Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.4.3 (phospholipase C)
 18,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Antibody-mediated ligation of the CD3/T cell antigen receptor (TcR) activates phospholipase C (PLC) via a tyrosine kinase signaling pathway that requires expression of the transmembrane tyrosine phosphatase CD45. In normal T cells, CD3-mediated PLC activation is significantly augmented by co-ligation of CD3 with the CD4 co-receptor; however, unlike CD3-associated tyrosine kinases, antibody-induced activation of the CD4-associated tyrosine kinase p56lck does not require CD45 expression. To explore the role of CD45 in the CD3 and CD4 activation pathways further, we examined the effect of CD3/CD4 cross-linking on tyrosine phosphorylation and activation of phospholipase C in CD45- mutant cells of the T cell leukemia line HPB.ALL. In accord with previous observations, anti-CD3 stimulation of the CD45-deficient cells failed to activate tyrosine kinases, or PLC as measured by mobilization of intracellular calcium. However, we show here that ligation of CD3 with CD4 leads to tyrosine phosphorylation of PLC gamma 1 and elevation in the intracellular free Ca2+ concentration in CD45- cells that is in excess of that seen in CD45+ cells. Since CD4 stimulation alone did not activate PLC, a component of the CD3 signaling pathway must be independent of CD45. Anti-CD4-induced tyrosine phosphorylation and activation of CD4-associated lck was also enhanced in CD45- cells, suggesting that increased lck activation compensates for the defect in CD3/TcR signaling, such that interaction of the CD3 signaling pathway with the CD4-associated pathway activates PLC even in the absence of CD45. The data demonstrate that the requirement for CD45 in coupling CD3/TcR to the PI-PLC activation cascade is not absolute, but rather substantiates a role for CD45 in modifying molecular interactions that control T cell activation.
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PMID:Interaction of CD4:lck with the T cell receptor/CD3 complex induces early signaling events in the absence of CD45 tyrosine phosphatase. 153 48

It has been proposed that during T cell receptor antigen recognition, CD4- or CD8-p56lck molecules interact with the T cell antigen receptor-CD3 complex (TCR-CD3) to phosphorylate various undefined substrates, which then initiate signal transduction through the TCR-CD3 complex. The ability of CD4 to modulate the TCR-CD3-induced increase in intracellular Ca2+, [Ca2+]i, and substrate tyrosine phosphorylation was studied in mutants of the human leukemic T cell line HPB-ALL characterized by their low expression of the TCR-CD3 complex on the cell surface. In TCR-CD3low cells, in which CD3-zeta was found to be associated with the TCR-CD3 complex, cross-linking CD3 with CD4 resulted in a profile of calcium mobilization, CD3-zeta, and phospholipase C-gamma 1 tyrosine phosphorylation similar to that observed in HPB-ALL cells, although the magnitude of generalized substrate tyrosine phosphorylation appeared to be smaller, as compared with wild-type cells. Responses were weak or absent when CD3 was cross-linked alone. In contrast, in a mutant in which association of CD3-zeta 2 with the TCR-CD3 was defective, cross-linking of CD3 with CD4 had a weaker effect on any of the activation parameters tested. These experiments showed that the presence of CD3-zeta 2 in the TCR-CD3 complex is of critical importance for the ability of CD4 to enhance early transducing signals inside the cell. The data also suggest that CD4-associated protein tyrosine kinase p56lck could up-regulate defective CD3-mediated induction of phospholipase C activity by increasing tyrosine phosphorylation of phospholipase C-gamma 1.
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PMID:CD3-zeta surface expression is required for CD4-p56lck-mediated upregulation of T cell antigen receptor-CD3 signaling in T cells. 153 98

