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)

IL-7 is a glycoprotein involved in the regulation of lymphocyte precursor growth. In addition, it has a comitogenic effect on mature T cells but not on mature B cells. The exact mechanism whereby IL-7R mediates these cell growth properties remains unknown. Because many growth factor receptor systems on various cell types transduce signals by activating a tyrosine kinase, we have studied here the effect of IL-7R ligation on protein tyrosine phosphorylation. We found that human rIL-7 consistently induced tyrosine phosphorylation of five major proteins, of 175, 155, 135, 110, and 85 kDa, and five minor proteins. The effect of human rIL-7 on tyrosine phosphorylation of these substrates was concentration and time dependent. One of the known substrates that is phosphorylated on tyrosine residues after binding of growth factors to their receptors is the phosphoinositide-specific phospholipase C. Several phospholipase C isozymes have been recently recognized; one isozyme, phospholipase C-gamma 1, was demonstrated to be phosphorylated rapidly after ligand binding to the platelet-derived growth factor receptor and the T cell Ag receptor. We show here that, in contrast to Ag receptor ligation, activation of IL-7R does not induce tyrosine phosphorylation on phospholipase C-gamma 1. Consistent with these results, human rIL-7 failed to increase phosphatidylinositol turnover and did not induce a rise in cytosolic free Ca2+ in the thymocytes, mature T cells, or pre-pre-B cells. The results indicate that the IL-7R mediates the activation of the tyrosine phosphorylation pathway but does not induce the phosphatidylinositol-phospholipase C pathway.
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PMID:IL-7 receptor mediates tyrosine phosphorylation but does not activate the phosphatidylinositol-phospholipase C-gamma 1 pathway. 153 50

We have recently described a novel glycoprotein, Kp43, expressed on the surface of human natural killer (NK) cells that appears to regulate their functional activity. In this report, signaling mechanisms through the Kp43 surface antigen have been studied. Incubation of interleukin 2 (IL-2)-treated NK cells with anti-Kp43 monoclonal antibody F(ab')2 fragments resulted in the time- and dose-dependent stimulation of NK cell phospholipase D. Phospholipase D activation through the Kp43 surface antigen was found to take place in the absence of polyphosphoinositide turnover and appeared not to depend on the presence of Ca2+ in the extracellular medium. On the other hand, signaling mechanisms through the CD16 receptor (FcR-III) on NK cells were comparatively studied. Stimulation of IL-2-treated NK cells with anti-CD16 monoclonal antibody F(ab')2 fragment also resulted in time- and dose-dependent activation of phospholipase D. However, CD16-triggered phospholipase D activation took place concomitant to phospholipase C-mediated polyphosphoinositide breakdown and showed a strong dependence on extracellular Ca2+. These results provide, to our knowledge, the first evidence for the presence of activatable phospholipase D in NK cells, as well as the first indication that distinct receptor-modulated pathways exist for activation of phospholipase D within the same cell type. On the other hand, phosphatidic acid, the physiologic product of phospholipase D action on phospholipids, was found to mimic the effect of anti-Kp43 monoclonal antibody regarding tumor necrosis factor alpha (TNF-alpha) biosynthesis and secretion by NK cells. Addition of phosphatidic acid vesicles to IL-2-treated NK cell cultures stimulated a TNF-alpha production that was abolished when the cells were previously treated with actinomycin D. Other phospholipids, including lysophosphatidic acid, were ineffective. However, phosphatidic acid-induced TNF-alpha production was strongly inhibited by the presence of propranolol, an inhibitor of phosphatidic acid phosphohydrolase. Moreover, in cells responding to phorbol myristate acetate, a compound that triggers activation of phospholipase D, TNF-alpha synthesis was also inhibited by propranolol. Thus, these data suggest a second messenger role for phosphatidic acid-derived diradylglycerol in the induction of TNF-alpha gene expression.
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PMID:Phospholipase D activation in human natural killer cells through the Kp43 and CD16 surface antigens takes place by different mechanisms. Involvement of the phospholipase D pathway in tumor necrosis factor alpha synthesis. 153 70

