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)

Chronic treatment of mice with insulin results in hypertrophy and hyperplasia of the parotid and submandibular glands (Wang et al.: 1994, Proc Soc Exp Biol Med 205:353-361). Hyperplasia of the parotid gland is mediated by the elevation of tyrosine phosphorylation of phospholipase C gamma, p21ras-GTPase activating protein (p21ras-GAP) and phosphatidylinositol 3-kinase. These proteins were found to be associated with the insulin receptor substrate-1 most likely through src homology (SH2) domains of these proteins. There was also a transient increase in intracellular cAMP and protein kinase A during the first day of treatment which declined by Day 3 to near control values. Protein kinase C activity, on the other hand, remained elevated for the 3-day injection regimen. Thus, acinar cell proliferation induced by insulin requires activation of many of the same signaling components as other tyrosine kinase possessing growth factor receptors.
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PMID:Activation of SH2-containing proteins by insulin in proliferating mouse parotid gland acinar cells. 780 Jun 88

The transforming protein of mouse polyomavirus, the mouse middle T antigen (MomT), and its counterpart in the hamster polyomavirus, the hamster middle T antigen (HamT), interact with a number of cellular proteins. Among these are members of the Src family of tyrosine kinases, the phosphatidylinositol 3-kinase, the serine/threonine phosphatase PP2A and the adaptor protein Shc (in the case of MomT). However, both the relative affinity of these antigens for the members of the Src family and the tumor profile induced by their respective viruses are quite distinct. Particularly noteworthy are the preferential binding of Fyn by HamT and the induction of lymphoid malignancies by the hamster polyomavirus. Here we report that, when expressed in fibroblasts, HamT also associated with phospholipase C gamma (PLC gamma), which led to an increased intracellular concentration of inositol-1, 4, 5-trisphosphate. We also show that expression of HamT in the mouse T cell line EL4 was sufficient to induce transcription from interleukin-2 (IL-2), NFAT and NF kappa B reporter constructs. The immunosuppressant FK506 as well as dominant negative alleles of Ras and Raf inhibited HamT-induced IL-2 transcription. This, together with the observation of NFAT responses, suggests that the action of HamT depended at least in part on the integrity of signal transduction pathways elicited by activated PLC gamma. Furthermore, dominant negative Fyn but not the equivalent allele of Lck blocked HamT activation of IL-2 transcription, while both Lck and Fyn dominant negative alleles blocked LT cell receptor-mediated IL-2 transcriptional activation. These results support the hypothesis that Fyn is involved in signal transduction events leading to IL-2 transcriptional activation in T cells. Finally, the activation of IL-2 transcription by HamT and not by MomT shown here parallels the ability of the hamster polyomavirus to induce lymphoid malignancies.
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PMID:Induction of interleukin-2 transcription by the hamster polyomavirus middle T antigen: a role for Fyn in T cell signal transduction. 787

Vascular endothelial cell growth factor (VEGF), an endothelial cell-specific mitogen that plays an important role in angiogenesis, promotes the tyrosine phosphorylation of at least 11 proteins in bovine aortic endothelial cells (BAEC). Proteins immunoprecipitated from lysates of control- and VEGF-stimulated BAEC with antisera to phospholipase C-gamma (PLC-gamma) were fractionated by SDS-polyacrylamide gel electrophoresis and transferred to Immobilon-P. Evaluation of the Western blots with antisera to phosphotyrosine demonstrated that PLC-gamma and two proteins (100 and 85 kDa) that associate with PLC-gamma were phosphorylated in response to VEGF. By using antisera specific to other mediators of signal transduction that contain SH2 domains for immunoprecipitation, it was demonstrated that VEGF promotes phosphorylation of phosphatidylinositol 3-kinase, Ras GTPase activating protein (GAP), and the oncogenic adaptor protein NcK. Proteins of M(r) consistent with the VEGF receptors Flt-1 and Flk-1/KDR were also tyrosine phosphorylated in stimulated cells. Tyrosine-phosphorylated Nck, PLC-gamma, and two GAP-associated proteins, p190 and p62, were in GAP immunoprecipitates of VEGF-stimulated BAEC, and tyrosine-phosphorylated NcK was in phosphatidylinositol 3-kinase immunoprecipitates. These observations suggest that VEGF promotes formation of multimeric aggregates of VEGF receptors with proteins that contain SH2 domains and activate various signaling pathways. VEGF-promoted proliferation of endothelial cells and tyrosine phosphorylation of SH2 domain containing signaling molecules were inhibited by the tyrosine kinase inhibitor genistein.
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PMID:Vascular endothelial cell growth factor promotes tyrosine phosphorylation of mediators of signal transduction that contain SH2 domains. Association with endothelial cell proliferation. 789 17

