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)

The chicken CT10 virus oncogene product, P47gag-crk, contains SH2/SH3 domains that have been identified as conserved domains among proteins involved in signal transduction. We studied the functional similarity of the SH2/SH3 domains by replacing those of v-Crk with those of phosphatidylinositol-specific phospholipase C-gamma, v-Src, or c-Src. The transforming activity of v-Crk was partially retained in a mutant with a v-Src SH3 domain but not in the other mutants with heterologous SH2/SH3 domains. Mutant viruses with Crk-SH2/SH2' domains induced tyrosine phosphorylation of cellular proteins, but mutants with phosphatidylinositol-specific phospholipase C-gamma or Src SH2/SH2' domains did not. However, the mutant proteins with heterologous SH2/SH2' regions were able to weakly associate with some phosphotyrosine-containing proteins in vitro. These results indicate that in the context of the P47gag-crk structure, the requirement of Crk-SH2/SH3 is more stringent for its activity to induce cell transformation than to cause phosphorylation of cellular proteins. The substitution with heterologous sequences least perturbs the capacity to bind phosphotyrosine-containing proteins. In each case, the SH3 domain is more flexible to substitution than is the SH2 domain.
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PMID:Biological and biochemical activity of v-Crk chimeras containing the SH2/SH3 regions of phosphatidylinositol-specific phospholipase C-gamma and Src. 137 84

In the course of our investigation of phospholipase C (PLC)-gamma 1 phosphorylation by using a set of anti-PLC-gamma 1 monoclonal antibodies (P.-G. Suh, S. H. Ryu, W. C. Choi, K.-Y. Lee, and S. G. Rhee, J. Biol. Chem. 263:14497-14504, 1988), we found that some of these antibodies directly recognize a 47-kDa protein. We show here that this 47-kDa protein is identical to the SH2/SH3-containing protein Nck (J. M. Lehmann, G. Riethmuller, and J. P. Johnson, Nucleic Acids Res. 18:1048, 1990). Nck was found to be constitutively phosphorylated on serine in resting NIH 3T3 cells. Platelet-derived growth factor (PDGF) treatment led to increased Nck phosphorylation on both tyrosine and serine. Nck was also found to be phosphorylated on tyrosine in epidermal growth factor (EGF)-treated A431 cells and in v-Src-transformed NIH 3T3 cells. Multiple sites of serine phosphorylation were detected in Nck from resting cells, and no novel sites were found upon PDGF or EGF treatment. A single major tyrosine phosphorylation site was found in Nck in both PDGF- and EGF-treated cells and in v-Src-transformed cells. This same tyrosine was phosphorylated in vitro by purified PDGF and EGF receptors and also by pp60c-src. We compared the phosphorylation of Nck and PLC-gamma 1 in several cell lines transformed by oncogenes with different modes of transformation. Although PLC-gamma 1 and Nck have significant amino acid identity, particularly in their SH3 regions, and both associate with growth factor receptors in a ligand-dependent manner, they were not always phosphorylated on tyrosine in a coincident manner.
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PMID:The SH2/SH3 domain-containing protein Nck is recognized by certain anti-phospholipase C-gamma 1 monoclonal antibodies, and its phosphorylation on tyrosine is stimulated by platelet-derived growth factor and epidermal growth factor treatment. 144 8

Phosphatidylinositol (PtdIns)-4- and -3-kinases, PtdIns(4)P-5-kinase, diacylglycerol (DAG) kinase, and PtdIns-phospholipase C were all detected in cytoskeletons of resting human platelets. The total cytoskeletal enzyme activities were greatly increased upon thrombin stimulation of the intact cells. Those reached a maximum after a 60-s stimulation for PtdIns(4)P-5-kinase and phospholipase C, while the other kinases appeared to be slightly delayed. Specific activities were stimulated from about 4-fold (PtdIns-3-kinase) to about 6-fold (PtdIns-4-kinase). Thrombin treatment also promoted a co-extraction of pp60c-src with the cytoskeletons and its disappearance from the Triton X-100 soluble fraction. These results suggest that stimulation of platelets by thrombin causes the association of enzymes responsible for lipid phosphorylation and hydrolysis with the cytoskeletons. This could occur at cytoskeleton anchoring points to the membranes.
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PMID:Interaction of pp60c-src, phospholipase C, inositol-lipid, and diacyglycerol kinases with the cytoskeletons of thrombin-stimulated platelets. 171 96

