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)

Cross-linking of the B cell AgR results in activation of mature B cells and tolerization of immature B cells. The initial signaling events stimulated by membrane immunoglobulin (mIg) cross-linking are tyrosine phosphorylation of a number of proteins. Among the targets of mIg-induced tyrosine phosphorylation are the tyrosine kinases encoded by the lyn, blk, fyn, and syk genes, the mIg-associated proteins MB-1 and Ig-beta, phospholipase C-gamma 1 and -gamma 2, as well as many unidentified proteins. In this report we show that mIg cross-linking also regulates phosphatidylinositol 3-kinase (PtdIns 3-kinase), an enzyme that phosphorylates inositol phospholipids and plays a key role in mediating the effects of tyrosine kinases on growth control in fibroblasts. Cross-linking mIg on B lymphocytes greatly increased the amount of PtdIns 3-kinase activity which could be immunoprecipitated with anti-phosphotyrosine (anti-tyr(P) antibodies. This response was observed after mIg cross-linking in mIgM- and mIgG-bearing B cell lines and after cross-linking either mIgM or mIgD in murine splenic B cells. Thus, regulation of PtdIns 3-kinase is a common feature of signaling by several different isotypes of mIg. This response was rapid and peaked 2 to 3 min after the addition of anti-Ig antibodies. The anti-Ig-stimulated increase in PtdIns 3-kinase activity associated with anti-Tyr(P) immunoprecipitates could reflect increased tyrosine phosphorylation of PtdIns 3-kinase, increased activity of the enzyme, or both. In favor of the first possibility, the tyrosine kinase inhibitor herbimycin A blocked the increase in ant-Tyr(P)-immunoprecipitated PtdIns 3-kinase activity as well as the anti-Ig-induced tyrosine phosphorylation. Moreover, this response was not secondary to phospholipase C activation but rather seemed to be a direct consequence of mIg-induced tyrosine phosphorylation. Activation of the phosphoinositide pathway by a transfected M1 muscarinic acetylcholine receptor expressed in WEHI-231 B lymphoma cells did not increase the amount of PtdIns 3-kinase activity which could be precipitated with anti-Tyr(P) antibodies. Similarly, inhibition of the phosphoinositide pathway did not abrogate the ability of mIg cross-linking to stimulate this response. Thus, mIg-induced tyrosine phosphorylation regulates PtdIns 3-kinase, an important mediator of growth control in fibroblasts and potentially an important regulatory component in B cells as well.
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PMID:Membrane Ig cross-linking regulates phosphatidylinositol 3-kinase in B lymphocytes. 137 19

The triggering of T- or B-cell antigen-specific receptors is accompanied by rapid tyrosine phosphorylation of distinct cellular substrates, one of which is the gamma 1 isoform of inositol phospholipid-specific phospholipase C (PLC-gamma 1). This phosphorylation event, mediated by a putative protein tyrosine kinase coupled to the antigen receptor, probably stimulates the enzymatic activity of PLC-gamma 1, thereby promoting inositol phospholipid hydrolysis and other downstream signal transduction events. Recently, another ubiquitously expressed PLC isoform, PLC-gamma 2 (which shares 50.2% amino acid homology with PLC-gamma 1), has been identified. PLC-gamma 2-specific antibodies were used to evaluate the distribution and potential signaling role of this isoform in lymphocytes. Here, we report that, in contrast to T lymphocytes that express predominantly PLC-gamma 1, the major isoform expressed in murine and human resting B cells is PLC-gamma 2. Among B-cell tumor lines, all five murine B-lymphoma lines tested and one of six human B-lymphoblastoid cell lines also expressed predominantly PLC-gamma 2. However, three other human lines preferentially expressed PLC-gamma 1, and two others displayed similar levels of the two PLC-gamma isoforms. Furthermore, the triggering of B-cell surface immunoglobulin by anti-receptor antibodies was accompanied by a rapid tyrosine phosphorylation of PLC-gamma 2, which peaked after 5 min of stimulation. Conversely, and in agreement with recent reports, triggering of the T-cell antigen receptor complex led to the predominant phosphorylation of PLC-gamma 1 on tyrosine. These findings identify PLC-gamma 2 as a substrate for a B-cell putative protein tyrosine kinase coupled to the antigen receptor and suggest that its tyrosine phosphorylation constitutes a critical and early event in B-cell activation and, furthermore, that PLC-gamma 1 and PLC-gamma 2 may participate in similar but distinct signal transduction pathways in lymphocytes.
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PMID:Predominant expression and activation-induced tyrosine phosphorylation of phospholipase C-gamma 2 in B lymphocytes. 137 28

The effect of interferon-alpha on Daudi lymphoma cells either sensitive or resistant to the action of this cytokine has been analysed in terms of phospholipase C (PLC) and D (PLD) activities. Results have shown a combined modulation of PIP2-specific phospholipase C and phospholipase D. In particular, a decreased activity of PIP2-specific PLC has been found, concomitant to a PLD-mediated phosphatidylcholine hydrolysis, suggesting that the intracellular signalling activated by interferon in Daudi cells involves a phospholipase D/phosphohydrolase pathway.
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PMID:Interferon-mediated intracellular signalling. Modulation of different phospholipase activities in Burkitt lymphoma cells. 144 36

