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)

When expressed in PC12 cells, the platelet-derived growth factor beta receptor (beta PDGF-R) mediates cell differentiation. Mutational analysis of the beta PDGF-R indicated that persistent receptor stimulation of the Ras/Raf/mitogen-activated protein (MAP) kinase pathway alone was insufficient to sustain PC12 cell differentiation. PDGF receptor activation of signal pathways involving p60c-src or the persistent regulation of phospholipase C gamma was required for PC12 cell differentiation. beta PDGF-R regulation of phosphatidylinositol 3-kinase, the GTPase-activating protein of Ras, and the tyrosine phosphatase, Syp, was not required for PC12 cell differentiation. In contrast to overexpression of oncoproteins involved in regulating the MAP kinase pathway, growth factor receptor-mediated differentiation of PC12 cells requires the integration of other signals with the Ras/Raf/MAP kinase pathway.
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PMID:Mitogen-activated protein kinase activation is insufficient for growth factor receptor-mediated PC12 cell differentiation. 754 Jul 18

Phosphorylation of two newly identified epidermal growth factor (EGF) receptor substrates, eps8 and eps15, which do not possess Src homology (SH2) domains, was investigated using EGF receptor mutants of the autophosphorylation sites and deletion mutants of the carboxyl-terminal region. Two mutants, F5, in which all five tyrosine autophosphorylation sites substituted by phenylalanine, and Dc 123F, in which four tyrosines were removed by deletion and the fifth (Tyr-992) was mutated into phenylalanine, phosphorylated eps8 and eps15 as efficiently as the wild-type receptor. In contrast, SH2-containing substrates, phospholipase C gamma, the GTPase-activating protein of Ras, the p85 subunit of phosphatidylinositol 3 kinase, and the Src and collagen homology protein, are not phosphorylated by the F5 and Dc 123F mutants. A longer EGF receptor deletion mutant, Dc 214, lacking all five autophosphorylation sites, was unable to phosphorylate eps15 but phosphorylated eps8 13-fold more than the wild-type receptor. To determine the EGF receptor region important for phosphorylation of eps8 and eps15, progressive deletion mutants lacking the final 123, 165, 196, and 214 COOH-terminal residues were used. eps8 phosphorylation was progressively increased in Dc 165, Dc 196, and Dc 214 EGF receptor mutants, indicating that removal of the final 214 COOH-terminal residues increases the phosphorylation of this substrate by the EGF receptor. In contrast, eps15 was phosphorylated by Dc 123 and Dc 165 EGF receptor mutants but not by Dc 196 and Dc 214 mutants. This indicates that a region of 30 residues located between Dc 165 and Dc 196 is essential for eps15 phosphorylation. This is the first demonstration of structural requirements in the EGF receptor COOH terminus for efficient phosphorylation of non-SH2-containing substrates. In addition, enhanced eps8 phosphorylation correlates well with the increased transforming potential of EGF receptor deletion mutants Dc 196 and Dc 214, suggesting that this substrate may be involved in mitogenic signaling.
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PMID:Structural requirements of the epidermal growth factor receptor for tyrosine phosphorylation of eps8 and eps15, substrates lacking Src SH2 homology domains. 760 94

The SH2 domains of cytoplasmic signaling proteins bind to autophosphorylated growth factor receptors by direct recognition of specific phosphotyrosine-containing sites. To identify the phosphotyrosine involved in association of phospholipase C (PLC)-gamma 1 with the beta platelet-derived growth factor receptor (PDGFR), and to investigate which contiguous residues confer specificity for PLC-gamma 1, phosphotyrosine-containing glutathione S-transferase (GST) fusion proteins possessing different regions of the beta-PDGFR were incubated with lysates of Rat-2 cells that overexpress PLC-gamma 1. The phosphorylated C-terminal tail of the PDGFR bound PLC-gamma 1, but did not associate with phosphatidylinositol (PI) 3'-kinase or GTPase-activating protein (GAP). High-affinity binding of PLC-gamma 1 was dependent on phosphorylation of Tyr-1021. Creation of a new phosphorylation site by replacing Asp-1018 with tyrosine did not restore binding of PLC-gamma 1 in the absence of Tyr-1021, indicating that the location of the phosphorylated tyrosine is important for PLC-gamma 1 binding. Substitution of the proline at the +3 position relative to Tyr-1021 with methionine (Y1021IIP-->Y1021IIM) in the phosphorylated PDGFR tail did not alter PLC-gamma 1 association, but conferred binding activity towards PI 3'-kinase, indicating that this residue is critical in discriminating between PLC-gamma 1 and PI 3'-kinase. Progressive conversion of the three residues C-terminal to Tyr-1021 to the consensus for PI 3'-kinase binding (YMDM) allowed PI 3'-kinase association, but did not block PLC-gamma 1 binding, suggesting that additional residues other than the three residues immediately following the phosphotyrosine may contribute to the association of PLC-gamma 1 with the PDGFR. These results indicate that phosphorylation at Tyr-1021 in the tail of the PDGFR creates a specific binding site for PLC-gamma 1. Proline at the +3 position relative to Tyr-1021 is crucial in conferring specificity for binding to PLC-gamma 1.
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PMID:Identification of residues in the beta platelet-derived growth factor receptor that confer specificity for binding to phospholipase C-gamma 1. 768 24