The transforming protein of polyomavirus, middle T (mT), forms a complex with two cellular enzymes: the protein tyrosine kinase pp60c-src and a phosphatidylinositol (PtdIns) 3-kinase. A mutant virus, Py1178T, encodes an mT protein which associates with and activates pp60c-src to the same extent as the wild type but fails to associate with PtdIns 3-kinase. To investigate relationships between activation of pp60c-src, association of PtdIns 3-kinase, and cellular levels of the second messenger inositol 1,4,5-trisphosphate (InsP3), we examined the effects of wild-type and mutant mT proteins on inositol metabolism in rat and mouse fibroblasts. Expression of either wild-type or 1178T mT caused a 300 to 500% increase in the InsP3 level. Cells transformed by Rous sarcoma virus also showed similar increases in InsP3 levels. Mutant mT proteins which failed to activate pp60c-src (NG59 and 1387T) had no effect on InsP3 levels. Pulse-chase experiments with [3H]inositol showed that the turnover of phosphoinositides was increased in cells transformed by either wild-type polyomavirus or Py1178T as compared with the normal parent cell line. The turnover of inositol phosphates was unchanged upon transformation. These data indicate that cells expressing either wild-type or mutant 1178T mT or pp60v-src exhibit elevated levels of InsP3 because of activation of phospholipase C. This activation appears to depend, directly or indirectly, upon activation of pp60src protein kinase activity. Activation of pp60c-src and elevation of InsP3 content are not sufficient for full transformation. Full transformation also requires the association of mT-pp60c-src complexes with PtdIns 3-kinase.
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PMID:Inositol trisphosphate levels in cells expressing wild-type and mutant polyomavirus middle T antigens: evidence for activation of phospholipase C via activation of pp60c-src. 215 7

The transforming protein of polyoma virus, middle T antigen, associates with two cellular enzymes, pp60c-src, a protein tyrosine kinase, and a phosphatidylinositol kinase that forms phosphatidylinositol 3-phosphate. The formation of a ternary complex of these proteins is essential for complete transformation and maximal tumor induction by the virus. A mutant virus encoding an altered middle T protein that activates pp60c-src but fails to bind phosphatidylinositol kinase is partially defective in transformation. We have confirmed, using an enzymological method, that the product of the in vitro reaction catalyzed by middle T-pp60c-src-phosphatidylinositol kinase complexes is phosphatidylinositol 3-phosphate (PtdIns(3)P), as previously reported (Whitman, M., Downes, C. P., Keeler, M., Keller, T., and Cantley, L. (1988) Nature 332, 644-646). PtdIns(3)P is present in normal as well as virus-infected and transformed cells at levels ranging from 0.6 to 2.6% of the major phosphatidylinositol phosphate isomer, phosphatidylinositol 4-phosphate (PtdIns(4)P). Steady-state levels of PtdIns(3)P do not appear to be affected by the expression of middle T in cells. PtdIns(3)P is not hydrolyzed by bovine brain phospholipase C II, which readily cleaves PtdIns(4)P and other phosphatidylinositols. This result underscores the likelihood that the metabolism of PtdIns(3)P is distinct from that of PtdIns(4)P and raises further questions regarding a possible role of PtdIns(3)P in normal and neoplastic cell growth.
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PMID:Phosphatidylinositol 3-phosphate is present in normal and transformed fibroblasts and is resistant to hydrolysis by bovine brain phospholipase C II. 254 86

