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)

Skeletal muscle triads are possessing the whole set of enzymes of the phosphatidylinositol (PI)-linked signal generating pathway, PI-kinase, PI(4)P-kinase, and PI(4,5)P2-phospholipase C (PLC). The activities of these enzymes are comparable to those found in other cell types for which a functional role of the PI-pathway in intracellular signal transduction has been established. For skeletal muscle an unequivocal function and an initiating signal for Ins(1,4,5)P3-liberation is still unknown. However, the observed Ca-dependency of PLC activity suggests that here Ins(1,4,5)P3 production is a consequence rather than a cause of increasing cytosolic Ca2+. Recently, the glycolytic enzyme aldolase, whose activity can be modulated by inositol polyphosphates, has been localized in the triadic structure. The enzyme which has a high affinity to Ins(1,4)P2, Ins(1,4,5)P3 and Ins(1,3,4,5)P4, seems to be compartmentalized to the junctional foot structure from which it is released upon binding of these molecules. This phenomenon could reflect a capability for regulation of the glycolytic flux even for aldolase, especially if a non steady-state situation in the junctional gap is considered. Meanwhile we have accumulated evidence for the operation of a partial glycolytic sequence in the junctional region established by the enzymes aldolase, glyceraldehyde-3-P (GAP) dehydrogenase and phosphoglycerate kinase. This system is able to produce ATP upon oxidation of GAP and could be, because of the inositol polyphosphate-sensing abilities of aldolase, a target for the membrane associated PI-pathway. The ATP production is however transient which indicates the coupling to an ATP hydrolyzing reaction.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Relation of phosphatidylinositol metabolism to glycolytic pathway in skeletal muscle membranes. 228 42

The receptors for insulin and PDGF are tyrosine kinases that mediate distinct effects in identical cellular backgrounds. Each receptor must therefore engage a unique subset of the available signaling elements--at least partly through the selection of proteins with src-homology 2 domains (SH2 proteins). Autophosphorylation sites in the PDGFr directly bind SH2 proteins, whereas activation of the insulin receptor leads to phosphorylation of IRS-1, which in turn binds SH2 proteins. In HIR 3.5 cells, which contain similar numbers of PDGF and insulin receptors, insulin, but not PDGF, stimulated tyrosyl phosphorylation of IRS-1. Similarly, insulin, but not PDGF, treatment of HIR 3.5 stimulated the association of IRS-1 with PtdIns 3'-kinase, although PDGF stimulated the association of PtdIns 3'-kinase with the tyrosine-phosphorylated PDGFr. Association with IRS-1 activated PtdIns 3'-kinase more effectively than association with the PDGFr. Whereas the PDGFr associated with PtdIns 3'-kinase, ras-GAP, GRB-2, and phospholipase C gamma, only GRB-2 and PtdIns 3'-kinase associated with IRS-1. Moreover, PDGF, but not insulin, caused tyrosine phosphorylation of phospholipase C gamma in HIR 3.5 cells. Thus, the insulin signal differs from that of PDGF by the insertion of a cytosolic, nonreceptor SH2 domain docking protein (IRS-1). Furthermore, IRS-1 binds a different subset of SH2 domain-containing proteins than does the PDGFr and regulates at least one common element (PtdIns 3'-kinase) differently than the PDGFr. These results support the hypothesis that IRS-1 differentiates the signals generated by the insulin receptor and PDGFr tyrosine kinases by binding and regulating a specific subset of SH2 domain-containing signaling molecules.
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PMID:Common and distinct elements in insulin and PDGF signaling. 748 83

