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

---

Query: EC:3.1.4.3 (phospholipase C)
18,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have previously shown that the binding to cells of a monoclonal antibody directed against the chick neural retina N-acetylgalactosaminylphosphotransferase (GalNAcPTase) results in inhibition of cadherin-mediated adhesion and neurite outgrowth. We hypothesized that the antibody mimics the action of an endogenous ligand. Chondroitin sulfate proteoglycans (CSPGs) are potential ligands because they inhibit adhesion and neurite outgrowth and are present in situ at barriers to neuronal growth. We therefore assayed purified CSPGs for their ability to inhibit homophilic cadherin-mediated adhesion and neurite outgrowth, as well as their ability to bind directly to the GalNAcPTase. A proteoglycan with a 250-kD core protein following removal of chondroitin sulfate chains (250-kD PG) inhibits cadherin-mediated adhesion and neurite outgrowth whether presented as the core protein or as a proteoglycan monomer bearing chondroitin sulfate. A proteoglycan with a 400-kD core protein is not inhibitory in either core protein or monomer form. Treatment of cells with phosphatidylinositol-specific phospholipase C, which removes cell surface GalNAcPTase, abolishes this inhibitory effect. Binding of the 250-kD core protein to cells is competed by the anti-GalNAcPTase antibody 1B11, suggesting that 1B11 and the 250-kD core protein bind to the same site or in close proximity. Moreover, soluble GalNAcPTase binds to the immobilized 250-kD core protein but not to the immobilized 400-kD core protein. Concomitant with inhibition of cadherin mediated adhesion, binding of the 250-kD core protein to the GalNAcPTase on cells results in the enhanced tyrosine phosphorylation of beta-catenin and the uncoupling of N-cadherin from its association with the cytoskeleton. Moreover, the 250-kD PG is present in embryonic chick retina and brain and is associated with the GalNAcPTase in situ. We conclude that the 250-kD PG is an endogenous ligand for the GalNAcPTase. Binding of the 250-kD PG to the GalNAcPTase initiates a signal cascade, involving the tyrosine phosphorylation of beta-catenin, which alters the association of cadherin with the actin-containing cytoskeleton and thereby inhibits adhesion and neurite outgrowth. Regulation of the temporal and spatial expression patterns of each member of the GalNacPTase/250-kD PG interactive pair may create opportunities for interaction that influence the course of development through effects on cadherin-based morphogenetic processes.
...
PMID:The interaction of the retina cell surface N-acetylgalactosaminylphosphotransferase with an endogenous proteoglycan ligand results in inhibition of cadherin-mediated adhesion. 777 82

a cDNA library transfer system based on retroviral vectors has been developed for expression cloning in mammalian cells. The use of retroviral vectors results in stable cDNA transfer efficiencies which are at least 100-fold higher than those achieved by transfection and therefore enables the transfer and functional screening of very large libraries. In our initial application of retroviral transfer of cDNA libraries, we have selected for cDNAs which induce oncogenic transformation of NIH 3T3 fibroblasts, as measured by loss of contact inhibition of proliferation. Nineteen different transforming cDNAs were isolated from a total of 300,000 transferred cDNA clones. Three of these cDNAs were derived from known oncogenes (raf-1, lck, and ect2), while nine others were derived from genes which had been cloned previously but were not known to have the ability to transform fibroblasts (beta-catenin, thrombin receptor, phospholipase C-gamma 2 and Spi-2 protease inhibitor genes). The Spi-2 cDNA was expressed in antisense orientation and therefore is likely to act as an inhibitor of an endogenous transformation suppressor. Seven novel cDNAs with transforming activities, including those for three new members of the CDC24 family of guanine nucleotide exchange factors, were also cloned from the retroviral cDNA libraries. Retroviral transfer of libraries should be generally useful for cloning cDNAs which confer selectable phenotypes on many different types of mammalian cells.
...
PMID:Expression cloning of oncogenes by retroviral transfer of cDNA libraries. 782 39