Platelet-derived growth factor (PDGF) stimulates phosphatidylcholine hydrolysis via phospholipase D (PLD) in several tissues. To determine whether PLD activation is dependent on phosphoinositide hydrolysis by phospholipase C (PLC), we measured the formation of phosphatidylbutanol (PtdBut), in TRMP cells overexpressing wild type or various mutant PDGF receptors. Both PLC and PLD were stimulated by PDGF in cells expressing wild type receptors whereas they were not in cells expressing kinase-deficient (R634) receptors. These data indicate that tyrosine phosphorylation is required for activation of both PLC and PLD. Mutation of Tyr-1021 of the PDGF receptor to Phe caused loss of PDGF stimulation of both PLC and PLD. On the other hand, a mutant PDGF receptor that was able to bind PLC gamma 1 but not other signaling proteins (including the Ras GTPase-activating protein, phosphatidylinositol 3-kinase, and a SH2-containing phosphotyrosine phosphatase (Syp)) restored the stimulatory effect of PDGF on PLC and PLD. Furthermore, receptors in which association with the GTPase-activating protein, phosphatidylinositol 3-kinase, or Syp was individually restored were unable to mediate PDGF stimulation of PLC or PLD. These data indicate that these other signal transduction proteins are not involved in the activation of PLD by PDGF. Treatment of the cells with the protein kinase C inhibitor, Ro-31-8220, and depletion of cellular protein kinase C by pretreatment with 4 beta-phorbol 12-myristate 13-acetate resulted in loss of PLD activation by PDGF indicating a PKC-dependent mechanism. In summary, these results indicate that activation of PLC gamma 1 and protein kinase C are necessary for the stimulation of PLD by PDGF and provide no evidence for alternative mechanisms.
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PMID:Activation of phospholipase C-gamma is necessary for stimulation of phospholipase D by platelet-derived growth factor. 796 10

Cultured vascular smooth muscle cells (VSMC) from spontaneously hypertensive rats express both alpha and beta isoforms of the platelet-derived growth factor (PDGF) receptors at high levels (100,000 and 240,000 sites/cell, respectively). In this cell type, PDGF-BB elicited a mitogenic response; however, PDGF-AA increased only protein synthesis without activating DNA synthesis. Protein kinase C (PKC) was activated by PDGF-AA as well as PDGF-BB with concomitant translocation from cytosol to membrane fractions. However, the hypertrophic effect of PDGF-AA was not affected by depletion of cellular PKC, whereas the mitogenic action of PDGF-BB was partially attenuated by the depletion. Following incubation with PDGF-AA or -BB, phospholipase C-gamma 1 (PLC-gamma 1) and phosphatidylinositol 3-kinase were tyrosine phosphorylated; however, the phosphorylation of Ras-GTPase-activating protein was induced only by PDGF-BB. Both PDGF isoforms resulted in a prompt and transient increase in the level of 1,2-diacylglycerol (DAG), presumably through the action of PLC-gamma 1. After returning to basal levels, the rate of DAG synthesis steadily increased for at least 15 min due to activation of phosphatidylcholine-hydrolyzing phospholipase C (PC-PLC). Incubation with PDGF-BB-activated phospholipase D (PLD) in a PKC-dependent manner resulting in the formation of phosphatidic acid (PA). PA was also formed by the sequential reactions of PC-PLC and DAG kinase in the PDGF-BB-stimulated VSMC, and these sequential reactions were not affected by PKC depletion. In contrast, PDGF-AA stimulation did not result in increased PA synthesis as neither PLD nor DAG kinase activities were affected. PA may be a significant second messenger in the activation of DNA synthesis by PDGF-BB. These results indicate that signaling mechanisms of the PDGF-alpha and -beta receptors in VSMC are distinctly different in signal transduction in VSMC and that the alpha receptor promotes cellular hypertrophy (but not hyperplasia), whereas a mitogenic response is mediated only through the beta receptor.
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PMID:Differences in signal transduction between platelet-derived growth factor (PDGF) alpha and beta receptors in vascular smooth muscle cells. PDGF-BB is a potent mitogen, but PDGF-AA promotes only protein synthesis without activation of DNA synthesis. 798 73