We have cloned a protein tyrosine kinase, MATK, which is expressed abundantly in megakaryocytes and the brain. We investigated whether MATK participates in the c-Kit ligand/stem cell factor (KL/SCF) signaling pathway in the megakaryocytic cell line CMK. After KL/SCF stimulation, five major proteins of molecular masses of 145, 113, 92, 76, and 63 kDa were rapidly and transiently tyrosine-phosphorylated in a time-dependent manner, peaking within 5 min, and returning to basal levels within 60 min. To study the role of MATK in the KL/SCF signaling pathway, glutathione S-transferase (GST) fusion proteins containing SH2 and SH3 domains of MATK were cloned, expressed in Escherichia coli, and purified. MATK-SH2, but not MATK-SH3, precipitated the tyrosine-phosphorylated c-Kit (molecular mass of 145 kDa) in KL/SCF-stimulated CMK cells. Other GST fusion proteins containing the SH2 domain of p85 of phosphatidylinositol 3-kinase, phospholipase C gamma-1, and ras-GAP also precipitated c-Kit. The tyrosine-phosphorylated c-Kit was co-immunoprecipitated with anti-MATK and anti-p85 antibodies in KL/SCF-stimulated CMK cells, but not in granulocyte-macrophage colony stimulating factor or interleukin-6-stimulated cells, suggesting receptor specificity. These results indicate that MATK associates with the c-Kit receptor following specific stimulation by KL/SCF via its SH2 domain and likely participates in transduction of growth signals induced by this cytokine in megakaryocytes.
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PMID:The MATK tyrosine kinase interacts in a specific and SH2-dependent manner with c-Kit. 753 44

Expression of certain subtypes of human muscarinic receptors in NIH 3T3 cells provides an agonist-dependent model of cellular transformation by formation of foci in response to carbachol. Although focus formation correlates with the ability of the muscarinic receptors to activate phospholipase C, the actual mitogenic signal transduction pathway is unknown. Through cotransfection experiments and measurement of the activation state of native and epitope-tagged Ras proteins, the contributions of Ras and Ras GTPase-activating protein (Ras-GAP) to muscarinic receptor-dependent transformation were defined. Transforming muscarinic receptors were able to activate Ras, and such activation was required for transformation because focus formation was inhibited by coexpression of either Ras with a dominant-negative mutation or constructs of Ras-GAP that include the catalytic domain. Coexpression of the N-terminal region of GAP or of its isolated SH3 (Src homology 3) domain, but not its SH2 domain, was also sufficient to suppress muscarinic receptor-dependent focus formation. Point mutations at conserved residues in the Ras-GAP SH3 domain reversed its action, leading to an increase in carbachol-dependent transformation. The inhibitory effect of expression of the Ras-GAP SH3 domain occurs proximal to Ras activation and is selective for the mitogenic pathway activated by carbachol, as cellular transformation by either v-Ras or trkA/nerve growth factor is unaffected.
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PMID:Muscarinic receptors transform NIH 3T3 cells through a Ras-dependent signalling pathway inhibited by the Ras-GTPase-activating protein SH3 domain. 796 34

Stimulation of the human monocytic cell line THP-1 by cross-linking either Fc gamma receptor I (Fc gamma RI) or Fc gamma receptor II (Fc gamma RII) gave rise to the rapid phosphorylation of multiple intracellular proteins. The pattern of proteins that were phosphorylated appeared to be identical. Analysis of these proteins by specific immunoprecipitation indicated that stimulation through either receptor did indeed give rise to phosphorylation of the same set of proteins. These included: Fc gamma RII, phospholipase C (PLC) gamma 1, PLC gamma 2, Vav, GAP, and a protein that co-precipitated with the Fc gamma receptors and migrated with a molecular weight of about 70,000. Co-cross-linking an F(ab')2 anti-CD45 monoclonal antibody together with monoclonal antibodies to either of the Fc gamma receptors inhibited phosphorylation of all these proteins. Analysis of the tyrosine kinases in the cells revealed that both receptors stimulated the phosphorylation and activation of a kinase recognized by antibodies to Syk. Furthermore, the Syk kinase became associated with the Fc gamma RII following receptor cross-linking. These data indicate that although the two Fc gamma receptors have different cytoplasmic tails, they are coupled to the same signal transduction cascade that is regulated by CD45 and involves the activation of Syk.
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PMID:Cross-linking of Fc gamma receptor I (Fc gamma RI) and receptor II (Fc gamma RII) on monocytic cells activates a signal transduction pathway common to both Fc receptors that involves the stimulation of p72 Syk protein tyrosine kinase. 822 94