We have previously shown that stimulation of the Ti/CD3 receptor complex on human T-cells potentiates adenylate cyclase activation by adenosine or forskolin. Anti-CD2 receptor antibodies shared with anti-CD3 antibodies the ability to potentiate dose dependently the adenosine- and forskolin-stimulated cyclic adenosine monophosphate (cAMP) accumulation, whereas stimulation of the CD45 receptor had no effect on cyclase activity. Modulation of the CD3 complex with anti-CD3 antibodies was found to decrease the CD2 receptor effect on adenylate cyclase activity greatly. The possible involvement of CD3-stimulated phospholipase C (PLC) activation on the cAMP potentiation was examined using HPB-ALL cells that express a CD3 complex with a defect coupling to PLC. Stimulation of the CD3 complex on HPB-ALL cells had only slight effects on adenosine-stimulated cAMP formation, whereas the effect on forskolin-stimulated cAMP was virtually unchanged. The CD3 effect was further analyzed in Jurkat cell membranes. In contrast to the results obtained after stimulation of intact cells, it was found that OKT3 stimulation of membranes did not potentiate the forskolin response. Finally, we tested whether inhibition of endogenous adenylate cyclase agonist production affected the CD3 effect. Inhibition of adenosine production or adenosine breakdown with 8-p-sulphophenyl theophylline (8-PST) or adenosine deaminase (ADA), respectively, did not alter the CD3 effects. Indometacin, which inhibits prostaglandin production, also had no effect. Together, these data show that stimulation of the CD2 receptor potentiates adenylate cyclase responses by a mechanism that is dependent on CD3 expression. Furthermore, the CD3 effect on cAMP appears to be mediated by two different mechanisms, one which is, and one which is not dependent on PLC. Finally, this effect is not due to an endogenous production of adenylate cyclase agonists.
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PMID:CD3-dependent increase in cyclic AMP in human T-cells following stimulation of the CD2 receptor. 167 13

T cell receptor-CD3 complex (TCR-CD3)-mediated signal transduction was analyzed in HPB-ALL and Jurkat T cell lines. Both cell lines express high levels of TCR-CD3 complex on the cell surface, but provide different model systems for TCR-CD3 signaling in T cells. Jurkat responds with both inositol phosphate generation and intracellular Ca2+ mobilization after triggering of TCR-CD3, whereas TCR-CD3 triggering of HPB-ALL induces Ca2+ mobilization without detectable inositol phosphate generation. By employing a permeabilized cell system, we show that the HPB-ALL line expressed normal levels of Ca2(+)-induced phospholipase C activity. However, the TCR-CD3 on this cell line seems to be uncoupled from phospholipase C activation. In agreement with this result we also show, by analysis of protein kinase C-dependent phosphorylation of three distinct substrates, that TCR-CD3 in HPB-ALL is apparently uncoupled from protein kinase C activation. These findings may have implications for understanding signal-transducing pathways in T cells at various stages of differentiation.
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PMID:Signal transduction through the T cell receptor-CD3 complex. Evidence for heterogeneity in receptor coupling. 197 May 88

CD43 (sialophorin, gpL115) is a sialoglycoprotein expressed on a wide variety of blood cells including lymphocytes, monocytes, neutrophils, and platelets. L10, an anti-CD43 mAb, has been shown to induce monocyte-dependent activation and proliferation of human T lymphocytes. We have studied the signaling mechanism involved in this activation process. Treatment of PBMC and purified populations of T cells and monocytes with L10 induced the hydrolysis of phosphoinositides with the resultant generation of the phosphoinositide-derived second messengers diacylglycerol and inositol phosphates. This was associated with the translocation of protein kinase C from cytosol to membrane fractions and an increase in free intracellular Ca2+ in treated cells. In human leukemic T cell lines, the magnitude of signaling via CD43 did not correlate with the density of the TCR/CD3 surface expression nor with the intensity of signaling via the TCR/CD3. Moreover, a mutant derived from the leukemic T cell line HPB-ALL that was severely defective in TCR/CD3 surface expression and signaling nevertheless had normal CD43 surface expression and signaling compared with the parent cell line. It is concluded that CD43 is functionally coupled to the phospholipase C/phosphoinositides signaling pathway. In human T cells, signaling via CD43 proceeds independently of TCR/CD3. The widespread expression of CD43 suggests a potentially important role for this molecule in orchestrating the activation of multiple cell types.
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PMID:Mechanism of mononuclear cell activation by an anti-CD43 (sialophorin) agonistic antibody. 254 4