The transforming protein of simian sarcoma virus is homologous to the platelet-derived growth factor (PDGF) B-chain. Fibroblasts transformed with simian sarcoma virus constitutively produce a growth factor that stimulates the endogenous tyrosine kinase of PDGF receptors in an autocrine manner. Autophosphorylation of PDGF receptors upon ligand stimulation provides binding sites for Src homology 2 domains of intracellular signaling molecules, which thereby become activated. We have characterized the PDGF receptor-mediated signal transduction in NIH 3T3 cells transformed with a PDGF B-chain cDNA (Sis 3T3 cells) in the absence and presence of suramin, a polyanionic compound that quenches PDGF-induced mitogenicity and reverts the transformed phenotype of the Sis 3T3 cells. Our data show that in the presence of suramin the general level of tyrosine phosphorylation was decreased. Nevertheless, autophosphorylated receptors complexed with substrates persisted in the cells. Suramin had no effect on activation of phosphatidylinositol 3'-kinase or on tyrosine phosphorylation of phospholipase C-gamma and GTPase-activating protein of Ras. On the other hand, kinase activation of Src and Raf-1, phosphorylation of protein-tyrosine phosphatase 1D/Syp and Shc, and complex formation with Grb2 were greatly diminished by suramin. A possible explanation for our findings is that different PDGF receptor-coupled signaling pathways are active in different structural or functional compartments in the cell. Those pathways that are not affected by suramin might elicit distinct cellular responses, which are not sufficient for growth and transformation.
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PMID:Compartmentalization of autocrine signal transduction pathways in Sis-transformed NIH 3T3 cells. 773 Mar 19

We have previously reported that platelet-derived growth factor (PDGF) receptor mutants that lack high affinity binding sites for phosphatidylinositol 3-kinase (PI 3-kinase) fail to concentrate in juxtanuclear vesicular structures after activation with PDGF. We have now identified the point in the endocytic pathway at which PI 3-kinase binding sites are required. Receptor internalization from the plasma membrane, measured as the acquisition of acid resistance of prebound 125I-PDGF, was only slightly decreased in cells expressing a PDGF receptor mutant (F5) lacking PI 3-kinase, GTPase-activating protein (GAP), phospholipase C gamma, and Syp binding sites but not expressing mutants where any of these individual sites were restored nor expressing a mutant lacking exclusively PI 3-kinase binding sites. In contrast, the extent of down-regulation of PDGF binding sites from the cell surface after prolonged incubation with PDGF as well as the degradation of [35S]methionine-labeled receptor were markedly reduced in cells expressing the F5 mutant, mutants restored in GAP, phospholipase C gamma, or Syp binding sites or expressing the mutant exclusively lacking PI 3-kinase binding sites but not in cells expressing the mutant where PI 3-kinase binding sites were restored. Inhibition of PI 3-kinase activity with wortmannin caused a dramatic decrease in the rates of down-regulation and degradation of wild-type receptors. These results suggest that PI 3-kinase binding sites are not required for internalization of PDGF receptor but are required to divert the PDGF receptor to a degradative pathway. Furthermore, the requirement for PI 3-kinase binding sites on the receptor appears to be due to a requirement for PI 3-kinase catalytic activity.
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PMID:Phosphatidylinositol 3-kinase activity is required at a postendocytic step in platelet-derived growth factor receptor trafficking. 776 21

src family tyrosine kinases contain two noncatalytic domains termed src homology 3 (SH3) and SH2 domains. Although several other signal transduction molecules also contain tandemly occurring SH3 and SH2 domains, the function of these closely spaced domains is not well understood. To identify the role of the SH3 domains of src family tyrosine kinases, we sought to identify proteins that interacted with this domain. By using the yeast two-hybrid system, we identified p62, a tyrosine-phosphorylated protein that associates with p21ras GTPase-activating protein, as a src family kinase SH3-domain-binding protein. Reconstitution of complexes containing p62 and the src family kinase p59fyn in HeLa cells demonstrated that complex formation resulted in tyrosine phosphorylation of p62 and was mediated by both the SH3 and SH2 domains of p59fyn. The phosphorylation of p62 by p59fyn required an intact SH3 domain, demonstrating that one function of the src family kinase SH3 domains is to bind and present certain substrates to the kinase. As p62 contains at least five SH3-domain-binding motifs and multiple tyrosine phosphorylation sites, p62 may interact with other signalling molecules via SH3 and SH2 domain interactions. Here we show that the SH3 and/or SH2 domains of the signalling proteins Grb2 and phospholipase C gamma-1 can interact with p62 both in vitro and in vivo. Thus, we propose that one function of the tandemly occurring SH3 and SH2 domains of src family kinases is to bind p62, a multifunctional SH3 and SH2 domain adapter protein, linking src family kinases to downstream effector and regulatory molecules.
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PMID:Association of p62, a multifunctional SH2- and SH3-domain-binding protein, with src family tyrosine kinases, Grb2, and phospholipase C gamma-1. 779 25

