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)

Vascular endothelial cell growth factor (VEGF), an endothelial cell-specific mitogen that plays an important role in angiogenesis, promotes the tyrosine phosphorylation of at least 11 proteins in bovine aortic endothelial cells (BAEC). Proteins immunoprecipitated from lysates of control- and VEGF-stimulated BAEC with antisera to phospholipase C-gamma (PLC-gamma) were fractionated by SDS-polyacrylamide gel electrophoresis and transferred to Immobilon-P. Evaluation of the Western blots with antisera to phosphotyrosine demonstrated that PLC-gamma and two proteins (100 and 85 kDa) that associate with PLC-gamma were phosphorylated in response to VEGF. By using antisera specific to other mediators of signal transduction that contain SH2 domains for immunoprecipitation, it was demonstrated that VEGF promotes phosphorylation of phosphatidylinositol 3-kinase, Ras GTPase activating protein (GAP), and the oncogenic adaptor protein NcK. Proteins of M(r) consistent with the VEGF receptors Flt-1 and Flk-1/KDR were also tyrosine phosphorylated in stimulated cells. Tyrosine-phosphorylated Nck, PLC-gamma, and two GAP-associated proteins, p190 and p62, were in GAP immunoprecipitates of VEGF-stimulated BAEC, and tyrosine-phosphorylated NcK was in phosphatidylinositol 3-kinase immunoprecipitates. These observations suggest that VEGF promotes formation of multimeric aggregates of VEGF receptors with proteins that contain SH2 domains and activate various signaling pathways. VEGF-promoted proliferation of endothelial cells and tyrosine phosphorylation of SH2 domain containing signaling molecules were inhibited by the tyrosine kinase inhibitor genistein.
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PMID:Vascular endothelial cell growth factor promotes tyrosine phosphorylation of mediators of signal transduction that contain SH2 domains. Association with endothelial cell proliferation. 789 17

Vascular endothelial growth factor (VEGF) is a homodimeric peptide growth factor which binds to two structurally related tyrosine kinase receptors denoted Flt1 and KDR. In order to compare the signal transduction via these two receptors, the human Flt1 and KDR proteins were stably expressed in porcine aortic endothelial cells. Binding analyses using 125I-VEGF revealed Kd values of 16 pM for Flt1 and 760 pM for KDR. Cultured human umbilical vein endothelial (HUVE) cells were found to express two distinct populations of binding sites with affinities similar to those for Flt1 and KDR, respectively. The KDR expressing cells showed striking changes in cell morphology, actin reorganization and membrane ruffling, chemotaxis and mitogenicity upon VEGF stimulation, whereas Flt1 expressing cells lacked such responses. KDR was found to undergo ligand-induced autophosphorylation in intact cells, and both Flt1 and KDR were phosphorylated in vitro in response to VEGF, however, KDR much more efficiently than Flt1. Neither the receptor-associated activity of phosphatidylinositol 3'-kinase nor tyrosine phosphorylation of phospholipase C-gamma were affected by stimulation of Flt1 or KDR expressing cells, and phosphorylation of GTPase activating protein was only slightly increased. Members of the Src family such as Fyn and Yes showed an increased level of phosphorylation upon VEGF stimulation of cells expressing Flt1 but not in cells expressing KDR. The maximal responses in KDR expressing porcine aortic endothelial cells were obtained at higher VEGF concentrations as compared to HUVE cells, i.e. in the presence of Flt1. This difference could possibly be explained by the formation of heterodimeric complexes between KDR and Flt1, or other molecules, in HUVE cells.
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PMID:Different signal transduction properties of KDR and Flt1, two receptors for vascular endothelial growth factor. 792 39

B lymphocyte antigen receptors, membrane immunoglobulins (mIg), function in focusing and internalization of antigen for subsequent presentation to T cells and in transmembrane transduction of signals leading to cell activation, anergy, or deletion. Until quite recently, the ability of this receptor to transduce signals in spite of a virtual lack of cytoplasmic structure, left a significant gap in our understanding of how it is coupled to cytoplasmic signal propagators. Studies conducted during the past five years have defined a mIg-associated protein complex homologous to the CD3 complex associated with the T cell antigen receptor. Components of this disulfide linked heterodimeric complex, Ig-alpha and Ig-beta, contain an approximately 26 residue sequence motif termed ARH1, also known as TAM, which binds to cytoplasmic effectors, including src-family tyrosine kinases, and contains all structural information needed for signal transduction. Receptor associated src-family kinases which are activated following receptor cross-linking, also associate with downstream effectors, including phospholipase C gamma (PLC gamma), p21ras. GTPase activating protein (GAP), phosphatidylinositol 3-kinase (PI3-k) and microtubule associate protein kinase (MAPk2). In some cases, these associations are induced by receptor cross-linking and lead directly to effector activation. The current literature indicates that these interactions may occur in sequence and culminate in the activation of three major pathways of signal propagation including those mediated by PLC gamma, p21ras and PI3-k. This chapter reviews various molecular aspects of the B cell antigen receptor complex, including extended structure of the complex, and receptor-effector interactions and their biologic consequences. Finally, an integrated model of antigen receptor signaling is presented.
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PMID:Signal transduction by the B cell antigen receptor and its coreceptors. 801 Dec 88

