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)

We have established the human nck sequence as a new oncogene. Nck encodes one SH2 and three SH3 domains, the Src homology motifs found in nonreceptor tyrosine kinases, Ras GTPase-activating protein, phosphatidylinositol 3-kinase, and phospholipase C-gamma. Overexpression of human nck in 3Y1 rat fibroblasts results in transformation as judged by alteration of cell morphology, colony formation in soft agar, and tumor formation in nude BALB/c mice. However, overexpression of nck does not induce detectable elevation of the phosphotyrosine content of specific proteins, as is observed for v-crk, another SH2/SH3-containing oncogene. Despite this fact, we demonstrate that Nck retains the ability to bind tyrosine phosphorylated proteins in vitro, using a fusion protein of Nck with glutathione-S-transferase (GST). Moreover, when incubated with lysates prepared from v-src-transformed 3Y1 cells or the nck-overexpressing cell lines, GST-Nck binds to both p60v-src and serine/threonine kinases, respectively. Although phosphotyrosine levels are not elevated in the nck-expressing fibroblasts, vanadate treatment of these cells results in a phosphotyrosine pattern that is altered from the parental 3Y1 pattern, suggestive of a perturbation of indigenous tyrosine kinase pathways. These results suggest the possibility that human nck induces transformation in 3Y1 fibroblasts by virtue of its altered affinity or specificity for the normal substrates of its rat homolog and that Nck may play a role in linking tyrosine and serine/threonine kinase pathways within the cell.
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PMID:The SH2- and SH3-containing Nck protein transforms mammalian fibroblasts in the absence of elevated phosphotyrosine levels. 128 Mar 26

Mechanisms of cathepsin B activation involved in methionine-enkephalin (ME) production induced by bradykinin (BK), des-Arg9-BK or L-arginine (L-Arg) were studied using cultured fibroblasts of the rat dental pulp, especially from a viewpoint of intracellular signal transduction. BK, des-Arg9-BK, L-Arg or cysteine enhanced the release of ME-like peptides from the cells, and the release of ME-like peptides induced by des-Arg9-BK was inhibited by des-Arg9-[Leu8]-BK (BK B1-receptor antagonist) and E-64 (a specific inhibitor of cysteine proteinases). The activation of cathepsin B by BK or des-Arg9-BK was inhibited by des-Arg9-[Leu8]-BK or islet-activating protein (IAP), and the activation of cathepsin B by L-Arg was inhibited by Leu-Arg (kyotorphin-receptor antagonist) or Botulinum C3-enzyme. The activation of cathepsin B by those stimulants was dependent on calcium ion. These results suggest that the ME production by BK or des-Arg9-BK may be mediated by Ca(2+)-dependent cathepsin B activation through B1-receptors and IAP-sensitive G-proteins, whereas the production by L-Arg may be mediated by Ca(2+)-dependent cathepsin B activation through kyotorphin-receptor and Botulinum C3-enzyme-sensitive G-proteins. On the other hand, the activation of cathepsin B was inhibited by neomycin B (phospholipase C inhibitor) and various serine/threonine kinase inhibitors. These results indicate that phospholipase C and serine/threonine kinases are involved in the activation of cathepsin B by BK, des-Arg9-BK or L-Arg. Genistein inhibited the activation of cathepsin B by des-Arg9-BK or L-Arg in a different fashion, suggesting that tyrosine kinase(s) is also involved in the activation. Cathepsin B activation by BK or L-Arg but not des-Arg9-BK was inhibited by L-NMMA (inhibitor of NO synthesis), and the activation by L-Arg was enhanced by beta-glycerophosphate (beta-GP: inhibitor of phosphatases), while the activation by BK or des-Arg9-BK was inhibited by beta-GP. These results suggest that BK-induced cathepsin B activation in the fibroblasts may be due to a combined effect of des-Arg9-BK and L-Arg.
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PMID:Activation of cathepsin B involved in enkephalin production by bradykinin and its cleavage products in cultured fibroblasts of the rat dental pulp. 134 8