The intraperitoneal injection of a vanadate/H2O2 mixture (peroxovanadate) into mice resulted within minutes in the appearance of numerous tyrosine-phosphorylated proteins in the liver and kidney. These effects are presumably due to the inhibition of phosphotyrosine phosphatase activity. Three of the tyrosine-phosphorylated proteins have been identified as the receptors for epidermal growth factor, insulin, and hepatocyte growth factor. The injection of peroxovanadate also enhanced the tyrosine phosphorylation of many of the proteins known to function downstream of these receptors, including SHC, signal transducer and activator of transcription (Stat) 1alpha,beta, Stat 3, Stat 5, phospholipase C-gamma, insulin receptor substrate 1, GTPase-activating protein, beta-catenin, gamma-catenin, p120cas, SHP-1, and SHP-2. The administration of peroxovanadate also induced nuclear translocation of a number of tyrosine-phosphorylated Stat proteins. In addition, the global effects on tyrosine phosphorylation permitted the detection of a number of novel intracellular protein interactions, including an association of Tyk2 with beta-catenin. The in situ administration of peroxovanadate may prove useful in the search for novel tyrosine-phosphorylated proteins and the identification of new interactions between previously identified tyrosine-phosphorylated substrates.
...
PMID:Peroxovanadate induces tyrosine phosphorylation of multiple signaling proteins in mouse liver and kidney. 899 30

The purpose of this study was to test the hypothesis that tyrosine phosphorylation signaling events and protein kinase C (PKC) activation mediate vascular endothelial growth factor-A(165) (VEGF)-induced endothelial cell (EC) proliferation and barrier dysfunction in bovine pulmonary artery EC monolayers. A size-selective permeability assay showed that VEGF stimulated a delayed, prolonged (6-45 h), concentration-dependent (50-200 ng/ml, approximately 1-4 nM) increase in the number of predominantly small-"pore" transport pathways (<60 A) across EC monolayers. The tyrosine kinase inhibitor herbimycin A (HA) and the selective PKC inhibitor bisindolylmaleimide (BIM) prevented this phenomenon. After 6-24 h, VEGF-treated monolayers displayed an HA- and BIM-sensitive reorganization of beta-catenin adherens junctions with fingerlike projections and the loss of beta-catenin at sites of small paracellular hole formation. HA and BIM prevented the VEGF-induced increase in EC growth. HA blocked the VEGF-induced rapid and prolonged (10 min-45 h) increases in the phosphotyrosine (PY) contents of VEGF receptor 2, phospholipase C-gamma1, paxillin, and beta-catenin as well as approximately 140- and 128- to 117-kDa proteins, whereas BIM inhibited only the tyrosine phosphorylation of beta-catenin. These data suggest that VEGF initiates increased EC growth and chronic, small-pore endothelial barrier dysfunction by PY signaling through beta-catenin that depends on PKC.
...
PMID:VEGF stimulates tyrosine phosphorylation of beta-catenin and small-pore endothelial barrier dysfunction. 1056 61

In this review, we discuss the role of phosphatidylinositol 3-kinase (PI3K) and Rap 1 in B-cell receptor (BCR) signaling. PI3K produces lipids that recruit pleckstrin homology domain-containing proteins to the plasma membrane. Akt is a kinase that the BCR activates in this manner. Akt phosphorylates several transcription factors as well as proteins that regulate apoptosis and protein synthesis. Akt also regulates glycogen synthase kinase-3, a kinase whose substrates include the nuclear factor of activated T cells (NF-AT)cl and beta-catenin transcriptional activators. In addition to Akt, PI3K-derived lipids also regulate the activity and localization of other targets of BCR signaling. Thus, a key event in BCR signaling is the recruitment of PI3K to the plasma membrane where its substrates are located. This is mediated by binding of the Src homology (SH) 2 domains in PI3K to phosphotyrosine-containing sequences on membrane-associated docking proteins. The docking proteins that the BCR uses to recruit PI3K include CD19, Cbl, Gab1, and perhaps Gab2. We have shown that Gab1 colocalizes PI3K with SH2 domain-containing inositol phosphatase (SHIP) and SHP2, two enzymes that regulate PI3K-dependent signaling. In contrast to PI3K, little is known about the Rap1 GTPase. We showed that the BCR activates Rap1 via phospholipase C-dependent production of diacylglycerol. Since Rap1 is thought to regulate cell adhesion and cell polarity, it may be involved in B-cell migration.
...
PMID:Targets of B-cell antigen receptor signaling: the phosphatidylinositol 3-kinase/Akt/glycogen synthase kinase-3 signaling pathway and the Rap1 GTPase. 1104 67