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

The roles of gastrin and sodium vanadate in proliferation were examined in cultured IEC-6 cells that are mitotically active and derived originally from jejunal crypts of the rat intestine. Incubation of the cells in the presence of gastrin at a concentration of 250 ng/ml or of sodium vanadate at a concentration of 0.2 mM leads to a 60% increase in cell growth in 24 hr. The stimulated growth in both cases was inhibited by genistein, a tyrosine kinase inhibitor. Incubation in the presence of gastrin and sodium vanadate together produced a small, albeit significant, potentiation of growth of the cells. Gastrin as well as sodium vanadate also promoted the phosphorylation on tyrosine of a similar group of proteins with molecular masses of 42, 45, 52, 60, 78, and 120 kDa. The phosphorylations were rapidly occurring as early as 5 min and lasted for only 15 min. Several proteins were detected in normal IEC-6 cells, including GTPase activating protein, raf1 kinase, phospholipase C gamma-1, and phosphoinositide 3-kinase. The results suggest that gastrin and sodium vanadate induce growth of IEC-6 cells by stimulation of tyrosine kinase and/or inhibition of tyrosine phosphatase. The gastrin and sodium vanadate effects also involve the phosphorylation of a number of proteins, the identities of which are not known at present but may include some of the kinases that are frequently associated with cell growth, such as mitogen-activated protein kinase, raf1 kinase, phosphoinositide 3-kinase, and others.
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PMID:Role of tyrosine kinase and phosphotyrosine phosphatase in growth of the intestinal crypt cell (IEC-6) line. 845 7

In the M1-muscarinic receptor-Gq-phospholipase C-beta 1 (PLC-beta 1) pathway, PLC-beta 1 is both the effector regulated by Gq and acts as GTPase activating protein (GAP) for Gq. To rapidly evaluate in vitro PLC-beta 1 mutants constructed by oligonucleotide-directed mutagenesis, we established a quick expression and purification procedure. A pQE60/His6PLC-beta 1 construct was expressed in E. coli SG13009[pREP4]. Purification (approximately 160-fold) was obtained after high-salt extraction and chromatography over Ni(+)-agarose, Mono Q and Mono S columns. Several His6PLC-beta 1 mutants were equally responsive to alpha q. GTP gamma S, although the mutant His6PLC-beta 1-P57 (G758D) had only 2.5% the intrinsic PLC activity of the wild type. Also, His6PLC-beta 1 wild type and mutants acted as GAPs for Gq in a reconstitution assay. Thus, the present procedure provides a method to quickly assess phospholipase activity, alpha q-responsiveness, and GAP activity of PLC-beta 1.
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PMID:Purification and characterization of phospholipase C-beta 1 mutants expressed in E. coli. 878 Jun 78

The Rho family belongs to the Ras-related small GTP-binding protein (G protein) superfamily and regulates various cell functions in which the actomyosin system is involved, including cell morphology, membrane ruffling, cell motility, cell aggregation, cytokinesis, smooth muscle contraction, and yeast budding. Three GDP/GTP exchange proteins (GEPs), named Smg GDS, Dbl, and Rho GDI, and two GTPase activating proteins (GAPs), named Rho GAP and p190 associated with Ras GAP, have been identified. The Rho activity is likely to be regulated by protein kinase C which is linked through phospholipase C to the tyrosine kinase-type membrane receptors and the heterotrimeric G protein-linked receptors. It is likely that both Ras and Rho receive signals from the membrane receptors through different pathways and transduce signals to genes and cytoskeleton, respectively. In carcinogenesis, mutational activation of any component in the Ras signaling pathway may cause abnormal cell proliferation, whereas mutational activation of any component in the Rho signaling pathway may cause invasiveness and metastasis of carcinoma cells.
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PMID:Rho small G protein and cytoskeletal control. 898 86