Hepatocyte Growth Factor (HGF) and Scatter Factor (SF) are identical glycoproteins secreted by cells of mesodermal origin. The factor has several activities on epithelial cells, including mitogenesis, dissociation of epithelial sheets, stimulation of cell motility, and promotion of matrix invasion. HGF is the ligand for p190MET, the receptor tyrosine kinase encoded by the MET proto-oncogene. This was proved by HGF binding to immunopurified p190MET, chemical cross-linking of radiolabelled ligand, HGF-induced tyrosine phosphorylation of p190MET, and reconstitution of high-affinity binding sites for HGF into insect cells infected with a recombinant baculovirus carrying the human MET cDNA. p190MET is a 190 kDa heterodimer of two (alpha beta) disulfide-linked protein subunits. The alpha subunit is heavily glycosylated and extracellular. The beta subunit bears an extracellular portion involved in ligand binding, a membrane spanning segment and a cytoplasmic tyrosine kinase domain with phosphorylation sites regulating its activity. Both subunits originate from glycosylation and proteolytic cleavage of a common precursor of 170 kDa. Alternative post-transcriptional processing originates two truncated Met proteins, endowed with ligand binding activity, lacking the cytoplasmic kinase domain of the beta subunit. One form is soluble and released from the cells. HGF binding triggers tyrosine autophosphorylation of the receptor beta subunit in intact cells. Autophosphorylation upregulates the kinase activity of the receptor, increasing the Vmax of the phosphotransfer reaction. The major phosphorylation site has been mapped to Tyr1235. Negative regulation of the receptor kinase activity occurs through distinguishable pathways involving protein kinase C activation or increase in the intracellular Ca2+ concentration. Both lead to the serine phosphorylation of a unique phosphopeptide of the receptor and to a decrease in its kinase activity. Receptor autophosphorylation also triggers the signal transduction pathways inside the target cells. The phosphorylated receptor associates ras GAP, phospholipase C-gamma, and src-related tyrosine kinase in vitro; Phosphatidylinositol 3-kinase, in vitro and in vivo, indicating that the generation of the D-3 phosphorylated inositol lipids is involved in effecting the motility and/or the growth response to HGF. The p190MET HGF receptor is expressed in several epithelial tissues and it is often overexpressed in neoplastic cells. In some tumors of the gastrointestinal tract the Met tyrosine kinase is constitutively activated, either by overexpression of the amplified MET oncogene or by lack of cleavage of the receptor precursor, due to defective post-translational processing.
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PMID:Structure, biosynthesis and biochemical properties of the HGF receptor in normal and malignant cells. 838 Jul 35

Xenopus oocytes from unprimed frogs possess insulin-like growth factor I (IGF-I) receptors but lack insulin and IGF-I receptor substrate 1 (IRS-1), the endogenous substrate of this kinase, and fail to show downstream responses to hormonal stimulation. Microinjection of recombinant IRS-1 protein enhances insulin-stimulated phosphatidylinositol (PtdIns) 3-kinase activity and restores the germinal vesicle breakdown response. Activation of PtdIns 3-kinase results from formation of a complex between phosphorylated IRS-1 and the p85 subunit of PtdIns 3-kinase. Microinjection of a phosphonopeptide containing a pYMXM motif with high affinity for the src homology 2 (SH2) domain of PtdIns 3-kinase p85 inhibits IRS-1 association with and activation of the PtdIns 3-kinase. Formation of the IRS-1-PtdIns 3-kinase complex and insulin-stimulated PtdIns 3-kinase activation are also inhibited by microinjection of a glutathione S-transferase fusion protein containing the SH2 domain of p85. This effect occurs in a concentration-dependent fashion and results in a parallel loss of hormone-stimulated oocyte maturation. These inhibitory effects are specific and are not mimicked by glutathione S-transferase fusion proteins expressing the SH2 domains of ras-GAP or phospholipase C gamma. Moreover, injection of the SH2 domains of p85, ras-GAP, and phospholipase C gamma do not interfere with progesterone-induced oocyte maturation. These data demonstrate that phosphorylation of IRS-1 plays an essential role in IGF-I and insulin signaling in oocyte maturation and that this effect occurs through interactions of the phosphorylated YMXM/YXXM motifs of IRS-1 with SH2 domains of PtdIns 3-kinase or some related molecules.
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PMID:Insulin-stimulated oocyte maturation requires insulin receptor substrate 1 and interaction with the SH2 domains of phosphatidylinositol 3-kinase. 841 61