Platelet-activating factor (PAF) is a versatile lipid mediator of inflammation in a variety of biologic systems. We have previously reported that one of the earliest events in the signal transduction pathway of PAF in a human B lymphoblastoid cell line was the induction of tyrosine kinase activity concomitant with the activation of phospholipase C (PLC). We now demonstrate the occurrence of multiple tyrosine phosphorylation-dependent events which follow the interaction of PAF with its receptor on B cells. Anti-phosphotyrosine immunoprecipitates from lysates of PAF-stimulated cells, when fractionated by SDS-PAGE and analyzed by Western blotting with anti-PLC-gamma 1, showed that maximal tyrosine phosphorylation of this enzyme occurred within 2 min of stimulation. This phenomenon was verified by immunoprecipitating with anti-PLC-gamma 1 and subsequently probing with anti-phosphotyrosine. Immunoprecipitation of the tyrosine kinases, Fyn and Lyn, from PAF-stimulated cells, and use of these immunoprecipitates in kinase assays established that the activation of both kinases also occurred within the first 2 min of stimulation with phosphorylation occurring on their tyrosine residues. Additionally, we also provide evidence for the tyrosine phosphorylation of the p85 subunit of phosphatidylinositol 3-kinase (PtdIns 3-kinase) and activation of this kinase by PAF in a dose-dependent manner, maximal activation occurring within 10 min post-stimulation. We have thus demonstrated that the activation of tyrosine kinases is an important proximate step in PAF-mediated signal transduction in B cells, leading to tyrosine phosphorylation and activation of PLC-gamma 1, Fyn and Lyn kinases, and PtdIns 3-kinase.
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PMID:Platelet-activating factor induces the tyrosine phosphorylation and activation of phospholipase C-gamma 1, Fyn and Lyn kinases, and phosphatidylinositol 3-kinase in a human B cell line. 798 48

B lymphocyte antigen receptors, membrane immunoglobulins (mIg), function in focusing and internalization of antigen for subsequent presentation to T cells and in transmembrane transduction of signals leading to cell activation, anergy, or deletion. Until quite recently, the ability of this receptor to transduce signals in spite of a virtual lack of cytoplasmic structure, left a significant gap in our understanding of how it is coupled to cytoplasmic signal propagators. Studies conducted during the past five years have defined a mIg-associated protein complex homologous to the CD3 complex associated with the T cell antigen receptor. Components of this disulfide linked heterodimeric complex, Ig-alpha and Ig-beta, contain an approximately 26 residue sequence motif termed ARH1, also known as TAM, which binds to cytoplasmic effectors, including src-family tyrosine kinases, and contains all structural information needed for signal transduction. Receptor associated src-family kinases which are activated following receptor cross-linking, also associate with downstream effectors, including phospholipase C gamma (PLC gamma), p21ras. GTPase activating protein (GAP), phosphatidylinositol 3-kinase (PI3-k) and microtubule associate protein kinase (MAPk2). In some cases, these associations are induced by receptor cross-linking and lead directly to effector activation. The current literature indicates that these interactions may occur in sequence and culminate in the activation of three major pathways of signal propagation including those mediated by PLC gamma, p21ras and PI3-k. This chapter reviews various molecular aspects of the B cell antigen receptor complex, including extended structure of the complex, and receptor-effector interactions and their biologic consequences. Finally, an integrated model of antigen receptor signaling is presented.
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PMID:Signal transduction by the B cell antigen receptor and its coreceptors. 801 Dec 88

