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)

In the mammalian nervous system, serotonin (5-hydroxytryptamine) binds to distinct cell surface receptor subtypes that are defined by their ligand binding and effector-coupling properties. The 5HT1c receptor is a G-protein coupled receptor that stimulates phospholipase C-catalyzed hydrolysis of phosphatidylinositol bisphosphate, leading to the mobilization of intracellular calcium and to the activation of protein kinase C. By using somatic cell hybrid analysis and FISH, we have mapped the HTR1C locus to the human X chromosome, band q24 and to the mouse X chromosome region D-F4. Comparison of these map positions offers new insights into the evolution of human and murine X chromosomes. Since HTR1C is expressed in certain parts of the central nervous system and abnormal function of the serotoninergic system has been implicated in affective disorders, obsessive-compulsive disorder and epilepsy, establishing the precise map position of HTR1C is an important first step toward evaluating this locus as a candidate for mutations in these syndromes and in X-linked mental disorders.
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PMID:Serotonin receptor 1c gene assigned to X chromosome in human (band q24) and mouse (bands D-F4). 130 5

Heparan sulfate proteoglycans (HSPG) are ubiquitous constituents of mammalian cell surfaces and most extracellular matrices. A portion of the cell surface HSPG is anchored via a covalently linked glycosyl-phosphatidylinositol (Pl) residue, which can be released by treatment with a glycosyl-Pl specific phospholipase C (Pl-PLC). We report that exposure of bovine aortic endothelial and smooth muscle cells to Pl-PLC resulted in release of cell surface-associated, growth-promoting activity that was neutralized by antibasic fibroblast growth factor (bFGF) antibodies. Active bFGF was also released by treating the cells with bacterial heparitinase. Under the same conditions there was no release of mitogenic activity from cells (BHK-21, NIH/3T3, PF-HR9) that expressed little or no bFGF, as opposed to Pl-PLC-mediated release of active bFGF from the same cells transfected with the bFGF gene. The released bFGF competed with recombinant bFGF in a radioreceptor assay. Addition of Pl-PLC to sparsely seeded vascular endothelial cells resulted in a marked stimulation of cell proliferation, but there was no mitogenic effect of Pl-PLC on 3T3 fibroblasts. Studies with exogenously added 125I-bFGF revealed that about 6.5% and 20% of the cell surface-bound bFGF were released by treatment with Pl-PLC and heparitinase, respectively. Both enzymes also released sulfate-labeled heparan sulfate from metabolically labeled 3T3 fibroblasts. Pl-PLC failed to release 125I-bFGF from the subendothelial extracellular matrix (ECM), as compared to release of 60% of the ECM-bound bFGF by heparitinase. Our results indicate that 3-8% of the total cellular content of bFGF is associated with glycosyl-Pl anchored cell surface HSPG. This FGF may exert both autocrine and paracrine effects, provided that it is released by Pl-PLC and adequately presented to high affinity bFGF cell surface receptor sites.
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PMID:Release of cell surface-associated basic fibroblast growth factor by glycosylphosphatidylinositol-specific phospholipase C. 131 17

Five rat thyroid cell lines were tested for the expression of the cell surface receptor for urokinase type plasminogen activator (uPA). All tested lines were found to bind uPA, but transformed 1-5G and Ki-Mol cells, which are also high uPA producers, bound at least ten times more uPA, as compared to non-producers, 'normal' TL5 cells. Moreover, it was possible to remove membrane-bound uPA by treating the cells with phosphatidylinositol-specific phospholipase C, suggesting that rat uPAR, like its human counterpart, is linked to the membrane by a glucosyl-phosphatidylinositol anchor. The specificity of the binding was tested by competition with three different synthetic peptides corresponding to amino acids 14-37 of human, rat and mouse uPA. The results indicate also that the receptor binding region of rat uPA is located within the growth factor domain of the molecule and that its expression may be dependent on the transformed state of the cells.
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PMID:The receptor for the plasminogen activator of urokinase type is up-regulated in transformed rat thyroid cells. 132 34