gp65 and gp55 are glycoprotein components of CNS synapses that are recognised by a single monoclonal antibody, SMgp65. This antibody has now been used to investigate the molecular properties of these two glycoproteins and the structural relationship between them. Both gp65 and gp55 occur in most brain regions as doublets of apparent molecular masses of 63 and 67 kDa, and 52 and 57 kDa, respectively. Striatal samples, however, are enriched in a novel gp65 isoform of 69 kDa. Removal of oligosaccharide residues from gp65 and gp55 with trifluoromethanesulphonic acid shows that gp65 and gp55 are composed of single polypeptide chains of 40 and 28 kDa, respectively. Removal of sialic acid residues with neuraminidase lowers the apparent molecular mass of both glycoproteins by 5-6 kDa. Triton X-114 phase partitioning and alkaline extraction of synaptic membranes indicate that both gp65 and gp55 are integral membrane glycoproteins. Treatment of synaptic membranes with phosphatidylinositol-specific phospholipase C does not solubilise either glycoprotein. One-dimensional peptide and epitope maps obtained by digestion of gp65 and gp55 with endoproteinase lys C or subtilisin are consistent with a close structural relationship between the two molecules. Tryptic digestion of samples enriched in gp65 and/or gp55 results in the formation of a novel immunoreactive 53-kDa species that is resistant to further trypsin degradation except in the presence of 0.1% (wt/vol) sodium dodecyl sulphate. Trypsin treatment of cultures of forebrain neurones in situ lowers the apparent molecular mass of gp65 to 53 kDa.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Molecular characterisation and structural relationship of the synapse-enriched glycoproteins gp65 and gp55. 157 91

Cells of the insect (procyclic) stage of the life cycle of the African trypanosome, Trypanosoma brucei, express an abundant stage-specific glycosylated phosphatidylinositol (GPI) anchored glycoprotein, the procyclic acidic repetitive protein (PARP). The anchor is insensitive to the action of bacterial phosphatidylinositol-specific phospholipase C (PI-PLC), suggesting that it contains an acyl-inositol. We have recently described the structure of a PI-PLC resistant glycosylphosphatidylinositol, PP1, which is specific to the procyclic stage, and have presented preliminary evidence that the phosphatidylinositol portion of the protein-linked GPI on PARP has a similar structure. In this paper we show, by metabolic labelling with [3H]fatty acids, that the PARP anchor contains palmitate esterified to inositol, and stearate at sn-1, in a monoacylglycerol moiety, a structure identical to PP1. Using pulse-chase labelling, we show that both fatty acids are incorporated into the GPI anchor from a large pool of metabolic precursors, rather than directly from acyl-CoA. We also demonstrate that the addition of the GPI anchor moiety to PARP is dependent on de novo protein synthesis, excluding the possibility that incorporation of fatty acids into PARP can occur by a remodelling of pre-existing GPI anchors. Finally we show that the phosphatidylinositol (PI) species that are utilized for GPI biosynthesis are a subpopulation of the cellular PI molecular species. We propose that these observations may be of general validity since several other eukaryotic membrane proteins (e.g. human erythrocyte acetylcholine esterase and decay accelerating factor) have been reported to contain palmitoylated inositol residues.
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PMID:A glycosylphosphatidylinositol protein anchor from procyclic stage Trypanosoma brucei: lipid structure and biosynthesis. 165 2

Receptor tyrosine kinases couple to multiple intracellular effector molecules that are crucial for normal cell growth and transformation. Stimulation of membrane phospholipid hydrolysis by receptor tyrosine kinases is one such pathway for generating intracellular second messengers that may be important for mitogenesis. Certain receptor tyrosine kinases tyrosine phosphorylate a phosphoinositide-specific phospholipase C that hydrolyses the membrane phospholipid phosphatidylinositol 4,5-bisphosphate. In contrast, the glycoprotein receptor for colony stimulating factor 1, a transmembrane tyrosine kinase, does not utilize this pathway, but rather stimulates the hydrolysis of phosphatidylcholine. Here we show that eluates of antiphosphotyrosine affinity purified lysates of colony-stimulating factor 1-stimulated cells contain elevated levels of phosphatidylcholine-specific phospholipase C activity. The affinity-purified activity is sensitive to tyrosine-specific T-cell phosphatase, and is detected in the membrane fraction of stimulated cells. Recovery of phospholipase C activity in the antiphosphotyrosine protein fraction is reduced by pertussis toxin pretreatment of cells. The phosphatidylcholine phospholipase C activity in isolated membranes of colony-stimulating factor 1-treated cells was also reduced by pertussis toxin treatment and stimulated by guanosine 5'-3-O-(thio)triphosphate. These results indicate that colony stimulating factor 1 receptor-mediated stimulation of phosphatidylcholine-specific phospholipase C requires tyrosine phosphorylation, and might be affected by a G-protein coupled pathway.
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PMID:Activation of a phosphatidylcholine-specific phospholipase C by colony stimulating factor 1 receptor requires tyrosine phosphorylation and a guanine nucleotide-binding protein. 147 33