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

Currently, a central question in biology is how signals from the cell surface modulate intracellular processes. In recent years phosphoinositides have been shown to play a key role in signal transduction. Two phosphoinositide pathways have been characterized, to date. In the canonical phosphoinositide turnover pathway, activation of phosphatidylinositol-specific phospholipase C results in the hydrolysis of phosphatidylinositol 4,5-bisphosphate and the generation of two second messengers, inositol 1,4,5-trisphosphate and diacylglycerol. The 3-phosphoinositide pathway involves protein-tyrosine kinase-mediated recruitment and activation of phosphatidylinositol 3-kinase, resulting in the production of phosphatidylinositol 3,4-bisphosphate and phosphatidylinositol 3,4,5-trisphosphate. The 3-phosphoinositides are not substrates of any known phospholipase C, are not components of the canonical phosphoinositide turnover pathway, and may themselves act as intracellular mediators. The 3-phosphoinositide pathway has been implicated in growth factor-dependent mitogenesis, membrane ruffling and glucose uptake. Furthermore the homology of the yeast vps34 with the mammalian phosphatidylinositol 3-kinase has suggested a role for this pathway in vesicular trafficking. In this review the different mechanisms employed by protein-tyrosine kinases to activate phosphatidylinositol 3-kinase, and its involvement in the signaling cascade initiated by tyrosine phosphorylation, are examined.
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PMID:Phosphatidylinositol 3-kinase. 808 5

Acetylcholine muscarinic m2 receptors (m2R) couple to heterotrimeric Gi proteins and activate the Ras/Raf/mitogen-activated protein kinase pathway and phosphatidylinositol 3-kinase in Rat 1a cells. In contrast to the m2R, stimulation of the acetylcholine muscarinic m1 receptor (m1R) does not activate the Ras/Raf/mitogen-activated protein kinase regulatory pathway in Rat 1a cells but rather causes a pronounced inhibition of epidermal growth factor and platelet-derived growth factor receptor activation of Raf. In Rat 1a cells, m1R stimulation of phospholipase C beta and the marked rise in intracellular calcium stimulated cyclic AMP (cAMP) synthesis, resulting in the activation of protein kinase A. Stimulation of protein kinase A inhibited Raf activation in response to growth factors. Platelet-derived growth factor receptor stimulation of phosphatidylinositol 3-kinase activity was not affected by either m1R stimulation or protein kinase A activation in response to forskolin-stimulated cAMP synthesis. GTP loading of Ras in response to growth factors was unaffected by protein kinase A activation but was partially inhibited by carbachol stimulation of the m1R. Therefore, protein kinase A action at the Ras/Raf activation interface selectively inhibited only one branch of the signal transduction network initiated by tyrosine kinases. Specific adenylyl cyclases responding to different signals, including calcium, with enhanced cAMP synthesis will regulate Raf activation in response to Ras.GTP. Taken together, the data indicate that G protein-coupled receptors can positively and negatively regulate the responsiveness of tyrosine kinase-stimulated mitogenic response pathways.
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PMID:Acetylcholine muscarinic m1 receptor regulation of cyclic AMP synthesis controls growth factor stimulation of Raf activity. 813 39


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