Activation of T cells through the TCR/CD3 receptor complex with either specific Ag or antibody results in tyrosine phosphorylation of intracellular protein substrates and phosphatidylinositol-phospholipase C (PLC) signaling, leading to the generation of PI breakdown products and the mobilization of intracellular calcium. Stimulation of the T cell surface receptor CD2 similarly propagates early signals through phosphatidylinositol-PLC activation. Previous reports have shown that CD3 activation leads to tyrosine phosphorylation of the PLC isozyme PLC gamma 1. In this report, we investigated the potential similarity between CD3-induced signaling through PLC gamma 1 and that induced by CD2. We show that stimulation of CD2 receptors on T cells caused tyrosine phosphorylation of PLC gamma 1. Cross-linking of CD2 with CD3 receptors augmented the phosphorylation of PLC gamma 1 on tyrosine, whereas ligation of the CD45 tyrosine phosphatase with CD2 receptors prevented PLC gamma 1 tyrosine phosphorylation. T cells stimulated by ligation of CD2 with its counter-receptor in the form of a soluble LFA-3/Ig fusion protein cross-linked on the cell surface, resulted in a low, but detectable level of PLC gamma 1 phosphorylation with prolonged kinetics, whereas that induced by cross-linking with anti-CD2 was stronger but transient. Co-ligation of LFA-3/Ig with suboptimal concentrations of anti-CD3 resulted in profound augmentation of PLC gamma 1 tyrosine phosphorylation, mobilization of intracellular calcium and T cell proliferation. To explore the relationship between CD3- and CD2-stimulated signaling, T cells were desensitized through 1 h incubation with anti-CD3. CD3 receptor modulation potently down-regulated CD2-induced PLC gamma 1 tyrosine phosphorylation and calcium mobilization. In contrast, PMA or ionomycin treatment did not alter CD2-stimulated tyrosine phosphorylation of PLC gamma 1, suggesting that tyrosine kinase inhibition by CD3 receptor modulation was not caused by signaling events downstream of PLC gamma 1. Taken together, these results support the hypothesis that CD2 provides a potent co-stimulatory signal for CD3-induced T cell activation that is associated with tyrosine kinase(s) and PLC gamma 1.
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PMID:CD2/LFA-3 ligation induces phospholipase-C gamma 1 tyrosine phosphorylation and regulates CD3 signaling. 137 20

Phospholipase C is a family of cellular proteins believed to play a significant role in the intracellular signaling mechanisms utilized by diverse hormones. One class of hormones, polypeptide growth factors, elicits its influence on cellular function through stimulation of cell surface receptor tyrosine kinase activity. Certain growth factors appear to stimulate cellular phospholipase C activity by selective, receptor-mediated tyrosine phosphorylation of the phospholipase C-gamma 1 isozyme. While the role of phospholipase C activity in growth factor regulation of cell proliferation remains to be clarified, the selective growth factor-stimulated tyrosine phosphorylation and activation of phospholipase C-gamma 1 is an interesting example of enzyme-substrate interaction at the crossroads of two important intracellular signaling pathways.
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PMID:Selective phospholipase C activation. 165 8

Neutrophil-specific alloantibodies and the antigens they recognize are important in clinical medicine but little is known about the structure of these antigens. Alloimmunization to the antigen NB1 is a clinically important cause of neonatal neutropenia and leukocyte-mediated transfusion reactions. A novel mechanism of protein attachment to cell membranes involving the covalent linkage of the protein through an oligosaccharide to phosphatidylinositol has recently been defined. Many proteins which are anchored to the cell membrane by this mechanism can be released by treatment with phosphatidylinositol-specific phospholipase C (PI-PLC). The 58-64-kDa human neutrophil surface protein which contains the NB1 antigen was labeled with 125I by using lactoperoxidase and examined for PI-PLC sensitivity. The 58-64-kDa protein was specifically released from the cell by treatment with PI-PLC, and the mobility of the protein under non-denaturing conditions using non-ionic detergent was increased by treatment with PI-PLC. Surface expression of the NB1 antigen was slightly up-regulated by treatment with the chemotactic peptide f-met-leu-phe. Removal of N-linked carbohydrates with endoglycosidase-F decreased the apparent molecular weight of the protein to approximately 45-kDa. The data suggest that most of the 58-64-kDa protein bearing the neutrophil-specific antigen NB1 is anchored to the membrane through a glycosyl-phosphatidylinositol linkage.
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PMID:Neutrophil-specific antigen NB1 is anchored via a glycosyl-phosphatidylinositol linkage. 182 10

Tumor necrosis factor (TNF) acts via a cell surface receptor to induce a variety of cellular events including cytolysis, differentiation, and mitogenesis. The mechanisms underlying the cell specific actions of TNF are not known. In the present study, postreceptor events associated with the autoinduction of TNF expression were examined in HL-60 cells. There was no detectable alteration in phospholipase C activity as measured by inositol phosphate generation or release of choline metabolites following TNF stimulation. However, TNF increased the release of arachidonic acid metabolites from HL-60 cells. This increase in arachidonic acid metabolism was associated with a 40% increase in phospholipase A2 activity. Furthermore, the release of arachidonic acid metabolites was blocked by inhibitors of phospholipase A2. Taken together, these findings indicated that TNF stimulates phospholipase A2 and arachidonic acid metabolism in HL-60 cells. The results also demonstrate that TNF expression is induced 15-30 min after stimulation with TNF and that this effect is associated with an increase in the rate of TNF transcription. This autoinduction of TNF mRNA was blocked by inhibitors of phospholipase A2. While the cyclooxygenase inhibitor indomethacin had no detectable effect, ketoconazole and nordihydroguaiaretic acid, inhibitors of lipoxygenase, also blocked the induction of TNF expression by TNF. These findings suggest that phospholipase A2 and lipoxygenase activity are required for the transcriptional activation of TNF gene expression associated with TNF stimulation of HL-60 cells.
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PMID:Phospholipase A2 activation and autoinduction of tumor necrosis factor gene expression by tumor necrosis factor. 212 30