When a blood vessel is disrupted, subendothelial structures such as collagen come into contact with circulating blood platelets. These will adhere and recruit additional platelets to form a platelet aggregate which will close the leak, but which can, under certain circumstances, give rise to the formation of a thrombus. In this work our personal contribution to a better understanding of this process is given. We could demonstrate the presence of an antibody interfering with the platelet-collagen interaction in two patients with a bleeding problem. One of the antibodies is directed against glycoprotein (GP) Ia, a known collagen receptor, the other one recognizes a less well characterized protein of 85-90 kD. It therefore can be concluded that activation of blood platelets requires the simultaneous interaction of collagen with multiple receptors. Activation of platelets following binding of an agonist in many instances involves activation of phospholipase C via a GTP-binding protein or G-protein. We have further studied this by using a direct stimulator of G-proteins, AlF4-, which in platelets indeed activates phospholipase C, together with other systems. Furthermore, we could demonstrate that activation of phospholipase C in a GTP-dependent manner also occurs in platelet cytosol, indicating that the action of G-proteins is not restricted to membrane-linked phenomena. Activation of phospholipase C gives rise to the formation of inositol phosphates, of which mainly inositol 1, 4, 5 trisphosphate increases intracellular Ca(2+)-levels. Following this, the Ca(2+)-dependent phospholipase A2 releases arachidonic acid from the membranes. In platelets arachidonic acid is metabolised to another platelet activator: thromboxane A2. We have studied the effects of the inhibition of this aggregation-amplifying pathway by using specific inhibitors of the synthesis of thromboxane A2 and of thromboxane A2 receptor antagonists both in vitro and in vivo. One of the conclusions that were reached from these studies was that theoretically the combination of these two classes of drugs should yield a significant stronger antiplatelet effect than either class used alone. We could later on confirm this hypothesis, which stimulated some pharmaceutical companies to look for dual action compounds, of which we have studied two so far.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:[Signal transduction in blood platelets]. 166 33

Several mammalian mutant cell lines are deficient in the biosynthesis of glycophosphatidylinositol anchors for membrane proteins. When metabolically labeled with [3H]myo-inositol or [3H]mannose, two out of five mutant lines (SIA-b and EL4-f) accumulated abnormal lipids which remained undetectable in the corresponding parental cell lines. The most abundant glycolipid of SIA-b cells (named lipid X) was isolated and partially characterized using hydrofluoric acid, nitrous acid deamination, acetolysis, and exoglycosidase treatments alone or in combination. The partial structure for the carbohydrate moiety of lipid X is Man alpha-(X----)Man alpha-GlcN-inositol, X being a charged, HF-sensitive substituent (possibly phosphoethanolamine). Lipid X is largely resistant to phosphatidylinositol-specific phospholipase C treatment but can be rendered sensitive to the enzyme by treatment with methanolic NH3, which suggests the presence of an acyl chain on the inositol moiety. The lipid moieties of lipid X are heterogenous in that about 50% of headgroups remain bound to a lipid moiety after mild alkaline hydrolysis. Similarly, about 50% of the lipid moieties of Thy-1, a glycophosphatidylinositol-anchored surface glycoprotein, isolated from SIA, the parent of SIA-b cells or from EL4 lymphoma cells, are resistant to mild alkaline hydrolysis. Altogether the data suggest that the SIA-b mutant line lacks an enzyme acting late in the anchor glycolipid biosynthesis pathway.
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PMID:Characterization of glycophospholipid intermediate in the biosynthesis of glycophosphatidylinositol anchors accumulating in the Thy-1-negative lymphoma line SIA-b. 168 15

