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 cellular basis of down-regulation and desensitization in phospholipase C-linked receptors is unclear. Recent studies with some receptors suggest that elements in the carboxyl terminus of the receptor are important in mediating these processes. Three mutant gastrin-releasing peptide receptors (GRP-R) were studied: one whose last 37 carboxyl-terminal amino acids were eliminated (construct MGT346); one that replaced all of the carboxyl-terminal Ser and Thr eliminated in MGT346 with Ala, Asn, or Gly (construct JF1); and one that selectively replaced the Ser and Thr of the protein kinase C consensus sequence (PKC-CS) located within the same region with alanine (construct TS360AA). Desensitization was assessed by measuring the ability to activate phospholipase C and increase cellular [3H]inositol phosphates, or increase [Ca2+]i, after pre-exposure to 3 nM bombesin for 24 h. Wild-type GRP-R was maximally desensitized and down-regulated after a 24-h exposure to 3 nM bombesin, and removal of the PKC-CS alone markedly attenuated each process. Elimination of additional serines and threonines by truncation (MGT346) or replacement (JF1) did not decrease down-regulation or desensitization further. To confirm the necessity of second messenger activation in mediating down-regulation, we further investigated two additional mutant GRP-R that bound agonist with high affinity but fail to activate phospholipase C (constructs R139G and A263E). Neither construct underwent significant down-regulation. Removal of all GRP-R carboxyl-terminal Ser or Thr, either by MGT346 or JF1, reduced internalization by > 80%, whereas elimination of the PKC-CS in TS360AA only attenuated internalization by 21 +/- 2%. These data suggest that activation of the distal carboxyl-terminal PKC-CS is essential for chronic desensitization and down-regulation of the GRP-R, and provide no evidence for involvement of second messenger-independent processes. In contrast, internalization is equally regulated by both second messenger-dependent and independent processes.
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PMID:Chronic desensitization and down-regulation of the gastrin-releasing peptide receptor are mediated by a protein kinase C-dependent mechanism. 785 20

Protein kinase C (PKC) serine/threonine kinases transduce cellular signals initiated by phospholipase C activation and diacylglycerol production. Human gene sequences from the beta and gamma isoforms were cloned and sequenced, and transcriptional regulation was studied. The major PKC beta transcription initiation site was identified by primer extension and S1 nuclease protection. Additional transcription initiation sites were located within a CpG-rich region proximal to the ATG. The transcription initiation site of the PKC gamma gene was identified by primed cDNA synthesis. In transfection experiments, the PKC gamma promoter was expressed at high level in U937 and HL60 cells but not in COS-1 cells. A sequence motif (AnAGATTCanAGAGnCa), reiterated over at least 1 kb, was located approximately 1.5 kb 5' of the PKC gamma translation initiation codon. This repetitive motif is abundant in run-on RNA in the hematopoietic and epithelial cell lines tested. Analysis of promoter deletion constructs by transient transcription assays in U937, IM9, and COS-1 cells showed negative regulation of the PKC beta promoter by sequences located between -3,000 and -690. although no homology between PKC beta and PKC-gamma 5'-flanking sequences was observed, both PKC beta and PKC gamma promoters were potently induced by 12-phorbol 13-myristate in transfected U937 cells.
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PMID:Autoregulation of cloned human protein kinase C beta and gamma gene promoters in U937 cells. 788 Apr 42

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 alpha subunits of Gq family G proteins, GL1 alpha (G14 alpha), GL2 alpha(G11 alpha), and Gq alpha were expressed with G protein beta 1 and gamma 2 subunits in insect cells using a baculovirus system. The trimeric forms of G proteins, GL1 (GL1 alpha beta gamma), GL2 (GL2 alpha beta gamma), and Gq (Gq alpha beta gamma), were solubilized by 1% sodium cholate and purified by sequential chromatography on three kinds of columns. GL1, GL2, and Gq activated phospholipase C-beta purified from bovine brain in the presence of aluminum fluoride to the same extent. Muscarinic acetylcholine receptor m1 subtype stimulated the guanosine 5'-O-(3-thiotriphosphate) (GTP gamma S) binding to GL1, GL2, and Gq in the presence of similar concentrations of carbamylcholine. When m1 receptor, G protein, and phospholipase C-beta were reconstituted in lipid vesicles, each subtype of Gq family G proteins mediated the activation of phospholipase C-beta by carbamylcholine in the presence of either 1 microM GTP gamma S or 1 mM GTP. Phospholipase C-beta stimulated the GTPase activity of GL1, GL2, and Gq in the presence of m1 receptor and carbamylcholine but did not stimulate the GTPase activity of GO. Protein kinase C phosphorylated m1 receptor and phospholipase C-beta, but the phosphorylation did not significantly affect the ability of the m1 receptor to stimulate phospholipase C-beta in the reconstitution system of purified proteins.
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PMID:Characterization of Gq family G proteins GL1 alpha (G14 alpha), GL2 alpha (G11 alpha), and Gq alpha expressed in the baculovirus-insect cell system. 789 Jul 62