The potent neurotoxin alpha-latrotoxin (alpha LTx), from black widow spider venom, induces neurotransmitter release in both Ca2(+)-containing and Ca2(+)-free medium, following interaction with a specific cell surface receptor. Binding studies revealed two populations of alpha LTx binding sites in bovine synaptosomal membranes, showing the same high affinity (Kd, 0.3 x 10(-10) M) for alpha LTx, with approximately 50% of the sites being Ca2+ sensitive and the rest being Ca2+ insensitive. In contrast, in PC12 cells alpha LTx binding was completely unaffected by the removal of extracellular Ca2+ (Kd, 5 x 10(-10) M). The use of La3+ as an inhibitor of alpha LTx action, previously shown in synaptosomes, was extended to PC12 cells. In this system, La3+ (100 microM) was shown to inhibit Ca2+ influx, both Ca2(+)-dependent and -independent dopamine release, and polyphosphoinositide (PPI) hydrolysis induced by alpha LTx. At the same time, La3+ did not block alpha LTx binding or dopamine release evoked by either the ionophore ionomycin (0.5 microM) or the phorbol ester tetradecanoylphorbol acetate (100 nM). La3+ also blocked the influx of Mn2+ ions through the alpha LTx-induced cation channel, as measured by quenching of fura-2 fluorescence. In this PC12 cell line, PPI hydrolysis could also be induced by ionomycin, but only when it was present at concentrations that caused an elevation of free intracellular Ca2+ ([Ca2+]i) that was not transient but was as persistent as that evoked by alpha LTx. Our conclusions with regard to the mode of action of alpha LTx are as follows. (i) All the effects of alpha LTx in PC12 cells (dopamine release, PPI hydrolysis, and Ca2+ influx) can be mediated via a single, Ca2(+)-insensitive alpha LTx receptor. (ii) alpha LTx-induced PPI hydrolysis is most likely due to the activation of a Ca2(+)-sensitive phospholipase C following the persistent rise in [Ca2+]i elicited by the toxin in Ca2(+)-containing medium, and not via direct coupling of the alpha LTx receptor to the enzyme. (iii) Toxin-evoked Ca2(+)-independent dopamine release can be blocked by La3+ at the extracellular level, most likely by prevention of the entry of divalent cations.
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PMID:Mode of action of alpha-latrotoxin: role of divalent cations in Ca2(+)-dependent and Ca2(+)-independent effects mediated by the toxin. 217 8

Transcription of the low-density lipoprotein receptor (LDL-R) gene in the human monocytic leukemic cell line THP-1 and in the human hepatocarcinoma cell line Hep-G2 is regulated by second messengers of the diacylglycerol-protein kinase C (DAG-PKC), inositol 1,4,5-triphosphate-Ca2+, and cyclic AMP pathways. Exogenous phospholipase C (which releases DAG and inositol 1,4,5-triphosphate), PKC activators (phorbol esters and DAG), Ca2+ ionophores, and a cyclic AMP analog all transiently induced accumulation of LDL-R mRNA. The effects of these three signal-transducing pathways were to a large extent additive. Furthermore, PKC stimulation effected an increase in LDL binding, which suggested that the increase in LDL-R mRNA resulted in an increase in functional cell surface receptor activity. These results suggest that uptake of cholesterol by these cells is under control of both intracellular cholesterol levels and external signals.
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PMID:Involvement of second messengers in regulation of the low-density lipoprotein receptor gene. 254 77

Procaryotic and eucaryotic cells have evolved multiple pathways for communication with their external environment. The inositol 1,4,5-trisphosphate/diacylglycerol second messenger system is an example of such a signal transduction pathway which is present in multicellular eucaryotic organisms. Binding of an agonist to a specific cell surface receptor promotes rapid hydrolysis of phosphatidylinositol 4,5-bisphosphate. The pivotal enzyme for this second messenger system is phosphoinositide-specific phospholipase C which hydrolyzes phosphatidylinositol 4,5-bisphosphate to generate the two second messengers, inositol 1,4,5-trisphosphate and diacylglycerol. Recently, much progress has been made in the purification, characterization and cDNA cloning of multiple PI-PLC isoenzymes. The results of the recent studies on phosphoinositide-specific phospholipase C are reviewed.
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PMID:Mammalian phosphoinositide-specific phospholipase C isoenzymes. 254 25


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