Procoagulant activity of gastric cancer tissues and leukocytes obtained from various types of leukemia have been studied with special reference to TTP. The following results were obtained. Homogenates of APL leukocytes and gastric cancer tissues contained strong procoagulant activities, most of which have been identified as TTP since the activities were neutralized by a specific antibody against purified human placenta TTP, inactivated by the removal of phospholipid with heptane-butanol mixture, and inactivated by the addition of phospholipase C. The delipidated homogenates regained procoagulant activities by relipidation procedures. These results also confirmed that TTP from APL leukocytes and gastric cancer tissues have the same lipoprotein properties as those of TTP in normal tissues. Though slight proteolytic activity and fibrinolytic activity were demonstrated in the homogenate of gastric cancer tissues, it was noted that the TTP activity was different from these two activities by partial purification of TTP from gastric cancer tissues. The TTP activity of 9 homogenates of gastric cancer tissues was 301 +/- 289 (mean +/- SD) units per mg protein, being higher in homogenates of mucinous adenocarcinoma and signet-ring cell carcinoma than in those of tubular and poorly differentiated adenocarcinoma. The mean TTP activity of leukocyte homogenates from 14 patients with APL and one out of 4 patients with CML in blastic crisis was 81 +/- 76 units/10(7) cells. The TTP activity of the homogenates of leukocytes from 7 out of 18 patients with AML and another patient with CML in blastic crisis ranged from one to six units/10(7) cells with a mean of 3.3 +/- 1.2. The TTP activity of leukocyte homogenates from the other 11 cases of AML, two cases of CML in blastic crisis, 6 cases of CML, and one case each of ALL and CLL were less than one unit/10(7) cells. In leukemic patients, all cases with a value of more than 202 for the product of units of TTP activity per 10(7) cells and differential count (%) of leukemic cells in the bone marrow smear (MU value) were accompanied by DIC. The MU value of leukemic patients correlated well to the plasma fibrinogen and serum FDP levels. All patients with a MU value of more than 277 died of DIC when a sufficient amount of heparin was not administered. On the other hand, no DIC developed in any of the patients with a MU value of less than 90.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:The role of tissue thromboplastin in the development of DIC accompanying neoplastic diseases. 666 48

The involvement of the early signaling messengers, inositol tris-phosphate (IP3), intracellular calcium, [Ca2+]i, and protein kinase C (PKC), in angiotensin II (AII)-induced fluid phase endocytosis was investigated in human brain capillary and microvascular endothelial cells (HCEC). ALL (0.01-10 microM) stimulated the uptake of Lucifer yellow CH, an inert dye used as a marker for fluid phase endocytosis, in HCEC by 50-230%. AII also triggered a fast accumulation of IP3 and a rapid increase in [Ca2+]i in cells loaded with the Ca(2+)-responsive fluorescent dye fura-2. The prompt AII-induced [Ca2+]i spike was not affected by incubating HCEC in Ca(2+)-free medium containing 2 mM EGTA or by pretreating the cultures with the Ca2+ channel blockers, methoxyverapamil (D600; 50 microM), nickel (1 mM), or lanthanum (1 mM), suggesting that the activation of AII receptors on HCEC triggers the release of Ca2+ from intracellular stores. The AII-triggered increases in IP3, [Ca2+]i, and Lucifer yellow uptake were inhibited by the nonselective AII receptor antagonist, Sar1, Val5, Ala8-AII (SVA-AII), and by the phospholipase C (PLC) inhibitors, neomycin and U-73122. By contrast, the protein kinase C (PKC) inhibitors, staurosporine and calphostin C, failed to affect any of these AII-induced events. This study demonstrates that increased fluid phase endocytotosis induced by AII in human brain capillary endothelium, an event thought to be linked to the observed increases in blood-brain barrier permeability in acute hypertension, is likely dependent on PLC-mediated changes in [Ca2+]i and independent of PKC.
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PMID:Angiotensin II-induced fluid phase endocytosis in human cerebromicrovascular endothelial cells is regulated by the inositol-phosphate signaling pathway. 895 95