Mutation of the autophosphorylation sites of receptor protein-tyrosine kinases alters ligand dependent internalization and down-regulation, indicating a critical role for these sites in receptor processing. Currently, no differences in receptor processing based on an individual autophosphorylation site have been defined. By using a glutathione S-transferase fusion protein containing the src homology 2 domains of phospholipase C-gamma1 to specifically recognize tyrosine 992 on the EGF receptor (Tyr(P)992), we have found differences in this subpopulation of receptors. Following EGF stimulation, the number of Tyr(P)992 receptors increased 2-fold over receptors identified by an antibody that recognizes activated EGF receptors (alpha-Act. EGFR) in A431 cells. Confocal fluorescence microscopy showed that Tyr(P)992 receptors underwent endocytosis at a slower rate and did not rapidly concentrate in juxtanuclear bodies. Tyr(P)992 receptors were associated with more SOS, Ras-GTPase activating protein, phosphatidylinositol 3-kinase, and SHPTP2/syp, but less Grb2, than receptors in the general population, and these receptors were more heavily phosphorylated than the general population of active receptors. These findings suggest that autophosphorylation status is relevant to the endocytosis, degradation, and effector molecule interaction of individual EGF receptors. Further investigations based on phosphorylation status should provide new insights into how receptor protein-tyrosine kinase signaling is regulated.
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PMID:Subsets of epidermal growth factor receptors during activation and endocytosis. 902 Jan 17

This review addresses a rapidly growing body of evidence suggesting that enhanced protein tyrosine phosphorylation may be a previously unrecognized mechanism for coupling receptor activation of vascular smooth muscle cells to increases In the intracellular concentration of Ca2+ and contraction. The hypothesis proposes that activation of diverse types of receptors that are not tyrosine kinase promotes stimulation of a cytosolic tyrosine kinase. In turn, the activated kinase induces tyrosine phosphorylation of substrates that are linked to regulatory mechanisms for release of intracellular Ca2+ stored in the sarcoplasmic reticulum and to regulatory mechanisms for influx of extracellular Ca2+. Within this framework, we examine some relevant functional aspects of receptor and nonreceptor tyrosine kinases in different types of cells, the emerging relationships between tyrosine kinase activity and regulation of intracellular Ca2+. We review studies of nonreceptor tyrosine kinase activity in vascular smooth muscle cells suggesting that a physiologically relevant kinase may be the enzyme called pp60. Data that appear to link tyrosine phosphorylation to contraction of smooth muscle are examined, particularly with respect to results obtained with tyrosine kinase inhibitors and measures of changes in tyrosine phosphorylation. Next, we review studies with cultured vascular smooth muscle cells that point to potential coupling between receptor activation, enhanced tyrosine phosphorylation of substrates such as the GTPase activating protein for ras, and the gamma-1 isoform of phospholipase C, and mechanisms controlling Ca2+ influx and release. Emphasis is placed on examining the strengths and weaknesses of different experimental approaches. Lastly, a summary of the data is provided which calls attention to some major issues requiring resolution to permit acceptance or rejection of the underlying hypothesis, and we briefly address some of its possible pathophysiological implications.
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PMID:Protein tyrosine phosphorylation in smooth muscle: a potential coupling mechanism between receptor activation and intracellular calcium. 911 20

Most mammalian cells have the capacity to migrate. When placed into culture, cells will generally display a set rate of basal, unstimulated locomotion. The cells will begin to move in one direction and, after some time, change directions resulting in a random walk. External stimuli can influence cell motility in several ways to either enhance or retard the rate of migration (chemokinesis), to change the average amount of cell migration observed before the cell turns (persistence), or to increase the directionality of movement by limiting the number of turns made by the cells. Several factors have been identified that stimulate cell movement, but the signaling mechanisms that mediate this induced cell movement have only recently begun to be studied. In this review, we discuss the signals that support the directional movement of fibroblasts and epithelial cells in response to chemoattractant gradients. The work will emphasize studies carried out by our laboratory and others on the stimulation of cell motility by the PDGF. These results indicate that at least two sets of signaling molecules cooperate to regulate cell motility in vivo. These include phospholipase C-gamma, phosphoinositide-3' kinase and the Ras-GTPase activating protein Ras-GAP. The first set are those which bind to the intracellular domain of the receptor tyrosine kinase and bring about the phosphorylation and/or activation of intracellular effectors proximal to the receptor. The second is a set of down-stream effectors that regulate either the rate of cell movement or the directionality of that movement depending on the cell type. These include Ras and the Ras-related GTPase Rac along with free phosphoinositides and calcium ions that regulate the actin polymerization machinery. Signals that mediate nuclear changes leading to cell proliferation, such as elements of the MAP kinase pathway, do not appear to play a role in PDGF-stimulated cell migration. Current work thus suggests that a coordinated spatial regulation of signaling elements that interact with the cell membrane and cytoskeleton but not necessarily with nuclear elements is the controlling mediator of directional cell motility.
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PMID:Signaling mechanisms in growth factor-stimulated cell motility. 925 9


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