This paper has reviewed, in a broad sense, the potential involvement of the oncogenes and their progenitors, the protooncogenes, in signal transduction pathways. The membrane-associated oncogene products appear to be connected with the generation and/or regulation of secondary messengers, particularly those associated with Ca2+/phospholipid-dependent activation of the serine/threonine kinase protein kinase C. Activation of transmembrane receptors, either through binding their native ligand or through point mutations that lead to constitutive expression, results in the expression of their intrinsic tyrosine-specific protein kinases. In PDGF-stimulated cells, this results in the increased turnover of phosphatidylinositols and the subsequent release of IP3 (Habenicht et al., 1981; Berridge et al., 1984). This coincides with activation of a PI kinase activity (Kaplan et al., 1987). Likewise, the fms product, which is the receptor for CSF-1, induces a guanine nucleotide-dependent activation of phospholipase C (Jackowski et al., 1986). Receptor functions are potentially regulated through differential binding of ligands (as proposed with PDGF), through interactions with other receptors, and through the "feedback" regulation mediated by protein kinase C. PDGF stimulation leads to modulation of the EGF receptor through protein kinase C (Bowen-Pope et al., 1983; Collins et al., 1983; Davis and Czech, 1985). Similarly, the neu product becomes phosphorylated on tyrosine residues following treatment of cells with EGF, although the neu protein does not bind EGF itself (King et al., 1988; Stern and Kamps, 1988). The tyrosine kinases of the src family are not receptors themselves, although they may mediate specific receptor-generated signals. The clck product is physically and functionally associated with the T-cell receptors CD4 and CD8, and becomes active upon specific stimulation of cells expressing those markers (Veillette et al., 1988a,b). The precise physiological role of the src family products has not been established, but their kinase activity is intrinsic to that function. The v- and c-src products are hyperphosphorylated during mitosis (Chackalaparampil and Shalloway, 1988), which correlates with periods of reduced cell-to-cell adhesion and communication (Warren and Nelson, 1987; Azarnia et al., 1988). Furthermore, pp60c-src is associated with a PI kinase activity when complexed with MTAg of polyoma virus, suggesting a function in stimulating increased turnover of the phosphatidylinositols (Heber and Courtneidge, 1987; Kaplan et al., 1987).(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Oncogenes, protooncogenes, and signal transduction: toward a unified theory? 269 May 95

Platelet glycoprotein (GP) VI is a so-far uncharacterized 62-kDa membrane protein, whose deficiency results in selective impairment in collagen-induced platelet aggregation. Our group previously reported a human polyclonal antibody (anti-p62 IgG) that induces activation of normal, but not of GPVI-deficient, platelets in an Fc-independent manner. The F(ab')2 fragments of this antibody (F(ab')2-anti-p62) stimulated tyrosine phosphorylation of numerous proteins, which was not prevented even in the presence of cAMP-increasing agents such as prostacyclin. Pretreatment of platelets with the protein-tyrosine kinase (PTK) inhibitor tyrphostin A47 completely abolished F(ab')2-anti-p62-induced platelet aggregation in parallel with dose-dependent inhibition of protein-tyrosine phosphorylation, indicating an essential requirement of PTK activity for generating GPVI-mediated signaling. We found that two cytosolic PTKs, c-Src and Syk, became rapidly activated in response to F(ab')2-anti-p62 in a way insensitive to elevation of cAMP. In contrast, in the presence of prostacyclin, F(ab')2-anti-p62 did not stimulate tyrosine phosphorylation of the focal adhesion kinase. cAMP-insensitive activation of c-Src and Syk was also observed in collagen but not thrombin-stimulated platelets. Moreover, either F(ab')2-anti-p62 or collagen stimulated cAMP-insensitive tyrosine phosphorylation of phospholipase C-gamma 2. These results indicate that the receptor-mediated activation of several PTKs in platelets is regulated through a cAMP-sensitive or -insensitive mechanism depending on the nature of each stimulus, and also suggest that GPVI engagement is coupled to cAMP-insensitive activation of c-Src and Syk accompanied by tyrosine phosphorylation of numerous substrates including phospholipase C-gamma 2 in a manner similar to collagen stimulation.
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PMID:Cyclic AMP-insensitive activation of c-Src and Syk protein-tyrosine kinases through platelet membrane glycoprotein VI. 749 87