Insulin is the only known hormone which rapidly stimulates glucose uptake in target tissues, mainly by translocation to the cell surface of the intracellular insulin-regulatable glucose transporter (glucose transporter type 4, GLUT4). We have developed a cell line for direct, sensitive detection of GLUT4 on the cell surface. We have suggested that insulin-activated phosphatidylinositol (PI) 3-kinase may be involved in the signaling pathway of insulin-stimulated GLUT4 translocation. We report that platelet-derived growth factor (PDGF), which stimulates PI 3-kinase activity, triggers GLUT4 translocation in Chinese hamster ovary (CHO) cells stably overexpressing the PDGF receptor and in 3T3-L1 mouse adipocytes. Using mutant PDGF receptors that cannot bind to Ras-GTPase-activating protein, phospholipase C-gamma, and PI 3-kinase, respectively, we obtained evidence that PI 3-kinase binding sites play a key role in the signaling pathway of PDGF-stimulated GLUT4 translocation in the CHO cell system.
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PMID:Platelet-derived growth factor triggers translocation of the insulin-regulatable glucose transporter (type 4) predominantly through phosphatidylinositol 3-kinase binding sites on the receptor. 786 37

A short, proline-rich region spanning residues 566-577 in human 5-lipoxygenase is a binding site for the Src homology 3 (SH3) domain of growth factor receptor-bound protein 2 (Grb2), an "adaptor" protein for tyrosine kinase-mediated cell signaling. Purified 5-lipoxygenase bound to glutathione S-transferase fusion products of Grb2 and a truncated version of Grb2 containing its SH3 domain. A peptide corresponding to the proline-rich, SH3-binding motif inhibited formation of the 5-lipoxygenase.Grb2 complex in vitro. The peptide also inhibited the redistribution of 5-lipoxygenase from the cytosol to the membrane in intact or permeabilized neutrophils activated by calcium ionophore A23187. 5-Lipoxygenase did not bind to the SH3 domains of other signaling proteins, such as GTPase-activating protein and phospholipase C gamma; however, it bound to certain cytoskeletal proteins including alpha-actinin and actin. 5-Lipoxygenase contains a consensus guanine nucleotide-binding site at residues 296-299, and guanine nucleotides inhibit 5-lipoxygenase activity in vitro. Our results suggest that 5-lipoxygenase may have a previously unrecognized role in tyrosine kinase signaling, distinct from its catalysis of lipid mediator formation. Our results also clarify the molecular basis for compartmentalization and translocation of 5-lipoxygenase in myeloid cells, implying that it binds to proteins other than its activating protein.
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PMID:5-Lipoxygenase contains a functional Src homology 3-binding motif that interacts with the Src homology 3 domain of Grb2 and cytoskeletal proteins. 792 73

Platelet-derived growth factor (PDGF) stimulates phosphatidylcholine hydrolysis via phospholipase D (PLD) in several tissues. To determine whether PLD activation is dependent on phosphoinositide hydrolysis by phospholipase C (PLC), we measured the formation of phosphatidylbutanol (PtdBut), in TRMP cells overexpressing wild type or various mutant PDGF receptors. Both PLC and PLD were stimulated by PDGF in cells expressing wild type receptors whereas they were not in cells expressing kinase-deficient (R634) receptors. These data indicate that tyrosine phosphorylation is required for activation of both PLC and PLD. Mutation of Tyr-1021 of the PDGF receptor to Phe caused loss of PDGF stimulation of both PLC and PLD. On the other hand, a mutant PDGF receptor that was able to bind PLC gamma 1 but not other signaling proteins (including the Ras GTPase-activating protein, phosphatidylinositol 3-kinase, and a SH2-containing phosphotyrosine phosphatase (Syp)) restored the stimulatory effect of PDGF on PLC and PLD. Furthermore, receptors in which association with the GTPase-activating protein, phosphatidylinositol 3-kinase, or Syp was individually restored were unable to mediate PDGF stimulation of PLC or PLD. These data indicate that these other signal transduction proteins are not involved in the activation of PLD by PDGF. Treatment of the cells with the protein kinase C inhibitor, Ro-31-8220, and depletion of cellular protein kinase C by pretreatment with 4 beta-phorbol 12-myristate 13-acetate resulted in loss of PLD activation by PDGF indicating a PKC-dependent mechanism. In summary, these results indicate that activation of PLC gamma 1 and protein kinase C are necessary for the stimulation of PLD by PDGF and provide no evidence for alternative mechanisms.
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PMID:Activation of phospholipase C-gamma is necessary for stimulation of phospholipase D by platelet-derived growth factor. 796 10

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


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