Platelet-derived growth factor (PDGF) is a cationic glycoprotein of approximately 30 kDa, composed of two subunits. These subunit chains are termed A (18 kDa) and B (12-14 kDa) with high homology of the peptide sequences, including 8 cysteine residues at identical positions. Three isoforms of PDGF, AA, BB homodimers and AB heterodimer are distributed in the different tissues and cell lines suggesting that these isoforms have different functions. Two types of PDGF receptors alpha, and beta with Mr of 160-180 kDa are seen on the cell surface. PDGFR alpha can bind to both A and B subunits of the PDGD, while PDGFR beta, only B subunit. PDGF (AA) combines alpha alpha, PDGF (AB) makes dimers of alpha alpha and alpha beta, and PDGF (BB) can make three types of dimers, alpha alpha, alpha beta, and beta beta. These dimeric PDGFRs are active forms and phosphorylate its own domain and other neighbor specific proteins. The substrates of the receptor kinase are phospholipase C-gamma, GTPase activating protein (GAP), serine/threonine kinase Raf-1 and others. These molecules are thought to transfer information of the PDGFs on its receptors to the nucleus.
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PMID:[Function, molecular structure and gene expression regulation of Platelet-derived growth factor]. 143 82

The chimeric EK-receptor (EK-R), consisting of the epidermal growth factor receptor (EGF-R) extracellular binding domain and p145c-kit cytoplasmic signal-generating sequences, was fully functional in forming high and low affinity EGF binding sites and in ligand-regulated receptor and substrate phosphorylation activities. Relative to EGF-R, EK-R activation stimulated kit-characteristic phosphorylation of human 293 fibroblast substrate polypeptides. Transient coexpression of EK-R with candidate substrates resulted in ligand-induced phosphorylation of phospholipase C gamma and guanosine triphosphatase-activating polypeptide. The RAF-1 serine/threonine kinase was shown to be associated with activated EK-R, but no tyrosine phosphorylation could be detected. The faithfulness of EK-R substrate phosphorylation specificity was confirmed with stem cell factor-stimulated p145c-kit.
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PMID:Substrate phosphorylation specificity of the human c-kit receptor tyrosine kinase. 171 57

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

We report that a 100 residue segment in the carboxy-terminus half of phosphatidylinositol-specific phospholipase C is similar to a segment in the amino-terminus half of protein kinase C. The computer-based comparison score is 9.5 standard deviations higher than that of 2500 comparisons of randomized sequences of these segments (P = 10(-21), suggesting that the two segments have similar biological properties. Phospholipase C has a segment that is homologous to part of the non-catalytic domain of src kinase and other tyrosine protein kinases. The similarity of phospholipase C with protein kinase C, a serine/threonine kinase suggests that novel exon shuffling occurred among serine/threonine and tyrosine kinases and phospholipase C.
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PMID:Similarity between phospholipase C and the regulatory domain of protein kinase C. 274 13

We have studied the signal transduction pathways of fibroblast growth factor receptor-4 (FGFR-4) and FGFR-1, which showed virtually identical acidic fibroblast growth factor binding profiles as well as tyrosine autophosphorylation upon activation in transfected L6 rat myoblasts and NIH3T3 mouse fibroblasts. A prominently tyrosyl-phosphorylated doublet of polypeptides of 85 kDa coprecipitated with activated FGFR-4 from both cell lines studied, but these polypeptides were not detected upon immunoprecipitation of activated FGFR-1. Furthermore, FGFR-4 induced only a weak tyrosyl phosphorylation of phospholipase C-gamma and no detectable tyrosyl phosphorylation of the SHC adaptor proteins in contrast to FGFR-1. No phosphorylation of Ras GTPase-activating protein, p64 Syp/PTP1D tyrosine phosphatase, or association of the GRB2 adaptor protein SH2 domain with these receptors was detected. Unlike FGFR-1, FGFR-4 induced only a barely detectable phosphorylation of the cellular serine/threonine kinase Raf-1 and a weaker tyrosyl phosphorylation of mitogen-activated protein kinases than FGFR-1. Despite these differences, stimulation of both receptors resulted in increased DNA synthesis.
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PMID:Signal transduction by fibroblast growth factor receptor-4 (FGFR-4). Comparison with FGFR-1. 751 29