Antibodies to pp60v-arc and phosphotyrosine were introduced into rabbit platelets using an electropermeabilization technique. The presence of these antibodies inside platelets was detected by flow cytometry. Platelet-activating factor (PAF)-stimulated phospholipase C activity (inositol phosphate production) and aggregation were dramatically inhibited in platelets transjected with either of these antibodies. Incubation of these antibodies with intact cells (i.e. nonpermeabilized) or electrotransjection of several nonspecific antibodies/agents (e.g. goat anti-mouse IgG, mouse serum, human platelet glycoprotein Ib monoclonal antibody, and fetal calf serum) into platelets had no effect on the PAF responses. trpE (another isotype-matched control antibody of pp60v-src) and pp56lck polyclonal antibody (another src-related kinase not present in platelets) also had no effect on PAF-induced aggregation and inositol phosphate production in permeabilized platelets. This indicates that the effect of internalized pp60v-src antibody is direct and specific in platelets. Stimulation of platelets by PAF increased the association and phosphorylation of both pp60c-src (60 kDa) and phospholipase C gamma 1 (145 kDa). This study provides the first evidence in platelets for a direct and specific involvement of pp60c-src in PAF-mediated phospholipase C activation and aggregation response.
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PMID:Electrotransjection of pp60v-src monoclonal antibody inhibits activation of phospholipase C in platelets. A new mechanism for platelet-activating factor responses. 751 Jul 3

Signaling by tyrosine kinase receptors is mediated by selective interactions between individual Src homology 2 (SH2) domains of cytoplasmic effectors and specific phosphotyrosine residues in the activated receptor. Here, we report the existence in the hepatocyte growth factor/scatter factor (HGF/SF) receptor of a multifunctional docking site made of the tandemly arranged degenerate sequence YVH/NV. Phosphorylation of this site mediates intermediate- to high-affinity interactions with multiple SH2-containing signal transducers, including phosphatidylinositol 3-kinase, phospholipase C gamma, pp60c-src, and the GRB-2-Sos complex. Mutation of the two tyrosines results in loss of biological function, as shown by abrogation of the transforming activity in the oncogenic counterpart of the receptor. The same bidentate motif is conserved in the evolutionarily related receptors Sea and Ron, suggesting that in all members of the HGF/SF receptor family, signal transduction is channeled through a multifunctional binding site.
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PMID:A multifunctional docking site mediates signaling and transformation by the hepatocyte growth factor/scatter factor receptor family. 751 58

A431 cells, a human epidermoid carcinoma, possess specific [3H]platelet-activating factor (PAF) and [3H]WEB 2086 binding sites indicating the presence of PAF receptors. PAF-stimulated PLC as determined by the increase in inositol phosphate levels. Pretreatment of A431 cells with genistein, a putative tyrosine kinase inhibitor, abolished the ability of PAF to activate PLC, whereas pretreatment with staurosporine, a protein kinase C inhibitor, potentiated the ability of PAF to activate PLC. Pretreatment of A431 cells with phorbol-12-myristate-13-acetate, a protein kinase C activator, blocked PAF-stimulated PLC. Overnight exposure of cells to pertussis toxin (PT) partially blocked the ability of PAF to stimulate PLC. Based on these observations the involvement of PT-sensitive and -insensitive guanine nucleotide-binding protein(s) (G-protein) as well as the role of tyrosine kinase in the activation of PLC by PAF was considered further. PT treatment of A431 cell membranes obliterated PAF-stimulated GTPase and indicated that PT-insensitive membrane-associated G-proteins were not involved in PAF actions. In alpha-toxin permeabilized cells, PT blocked GTP-gamma-S potentiation of PLC activation by PAF, thus suggesting that PT-insensitive G-proteins were not involved in PAF activation of PLC in A431 cells. PAF stimulated tyrosine kinase activity as observed with the increase in radioactivity associated with proteins immunoprecipitated with polyclonal antibodies to phosphotyrosine residues. This increase was blocked by PAF receptor antagonists, CV 6209 and TCV 309, and by pretreatment with genistein. PAF also activated the phosphorylation of pp60c-src and Src associated proteins in A431 cells.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Role of guanine nucleotide-binding protein and tyrosine kinase in platelet-activating factor activation of phospholipase C in A431 cells: proposal for dual mechanisms. 768


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