M1 muscarinic cholinergic receptors, G1 and G11 (Gq/11), and phospholipase C-beta 1 were highly purified from both natural sources and cells that express the appropriate cDNA's. When the proteins were co-reconstituted into phospholipid vesicles, the receptor efficiently and selectively promoted the activation of Gq/11, leading to marked stimulation of PLC activity in the presence of GTP gamma S. No stimulation was observed in the presence of GTP, however, which led to the finding that PLC-beta 1 stimulates the hydrolysis of GQ/11-bound GTP at least 50-fold. Thus, PLC-beta 1 is a GTPase activating protein, a GAP, for its physiologic regulator Gq/11. We discuss the implications of PLC-beta 1's GAP activity on the M1 muscarinic cholinergic signaling pathway.
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PMID:Regulation of the M1 muscarinic receptor-Gq-phospholipase C-beta pathway by nucleotide exchange and GTP hydrolysis. 844 22

nef is a human immunodeficiency virus (HIV) gene encoding a 27-kDa myristoylated protein with structural features of a signal transducing molecule, but whose functions are largely unknown. We studied the interactions of Nef with the signal transduction pathways triggered by the platelet-derived growth factor (PDGF) receptor. The association of phosphatidylinositol (PI) 3-kinase with the activated receptor was severely impaired by nef expression. Conversely, PDGF-induced receptor tyrosine phosphorylation, binding to phospholipase C-gamma and to Ras-GAP were not modified. Microtubule-associated protein kinase activation and intracellular calcium influx in response to PDGF were either unaffected or only slightly enhanced. Nef significantly reduced the proliferative response to the growth factor, while the chemotactic response was unchanged. These data show that Nef affects selectively the PI 3-kinase signaling pathway and suggest that this interference results in some of the HIV adverse effects on host cell functions.
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PMID:The HIV-1 nef protein interferes with phosphatidylinositol 3-kinase activation 1. 863 73

The intracellular effects of bradykinin are mediated through the recently cloned B2 kinin receptor which belongs to the superfamily of receptors with seven transmembrane domains. The molecular events which transduce the bradykinin signal on the post-receptor level are not understood in detail. We studied whether in human foreskin fibroblasts bradykinin treatment induces tyrosine phosphorylation of cellular proteins. Using phosphotyrosine antibodies we detected a bradykinin-dependent phosphorylation of a group of proteins of about 130 kDa and an additional signal around 70kDa after starvation of cells. The effect evoked by 10 nM bradykinin was rapid (2 min) and it was partially reduced by the B2-kinin-receptor antagonist Hoe 140 which was shown to be a weak inducer of tyrosine phosphorylation. The bradykinin-mediated tyrosine phosphorylation events were reproduced in human embryonal kidney 293 fibroblasts which were transiently transfected with the rat B2 kinin receptor, but they were not observed in untransfected 293 control cells. These data suggest that the B2 kinin-receptor subtype is involved. Upon fractionation of cells the 130kDa protein group was recovered both in the membrane and the cytosolic protein fraction. To assess the specificity of this bradykinin effect we stimulated human foreskin fibroblasts with epidermal growth factor (EGF), platelet-derived growth factor (PDGF), insulin-like growth factor (IGF-I) and insulin. While IGF-I, insulin and EGF were almost ineffective, PDGF stimulated the tyrosine phosphorylation of 130-kDa bands with a similar pattern to that produced by bradykinin. Immunoprecipitation experiments with specific antibodies against potential candidate proteins in the molecular-mass range around 130kDa revealed positive results for the focal adhesion kinase FAK and the p130 Src substrate while negative results were obtained for the GTPase-activating protein GAP, the phospholipase C-gamma1, the Janus kinase JAK-1 and vinculin. The data suggest that the tyrosine phosphorylation of FAK and the pl30 Src substrate might be involved in the B2-kinin-receptor signalling cascade.
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PMID:Bradykinin induces tyrosine phosphorylation in human foreskin fibroblasts and 293 cells transfected with rat B2 kinin receptor. 866 18


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