In normal lymphocytes an inside-out signal up-regulating integrin adhesion is followed by a ligand-mediated outside-in cell spreading signal. Protein kinase C (PKC) inhibition blocks lymphocyte adherence to and spreading on fibronectin. In contrast, putative PLC inhibitors yield distinct differences with respect to adhesion and morphology. The phosphatidylinositol-specific phospholipase C (PLC) inhibitor neomycin blocked spreading of CD3/CD28-activated T cells on fibronectin by disrupting adhesion. Furthermore, when an additional inside-out signal for fibronectin adhesion is unnecessary such as with HPB-ALL T leukemic or phorbol-myristate-acetate-treated normal T cells, neomycin treatment does not alter adhesion or morphology. However, the phosphatidylcholine-specific PLC inhibitor D609 abrogates cell spreading without affecting adhesion to fibronectin in these cells as well as the CD3/CD28-activated T cells. These results strongly suggest that inside-out signaling for the integrin alpha4beta1 in lymphocytes proceeds through phosphatidylinositol-specific PLC and PKC, whereas the outside-in signal utilizes phosphatidylcholine-specific PLC and PKC.
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PMID:Separation of integrin-dependent adhesion from morphological changes based on differential PLC specificities. 988 55

It has been well established that certain polycyclic aromatic hydrocarbons (PAHs), such as 7,12-dimethylbenz[a]anthracene (DMBA), 3-methylcholanthrene (3MC), and benzo[a]pyrene (BaP), produce immunotoxicity and cancer in rodents and that these effects are also likely seen in humans. Our laboratory has found that polycyclic aromatic hydrocarbons (PAHs) produce an increase in intracellular Ca2+ in lymphocytes that appears to correlate with their immunotoxicity. Specifically, immunotoxic PAHs, such as DMBA and BaP, have been shown to produce a sustained increase in intracellular Ca2+ in lymphocytes, whereas nonimmunosuppressive PAHs, such as benzo[e]pyrene (BeP) and anthracene, do not. Our studies previously demonstrated that the rapid increase in intracellular Ca2+ produced by DMBA in HPB-ALL T cells was caused by protein tyrosine kinase (PTK) activation in human T cells, leading to tyrosine phosphorylation of phospholipase C (PLCgamma) and IP3-dependent Ca2+ mobilization. However, the specificity of PTK activation by PAHs was not established. In the present studies, we extend our observations of PTK activation by examining a number of PAHs for their effects on total and specific (Fyn and ZAP-70) PTK activity. We show that 10 microM concentrations of PAHs nonspecifically and rapidly (within 5 min) stimulate PTKs in the HPB-ALL human T cell line. BeP and anthracene were found to be nearly as effective at increasing total tyrosine kinase activity as DMBA, 3MC, and BaP, observed 5 min after exposure. We found that only immunotoxic PAHs activated the Fyn and ZAP-70 PTKs at 10 min, but total PTK activity was still increased by nonimmunotoxic PAHs, BeP, or anthracene after 10 min of exposure. These studies demonstrate that immunotoxic PAHs increase total and specific PTK activity in the human HPB-ALL T cell line. Thus the rapid increase in PTK activity produced by PAHs may not correlate with the immunotoxicity of these agents.
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PMID:Protein tyrosine kinase activation by polycyclic aromatic hydrocarbons in human HPB-ALL T cells. 1070 43