We have been investigating the molecular mechanisms underlying pathophysiological regulation of microvascular permeability on isolated venules and cultured venular endothelial monolayers. Physiological approaches have been employed in combination with molecular analyses to probe the signal transduction pathways leading to enhanced microvascullar permeability. A newly developed technique of protein transfection into cells and intact microvessels enables the correlation of fullctional reactions and signaling events at the molecular level in a direct and specific fashion. The results indicate that inflammatory mediators increase microvascular permeability via intracellular signaling pathways involving the activation of phospholipase C, cytosolic calcium, protein kinase C, nitric oxide synthase, guanylate cyclase, and protein kinase G. In response to the signaling stimulation, complex biochemical and conformational reactions occur at the endothelial structural proteins. Specifically, myosin light-chain activation-mediated myosin light-chain phosphorylation can result in cell contraction. VE-cadherin and beta-catenin phosphorylation may induce dissociation of the junctional proteins and their connection to the cytoskeleton, leading to a loose or opened intercellular junction. Focal adhesion phosphorylation and redistribution further provide an anchorage support for the conformational changes in the cells and at the cell junction. The three processes may act in concert to facilitate the flux of fluid and macromolecules across the microvascular endothelium.
...
PMID:Signal transduction pathways in enhanced microvascular permeability. 1114 36

Beta-catenin is a transcriptional activator that is regulated by glycogen synthase kinase-3 (GSK-3). GSK-3 is constitutively active in unstimulated cells where it phosphorylates beta-catenin, targeting beta-catenin for rapid degradation. Receptor-induced inhibition of GSK-3 allows beta-catenin to accumulate in the cytoplasm and then translocate to the nucleus where it promotes the transcription of genes such as c-myc and cyclin D1. Wnt hormones, the best known regulators of beta-catenin, inhibit GSK-3 via the Disheveled protein. However, GSK-3 is also inhibited when it is phosphorylated by Akt, a downstream target of phosphatidylinositol 3-kinase (PI3K). We have previously shown that B cell Ag receptor (BCR) signaling leads to activation of PI3K and Akt as well as inhibition of GSK-3. Therefore, we hypothesized that BCR engagement would induce the accumulation of beta-catenin via a PI3K/Akt/GSK-3 pathway. We now show that BCR ligation causes an increase in the level of beta-catenin in the nuclear fraction of B cells as well as an increase in beta-catenin-dependent transcription. Direct inhibition of GSK-3 by LiCl also increased beta-catenin levels in B cells. This suggests that GSK-3 keeps beta-catenin levels low in unstimulated B cells and that BCR-induced inhibition of GSK-3 allows the accumulation of beta-catenin. Surprisingly, we found that the BCR-induced phosphorylation of GSK-3 on its negative regulatory sites, as well as the subsequent up-regulation of beta-catenin, was not mediated by Akt but by the phospholipase C-dependent activation of protein kinase C. Thus, the BCR regulates beta-catenin levels via a phospholipase C/protein kinase C/GSK-3 pathway.
...
PMID:The B cell antigen receptor regulates the transcriptional activator beta-catenin via protein kinase C-mediated inhibition of glycogen synthase kinase-3. 1209 78