Previous studies showed that the human monocytic leukemia cell line THP-1 can be induced to undergo monocytic differentiation by tumor promoting phorbol esters (TPA), suggesting that protein kinase C (PK-C), the primary binding site of TPA, may play a role in the control of monocytic differentiation: The effect of exogenous phospholipase C (PLC) on THP-1 cells was investigated. Within 24-48 hr, PLC induced over 40% of THP-1 cells to undergo monocytic differentiation as manifested by adherence, growth arrest, functional expression, morphological changes and expression of c-fms gene which encode for M-CSF receptors. Compared to TPA, however, the inducing activity of PLC was weaker, slower and not as effective. PLC treatment also induced a transient expression of c-fos proto-oncogene prior to c-fms expression. On the contrary, the level of c-myc RNA, which is constitutively expressed in THP-1 cells, was down-regulated 48 hr after PLC treatment. The PLC-induced monocytic differentiation in THP-1 cells was inhibited by staurosporine, a potent PK-C inhibitor, further suggesting that direct activation of the PK-C is one of the metabolic events essential for monocytic differentiation. It is postulated that in THP-1 cells the metabolic pathway transducing PK-C activation has been permanently blocked, thereby leading to uncontrolled proliferation without differentiation.
Leuk Lymphoma 1992 Jul
PMID:Phospholipase C-induced monocytic differentiation in a human monocytic leukemia cell line THP-1. 149 32

The aim of this study was to explore whether Thy-1, like other members of the Ig-like superfamily (e.g., CD2 and neural cell adhesion molecule), participates in cell-cell adhesion. This was investigated by measuring the binding of Thy-1+ probe cells (thymocytes or AKR1 T lymphoma cells) to Thy-1- cloned mouse thymic epithelial (MTE) cells using a quantitative cell adhesion assay. The results were as follows: (a) the thymo-epithelial cell interaction was found to be inhibitable (by 25-40%) by soluble Thy-1 molecules purified from phosphatidylinositol-specific phospholipase C-treated mouse thymocytes as well as by Fab' fragments of a Thy-1-specific mAb; (b) the binding of the Thy-1- AKR1 (Thy-1-d) mutant to MTE cells was found to be reduced (by 50%) as compared with that of the wild type T lymphoma; (c) the Thy-1-mediated adhesion pathway did not require Ca2+ and promoted the initial thymo-epithelial binding measured at 4 degrees C. These data provide the first direct evidence of an adhesive function of Thy-1 and suggest that this molecule, in addition to its T cell triggering properties, might play a role during the early T cell maturation by promoting thymocyte adhesion to thymic stroma.
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PMID:Thy-1 supports adhesion of mouse thymocytes to thymic epithelial cells through a Ca2(+)-independent mechanism. 167 Oct 83

Murine Thy-1-negative lymphoma mutants synthesize membrane proteins that normally bear glycolipid anchors but do not express these proteins on the cell surface. This phenotype may reflect altered regulation of gene(s) required for anchor biosynthesis. Since tissue culture cells treated with sodium butyrate transcribe new DNA sequences and since these transcripts are translated, it was of interest to determine whether butyrate treatment could restore surface expression of lipid-anchored proteins. When Thy-1-negative lymphoma mutants (complementation groups A-C, E, F, and H) were cultured for three days in 1.5 mM butyrate, a small percentage of the class H cells acquired phosphatidylinositol-specific phospholipase C-releasable surface Thy-1 and J11d. Membrane-associated Thy-1 was not observed before 24 h of treatment. Induction was reversible. Cell fusion studies have shown that murine LM (TK-) fibroblasts can be assigned to the class H lymphoma complementation group. Although these cells synthesize Ly-6, this normally lipid-anchored protein is absent from the cell surface. When LM (TK-) cells were cultured for three days in butyrate, 10% of the cells reversibly expressed Ly-6. In addition, LM (TK-) cells transfected with a plasmid encoding Thy-1 do not express Thy-1, but could be induced to express both Ly-6 and Thy-1 by butyrate treatment. Northern analysis of total RNA from Ly-6/Thy-1-expressing cells indicates that increased steady-state transcript levels cannot account for surface expression of these proteins. We conclude that the lack of expression of three proteins at the surface of class H mutant and the LM (TK-) cells is not due to gross structural lesions in genes along the anchor biosynthetic pathway.
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PMID:Sodium butyrate causes reexpression of three membrane proteins on glycolipid-anchoring mutants. 167 68