The clinical efficacy of dopamine (DA) replacement therapy for patients with Parkinson's disease (PD) depends on the preservation of postsynaptic DA receptors and their intracellular signalling mechanisms in the striatum long after degeneration of the nigrostriatal DA pathway. DA activates adenylyl cyclase (AC) and phospholipase C (PLC) via the D1 receptor, and inhibits through the D2 receptor, thereby regulating the production of intracellular second messengers, cyclic adenosine 3',5'-monophosphate (cAMP), 1,2-diacylglycerol (DAG) and Ca2+. Recent advances in molecular biology have made it possible to monitor the intracellular signal transduction cascade following receptor activation by various transmitters. The authors review the literature addressing this issue, summarized as follows: (1) striatal D1 and D2 receptor densities remain constant, at least in treated and non-demented patients; (2) DA-sensitive AC activity appears to be increased in the putamen of treated patients, although this remains to be confirmed; (3) levels of cAMP-dependent protein kinase (PKA) are normal in non-demented patients, consistent with unchanged levels of DARPP-32 (dopamine- and cAMP-regulated phosphoprotein of M(r) 32,000); (4) levels of Ca2+/phospholipid-dependent protein kinase (PKC) and of inositol 1,4,5-trisphosphate (InsP3) receptor also remain unchanged in non-demented patients; (5) the above three second messenger sites as well as densities of D1 and D2 receptors are decreased in the striatum of demented PD patients (PDD). We tentatively conclude that postreceptor signalling function is intact in the striatum of non-demented PD patients and that there is a clear difference between non-demented patients and PDD, i.e. striatal dopaminoceptive neurons are affected in PDD.
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PMID:Transmembrane signalling systems in the brain of patients with Parkinson's disease. 795 88

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

Changes of intracellular activity of lysolecithin acyltransferase (LAT) during an interaction between endothelial cells (EC) and low-density lipoprotein (LDL) were investigated. Following an incubation of EC with LDL, endothelial LAT activity was assayed using [3H]lysophosphatidylcholine as the substrate. Stimulation of EC with either thrombin (0.01-1 U/ml) or Ca(2+)-ionophore A23187 (10(-10)-10(-7) M) dose- and time-dependently enhanced LAT activity in the presence of LDL (1 mg protein/ml), but no enhancement was observed in quiescent cells. Ionomycin together with 1-oleoyl-2-acetyl glycerol, a synthetic analog of diacylglycerols enhanced LAT activity in a similar degree to thrombin in the presence of LDL. Either staurosporine, a protein kinase C inhibitor or neomycin, a phospholipase C inhibitor completely blocked an increase of LAT activity in stimulated EC. Stimulation of EC with various agonists including 12-o-tetradecanoylphorbol-13-acetate, an activator of protein kinase C caused a marked increase in cellular uptake of LDL, and staurosporine inhibited the uptake. These results suggest that the transport of LDL into EC is facilitated by stimulation with thrombin and other agonists, and LDL subsequently activates intracellular LAT. Protein kinase C seems to mediate LDL uptake into EC. Intracellular regulatory roles of LDL in the presence of vasoactive substances were discussed.
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PMID:Enhancement of lysolecithin acyltransferase activity by LDL in thrombin-stimulated porcine-cultured endothelial cells. 801 83

Previously, we characterized the prostaglandin (PG) F2 alpha receptor linked to phospholipase C activation and DNA synthesis in NIH-3T3 cells (Nakao, A., Watanabe, T., Taniguchi, S., Nakamura, M., Honda, Z-I., Shimizu, T., and Kurokawa, K. (1993) J. Cell. Physiol. 155, 257-264). To elucidate intracellular events evoked via this receptor, we examined changes caused by PGF2 alpha stimulation in the phosphotyrosine composition of cellular proteins. The addition of PGF2 alpha to cells in quiescent culture rapidly increased the levels of phosphotyrosine in cellular proteins with Mr values of 70,000 (pp70), 85,000 (pp85), 92,000 (pp92), 100,000 (pp100), and 125,000 (pp125); the latter was immunologically identified as p125 focal adhesion kinase. The PGF2 alpha-induced changes in the level of intracellular Ca2+ ([Ca2+]i) elevation, formation of inositol phosphates, and [3H]thymidine incorporation followed a similar dose dependence as PGF2 alpha-induced tyrosine phosphorylation. This tyrosine phosphorylation was independent of extracellular Ca2+, while a [Ca2+]i chelator, 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (50 microM), completely inhibited the PGF2 alpha-induced elevation of [Ca2+]i, tyrosine phosphorylation, and [3H]thymidine incorporation. Ionomycin (0.1 microM), which induced [Ca2+]i elevation without formation of inositol phosphates, mimicked the PGF2 alpha-induced tyrosine phosphorylation. 12-O-Tetradecanoylphorbol-13-acetate (TPA) also induced [3H]thymidine incorporation in a dose-dependent manner but had no significant effect on tyrosine phosphorylation. The PGF2 alpha-induced tyrosine phosphorylation could be observed even in the cells pretreated with TPA (5 microM, 24 h). PGF2 alpha exhibited an additive effect on TPA-induced [3H]thymidine incorporation but had no effect on the 32P-phosphorylation of a known 80-kDa protein kinase (PK) C substrate. Both staurosporine and H-7 inhibited the PGF2 alpha-induced increase in [3H]thymidine incorporation and tyrosine phosphorylation in a similar dose-dependent manner whether or not cells were pretreated with TPA (5 microM, 24 h). However, W-7 and KN-62 had no effect on these cellular responses even at the concentration for the almost complete inhibition of Ca2+/calmodulin-dependent PKs (20 microM). These results, taken together, indicate that PGF2 alpha receptor-mediated tyrosine phosphorylation is evoked by a [Ca2+]i-dependent mechanism that is sensitive to staurosporine and H-7 but which is independent of PKC or Ca2+/calmodulin PKs. Finally, the data suggest that this PGF2 alpha-induced signaling pathway is linked to the proliferation of cells.
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PMID:Prostaglandin F2 alpha enhances tyrosine phosphorylation and DNA synthesis through phospholipase C-coupled receptor via Ca(2+)-dependent intracellular pathway in NIH-3T3 cells. 802 Dec 71


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