receptors after ligand stimulation. In the beta platelet-derived growth factor (beta PDGF) receptor, phosphorylation of a specific tyrosine residue within the kinase insert domain was required for its interaction with this enzyme. We show that substitutions of phenylalanine for tyrosine residue 731 or 742 within the kinase insert domain of the alpha PDGF receptor do not impair PDGF-induced tyrosine phosphorylation of the receptor or of an in vivo substrate, phospholipase C-gamma. Moreover, phosphatidylinositol turnover in response to ligand stimulation is unaffected. However, both lesions markedly impair receptor association with PI-3 kinase. Antiphosphotyrosine antibody-recoverable PI-3 kinase was also dramatically reduced in PDGF-stimulated cells expressing either mutant receptor. Since neither mutation abolished PDGF-induced mitogenesis or chemotaxis, we conclude that alpha PDGF receptor-associated PI-3 kinase activity is not required for either of these major PDGF signalling functions.
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PMID:Tyrosine mutations within the alpha platelet-derived growth factor receptor kinase insert domain abrogate receptor-associated phosphatidylinositol-3 kinase activity without affecting mitogenic or chemotactic signal transduction. 164 96

The mitogenic neuropeptides bombesin and vasopressin markedly increased tyrosine and serine phosphorylation of multiple substrates in quiescent Swiss 3T3 fibroblasts, including two major bands of Mr 90,000 and 115,000. Tyrosine phosphorylation of these proteins was increased as judged by immunoprecipitation of 32Pi-labeled cells and immunoblotting of unlabeled cells with monoclonal antiphosphotyrosine antibodies, elution with phenyl phosphate, and phospho amino acid analysis. Phosphotyrosyl proteins generated by bombesin and vasopressin did not correspond either by apparent molecular weight or by immunological and biochemical criteria to several known tyrosine kinase substrates, including phospholipase C gamma, the microtubule-associated protein 2 kinase, GTPase-activating protein, or phosphatidylinositol kinase. The effect was rapid (within seconds), concentration dependent, and inhibited by specific receptor antagonists for both bombesin and vasopressin. The endothelin-related peptide, vasoactive intestinal contractor, also elicited a rapid and concentration-dependent tyrosine/serine phosphorylation of a similar set of substrates. These results demonstrate that neuropeptides, acting through receptors linked to GTP-binding proteins, stimulate tyrosine phosphorylation of a common set of substrates in quiescent Swiss 3T3 cells and suggest the existence of an additional signal transduction pathway in neuropeptide-induced mitogenesis.
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PMID:Bombesin, vasopressin, and endothelin rapidly stimulate tyrosine phosphorylation in intact Swiss 3T3 cells. 164 10

Rat embryo fibroblasts (REF52) exhibit a distinctive, transformation-sensitive distribution of alpha-protein kinase C (alpha-PKC). Receptor-mediated activation of phospholipase C (PLC)-gamma generates diacylglycerol, the major cellular activator of PKC. Immunofluorescence techniques were used to investigate the subcellular localization of two PLC isozymes (PLC-gamma and PLC-delta) in normal and simian virus 40-transformed REF52 cells to determine (i) if PLC colocalizes with alpha-PKC and (ii) if PLC isozyme distribution is sensitive to transformation. PLC-delta was not detected in either cell type. In REF52 cells, PLC-gamma was associated with the actin cytoskeleton and was evenly distributed along the length of the actin microfilaments. PLC-gamma was coincident with alpha-PKC at the points where the filaments are anchored to the membrane (i.e., the focal contacts). Cytoskeletal association of PLC-gamma was not transformation sensitive, although the actin cytoskeleton was more disordered in simian virus 40-transformed cells. In REF52 cells, platelet-derived growth factor induced tyrosine phosphorylation of both soluble and cytoskeletal PLC-gamma. Tyrosine phosphorylation of PLC-gamma did not seem to be a determinant of its subcellular localization, but there was a detectable increase in cytoskeleton-associated PLC-gamma in response to platelet-derived growth factor treatment.
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PMID:Immunocytochemical localization of phospholipase C-gamma in rat embryo fibroblasts. 165 94


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