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

Activation of T lymphocytes leads to the production of the T cell growth factor IL-2 that regulates T cell proliferation. This activation is associated with several potential intracellular signalling events including increased activity of phospholipase C (PLC) and resultant increases in production of inositol phosphates and diacylglycerols. In addition, phosphorylation of specific intracellular proteins on serine, threonine, and tyrosine residues increases. The role of each of these events in IL-2 production is unclear. Using Western blotting with antiphosphotyrosine antibodies, we demonstrate that activation of murine T cells with mitogenic lectins or anti-CD3 antibodies leads to a rapid increase in tyrosine phosphorylation of proteins of 120, 72, 62, 55, and 40 kDa. Similar patterns of antiphosphotyrosine antibodies reactivity were observed in splenocytes, a T cell hybridoma, and a T lymphoma. Tyrosine phosphorylation was detectable within minutes of addition of mitogenic lectins and persisted for at least 6 h. Pretreatment of the cells with pertussis toxin did not inhibit tyrosine phosphorylation indicating that a pertussis toxin-sensitive G protein is not involved in signal transduction. Neither increasing cytosolic-free calcium nor activating protein kinase C mimicked the effects of mitogenic lectins suggesting that tyrosine phosphorylation was not a consequence of activation of PLC. This was confirmed by demonstrating that mitogenic lectins induced similar patterns of tyrosine phosphorylation in cells in which activation of the TCR leads to increased PLC activity and in cells in which PLC is not stimulated. To test whether tyrosine phosphorylation is linked to IL-2 secretion, we determined the effect of three specific tyrosine kinase inhibitors (tyrphostins) on tyrosine phosphorylation, IL-2 secretion, and cellular proliferation. The concentration dependence of inhibition of tyrosine phosphorylation and IL-2 production were similar. However, higher concentrations of the tyrphostins were required to inhibit constitutive proliferation of the T cell line indicating that inhibition of IL-2 secretion was not secondary to nonspecific toxic effects of the tyrphostins. Addition of the tyrphostins after mitogenic lectin decreased the amount of tyrosine phosphorylation and IL-2 secretion in parallel. This indicates that both tyrosine kinases and phosphatases are activated and that continuous tyrosine phosphorylation is likely required for IL-2 secretion. Therefore, tyrosine phosphorylation appears to represent an obligatory event in the transmembrane signaling processes that lead to IL-2 secretion.
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PMID:Tyrosine phosphorylation is an obligatory event in IL-2 secretion. 169 78

BAL17 B lymphoma cells, representing mature B lymphocytes, were used to analyze the role of tyrosine kinase in B cell activation. Anti-IgM-induced tyrosine phosphorylation was inhibited by preincubation of cells with tyrosine kinase inhibitor herbimycin A. Enzymatic activity of lyn protein was also inhibited by this drug, accompanied by down-regulation of p53lyn and p56lyn. However, a protein kinase C-mediated event was intact in the herbimycin A-pretreated cells, suggesting that the inhibitor acts selectively on tyrosine kinase. Anti-IgM failed to stimulate herbimycin A-pretreated cells to induce increases in inositol phospholipid metabolism or increased [Ca2+]i, whereas aluminum fluoride-induced metabolism was not altered. Moreover, membrane IgM density as revealed by flow cytometry was not changed by herbimycin A. These results indicate that tyrosine kinase(s) participates in the coupling of an Ag receptor cross-linkage to phospholipase C activation through a phosphorylation event in B lymphoma cells.
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PMID:Tyrosine protein kinase is involved in anti-IgM-mediated signaling in BAL17 B lymphoma cells. 173 Aug 66

Immunological and biochemical characteristics of the Qa-2 murine nonclassical histocompatibility class 1 antigen expressed on tumor cells derived from H-2k (Qa-2-) mice were studied. It was found that the Qa-2 antigen on normal H-2b lymphocytes reacted with Qa-2-specific monoclonal antibodies (mAbs) 34-1.2, 59 (both specific to the alpha 1/alpha 2 region) and 141-15.8 (specific to the alpha 3 domain), and the Qa-2 antigen on H-2k tumor cells (Qa-2k antigen) reacted with mAbs 59 and 141-15.8, but not with 34-1.2. The normal Qa-2 antigen was susceptible to treatment with phosphatidylinositol-specific phospholipase C, but the Qa-2k antigen was insensitive to it. By Northern hybridization, polymerase chain reaction (PCR) studies on cDNA, Southern hybridization, Western blotting, and nucleotide sequence analysis, the Q5k gene was identified as the gene encoding the Qa-2k antigen expressed on BW5147 lymphoma cells derived from a mouse of AKR strain (H-2k, Qa-2-). The nucleotide sequence of PCR-amplified BW5147 Q5k cDNA showed complete agreement with the reported sequence of exons 1-5 of the Q5k gene of C3H/He. It also showed complete deletion of the region corresponding to exons 6 and 7, and a very short coding region in exon 8, resulting in very short cytoplasmic domain of the product compared with regular class 1 antigens. These characteristics were expected from the reported Q5k genomic sequence. These results revealed that the Qa-2k antigen was distinct from the normal Qa-2 antigen expressed on H-2b lymphocytes although it cross-reacted with some Qa-2-specific mAbs.
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PMID:Expression of the Qa-2k phenotype encoded by the Q5k gene on the surface of tumor cells derived from H-2k mice. 174 Jun 59


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