Griffonia simplicifolia agglutinin-2-binding glycoprotein (GBG) in human colonic carcinoma was examined immunochemically and histochemically, GBG was extracted from colonic carcinoma as a serum-type glycoprotein of 160 kilodaltons. GBG was not identical with carcinoembryonic antigen (CEA), since its molecular weight and localization in tissue sections were different from those of CEA. The non-reducing terminals of GBG probably carry N-acetylglucosamine, but not blood group determinants. Furthermore, GBG was released by phosphatidylinositol-specific phospholipase C from cell membrane. GBG was suggested to be anchored to the membrane via linkage to a glycosyl-phosphatidylinositol molecule. Among colonic carcinoma-associated antigens, serum-type glycoproteins having N-acetylglucosamine at non-reducing terminals have not previously been reported. GBG is a novel carbohydrate antigen of human colonic carcinoma.
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PMID:Griffonia simplicifolia agglutinin-2-binding glycoprotein as a novel carbohydrate antigen of human colonic carcinoma. 169 41

Dimeric acetylcholinesterase is anchored in the cell membrane by a glycosyl-phosphatidylinositol attached to the C-terminus of the protein. The complex glycan contains an antigenic epitope, the cross-reacting determinant (CRD), which is only revealed after removal of the diradylglycerol by phosphatidylinositol-specific phospholipase C (PI-PLC) but is cryptic in the amphiphilic form. Polyclonal antibodies were raised against the CRD of vertebrate acetylcholinesterase. The purified anti-CRD antibodies recognized only the PI-PLC treated hydrophilic forms of acetylcholinesterase from bovine erythrocytes and Torpedo, and of variant surface glycoprotein from trypanosomes but not the corresponding amphiphilic proteins. Competition experiments showed that inositol-1,2-cyclic phosphate and glucosamine inhibited the binding of the antibodies to the CRD. Furthermore, binding of the anti-CRD antibodies to acetylcholinesterase containing N-methylated glucosamine was markedly reduced. The amphiphilic N-methylated enzyme is less sensitive to digestion with PI-PLC than the non-methylated form. From our results we conclude that inositol-1,2-cyclic phosphate and glucosamine, especially the free amine group of this residue, contribute significantly to the epitope recognized by the anti-CRD antibodies.
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PMID:Production and characterization of antibodies against the cross-reacting determinant of glycosyl-phosphatidylinositol-anchored acetylcholinesterase. 169 31

We have previously cloned the murine homolog of cDNA for the human myelomonocytic differentiation antigen, CD14. We synthesized three hydrophilic peptides derived from the predicted amino acid sequence of murine CD14 (mCD14), designated MS7.1, MS7.2, and MS7.3, respectively, and raised antisera against them. Each antiserum showed specific reactivity to the same peptide used for immunization. One of the anti-mCD14 antisera directed against MS7.3 peptide (AMS7.3) demonstrated the highest titer and definitively reacted with monocytic cell lines, inflammatory polymorphonuclear cells, and macrophages. Significant cross-reactivity of AMS7.3 was observed in the human monocytic cell line, THP-1. COS-1 cells transfected with MS7 cDNA expressed an antigen recognized by AMS7.3. Resident peritoneal and alveolar macrophages both expressed mCD14. mCD14 expression in peritoneal but not alveolar macrophages increased after treatment with lipopolysaccharide. Expression of mCD14 varied among monocytic cell lines and roughly paralleled the mRNA levels except in MI cells. SDS-PAGE and isoelectric focusing analysis of immunoprecipitated mCD14 showed that mCD14 was a 53 kd disulfide-linked protein with a pI of 4.5-5.1. Reduction of molecular weight by endo F treatment demonstrated that mCD14 was an N-linked glycoprotein. Since mCD14 is shed from the cell surface membrane by phosphatidylinositol-specific phospholipase C treatment, the indication is that mCD14 is a phosphatidylinositol-linked protein. The soluble form of mCD14 was detectable. Treatment with anti-mCD14 before interferon gamma (IFN gamma) stimulation significantly enhanced IFN gamma-induced H-2 antigen expression in the macrophage cell line.
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PMID:Molecular and physiological properties of murine CD14. 170 50


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