Wnt-Frizzled signaling is an essential aspect of early development, regulating cell fate, polarity, differentiation, and migration. In addition to the well-known Wnt/beta-catenin pathway characterized for Frizzled-1, there are other pathways regulated by Wnts that are not mediated by Frizzled-1 and do not lead to stabilization of beta-catenin and activation of the Lef/Tcf-sensitive transcription of genes. The first of these non-canonical pathways to be identified is the Wnt/Ca++ pathway in which Frizzled-2 activation leads to release of beta/gamma subunit complexes from heterotrimeric G-proteins (presumably Go and Gt) to activate phospholipase C and other effectors to stimulate a mobilization of intracellular Ca++. More recently a second, related pathway of Wnt-Frizzled signaling has been discovered that regulates the intracellular levels of cyclic GMP. Frizzled-2, established as a member of the family of 7TMS receptors that couple by heterotrimeric G-proteins to effectors, can signal via the G-protein Gt2, transducin, a G-protein prominent in phototransduction in the eye, to cyclic GMP phosphodiesterase. The discovery of the expression of Gt2 in embryonic cells was co-incident with the demonstration that inhibitors of cyclic GMP phosphodiesterase potently blocked various features of Frizzled-2 signaling in mouse embryonic F9 cells and in zebrafish embryos. The signal linkage map from Wnt to changes in intracellular cyclic GMP and development is the focus of this review. The molecular features of how changes in intracellular cyclic GMP concentrations control development remain to be elucidated.
...
PMID:WNT-frizzled signaling via cyclic GMP. 1497 27

Cerebrospinal fluid prostaglandin E2 (PGE2) and tumor necrosis factor-alpha (TNF-alpha) levels are elevated in patients with Alzheimer's disease (AD), which suggests that they are involved in neurodegeneration. We previously reported that TNF-alpha derived from human macrophages, in response to beta-amyloid or amyloidogenic C-terminal peptide, is a main mediator of inflammatory neurotoxicity. In a continuation of this work, the present study investigated the direct effect of PGE2, one of the major prostaglandins produced in the brain, on cell viability in SH-SY5Y neuronal cells treated with TNF-alpha. PGE2 did not promote neurotoxicity, but rather had a strong protective effect against TNF-alpha by ameliorating TNF-alpha-induced apoptosis and also by rescuing the intracellular level of beta-catenin, a key transducer of the Wnt signaling pathway. PGE2-mediated stabilization of beta-catenin was accompanied by T-cell factor/lymphoid enhancer factor (Tcf/Lef)-mediated transcriptional activation, which was followed by an increase in the cyclinD1 level. Pharmacological studies provided further evidence supporting the notion that PGE2-mediated neuroprotection against TNF-alpha involves the stimulation of Tcf/Lef signaling through EP1-, EP2-, and EP4-mediated increases of beta-catenin in SH-SY5Y cells. In addition, this PGE2 effect appears to be dependent on the activation of protein kinase A, phosphatidylinositol 3-kinase, phospholipase C, and to a lesser extent protein kinase C. Thus, the molecular mechanism governing the inhibitory effect of PGE2 against TNF-alpha may involve the activation and cross talk of multiple signal transduction and play an important role in regulating the survival of neurons during the neurotoxic inflammatory response associated with neurodegenerative diseases including AD.
...
PMID:Mechanisms involved in prostaglandin E2-mediated neuroprotection against TNF-alpha: possible involvement of multiple signal transduction and beta-catenin/T-cell factor. 1534 93

Wnt signaling is a complex pathway in which beta-catenin is typically viewed as a central mediator. However, within the past 15 years, at least three Wnt-mediated pathways have been proposed that function independent of beta-catenin. One pathway involves activation of calcium/calmodulin-dependent kinase II (CamKII) and protein kinase C (PKC). Another includes recruitment of heterotrimeric GTP-binding proteins to activate phospholipase C (PLC) and phosphodiesterase (PDE). Lastly, a pathway similar to the planar cell polarity (PCP) pathway in Drosophila has been identified that activates the Jun-N-terminal kinase (JNK) and, perhaps, small GTP-binding proteins. Calcium has been implicated as an important second messenger in all of these pathways. This review will focus on the role of calcium in Wnt signaling and, as a consequence, provide a limited overview of beta-catenin-independent Wnt signaling.
...
PMID:Wnt and calcium signaling: beta-catenin-independent pathways. 1609 39


1 2 Next >>

---