We have isolated a novel member of the mammalian PAK (p21 activated kinase) and yeast Ste20 serine/threonine kinase family from a mouse fibroblast cDNA library, designated mPAK-3. Expression of mPAK-3 in Saccharomyces cerevisiae partially restores mating function in ste20 null cells. Like other PAKs, mPAK-3 contains a putative Cdc42Hs/Rac binding sequence and when transiently expressed in COS cells, full-length mPAK-3 binds activated (GTP gamma S (guanosine 5'-3-O-(thio-triphosphate)-bound) glutathione S-transferase (GST)-Cdc42Hs and GST-Rac1 but not GST-RhoA. As expected for a putative target molecule, mPAK-3 does not bind to an effector domain mutant of Cdc42Hs. Furthermore, activated His-tagged Cdc42Hs and His-tagged Rac stimulate mPAK-3 autophosphorylation and phosphorylation of myelin basic protein by mPAK-3 in vitro. Interestingly, the amino-terminal region of mPAK-3 contains potential SH3-binding sites and we find that mPAK-3, expressed in vitro and in vivo, shows highly specific binding to the SH3 domain of phospholipase C-gamma and at least one SH3 domain in the adapter protein Nck. These results raise the possibility of an additional level of regulation of the PAK family in vivo.
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PMID:Identification of a mouse p21Cdc42/Rac activated kinase. 755 98

Transforming growth factor-beta (TGF-beta) is a multifunctional peptide that elicits a wide variety of responses in cells. TGF-beta binds to cell surface receptors that contain cytoplasmic serine/threonine kinase domains. Here we provide evidence that both phospholipase C and protein kinase C (PKC) are involved in the TGF-beta activation of transcription and luciferase expression from the p3TP-Lux plasmid. Down-regulation of PKC prevents TGF-beta 1 induction of luciferase expression. Staurosporin and Calphostin C, inhibitors of PKC, block the ability of TGF-beta 1 to initiate transcription of the luciferase gene. Further, D609, an inhibitor of phosphatidylcholine-phospholipase C (PC-PLC), and secondarily PKC also blocks TGF-beta 1-induced transcription of the transgene in A549 cells while the phosphatidylinositol-PLC pathway inhibitor U73122 is without effect. TGF-beta elevates steady-state mRNA levels for the endogenous PAI-1 and fibronectin genes. Treatment of cells with calphostin C or D609 prevents the TGF-beta-induced increase in these mRNAs. Together, these results suggest that PC-PLC and PKC are in a TGF-beta signaling pathway that results in elevated gene expression.
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PMID:Evidence for involvement of phosphatidylcholine-phospholipase C and protein kinase C in transforming growth factor-beta signaling. 777 10

Ecto-protein kinases (ecto-PK), primarily of the serine/threonine kinase type, have been previously described on the surface of various normal, transformed, and tumor cells. We have found that in the presence of ATP and Mg2+, exogenously added substrates such as phosvitin and poly(Glu4-Tyr) are phosphorylated by intact K562 erythroleukemia, HL60 promyelocytic leukemia, and U937 histiocytic leukemia human cells. Phosphoamino acid analysis indicated that phosvitin, histone H2B, casein, and protamine are phosphorylated on serine and threonine residues, whereas poly(Glu4-Tyr) is phosphorylated on tyrosine. We also present evidence showing that the C9 complement protein, a key component of the membranolytic protein complex of the complement system, is exclusively phosphorylated by the K562 cells on serine residues. Phosphorylation of poly(Glu4-Tyr) is markedly enhanced by Mn2+, whereas C9 phosphorylation is rather inhibited by Mn2+. It is concluded that human leukemic cells express on their surface two types of ecto-PK, one phosphorylating serines and threonines and one specific to tyrosines. The ecto-PKs are spontaneously shed from fully viable cells into the medium in a temperature-dependent manner. Upon sedimentation of cell supernatants at 100,000g, the ecto-PKs are found sedimented with small membrane vesicles. Treatment of intact K562 cells or of released membrane vesicles with bacterial phospholipase C, but not with trypsin or pronase, releases the two types of ecto-PK from the cell or vesicle membrane, respectively. This is accompanied by a marked increase in the released phosphorylating activity. It is, therefore, suggested that these ecto-PKs are either covalently linked to phospholipids or strongly attached to lipid-anchored molecules in the cell surface membrane. Several endogenous proteins in the released membranes are phosphorylated by the ecto-PKs on serines and to a lesser extend on threonines. Two proteins (PTP79 and PTP54) are phosphorylated in a manganese-dependent manner on tyrosines.
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PMID:Shedding of tyrosine and serine/threonine ecto-protein kinases from human leukemic cells. 786 34


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