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)

Protein kinase Calpha (PKCalpha) activation is known to be dependent on the metabolic product of phosphatidylinositol 4,5-bisphosphate (PIP2) by phospholipase C (PLC). Here we report that fibroblasts may have an additional PIP2-dependent mechanism for membrane localization of PKCalpha. We observed PKCalpha membrane localization in both wild type and PLCgamma1 -/- mouse embryonic fibroblasts. Treatment of cells with a specific PLC inhibitor U73122 resulted in increased PIP2 levels and enhanced membrane localization of PKCalpha. PKCalpha levels in the membrane fraction decreased following incubation with PLCgamma, but increased following treatment with U73122 or addition of exogenous PIP2 in vitro. In addition, PKCalpha interacted with PIP2-conjugate bead and mixed micelles containing PIP2. Finally, we found that PIP2 is involved in syndecan-4-mediated membrane localization of PKCalpha. Taken together, these data suggest that PIP2 might contribute to directly regulating the membrane localization of PKCalpha.
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PMID:Protein kinase Calpha can undergo membrane localization via an alternative phosphatidylinositol 4,5-bisphosphate-dependent pathway. 1696 88

Tenascin-C, an extracellular matrix molecule of the tumor-specific microenvironment, counteracts the tumor cell proliferation-suppressing effect of fibronectin by blocking the integrin alpha(5)beta(1)/syndecan-4 complex. This causes cell rounding and stimulates tumor cell proliferation. Tenascin-C also stimulates endothelin receptor type A (EDNRA) expression. Here, we investigated whether signaling through endothelin receptors affects tenascin-C-induced cell rounding. We observed that endothelin receptor type B (EDNRB) activation inhibited cell rounding by tenascin-C and induced spreading by restoring expression and function of focal adhesion kinase (FAK), paxillin, RhoA, and tropomyosin-1 (TM1) via activation of epidermal growth factor receptor, phospholipase C, c-Jun NH(2)-terminal kinase, and the phosphatidylinositol 3-kinase pathway. In contrast to EDNRB, signaling through EDNRA induced cell rounding, which correlated with FAK inhibition and TM1 and RhoA protein destabilization in the presence of tenascin-C. This occurred in a mitogen-activated protein kinase/extracellular signal-regulated kinase kinase-dependent manner. Thus, tumorigenesis might be enhanced by tenascin-C involving EDNRA signaling. Inhibition of tenascin-C in combination with blocking both endothelin receptors could present a strategy for sensitization of cancer and endothelial cells toward anoikis.
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PMID:Endothelin receptor type B counteracts tenascin-C-induced endothelin receptor type A-dependent focal adhesion and actin stress fiber disorganization. 1761 73

Murine gammaherpesvirus 68 (MHV68) is used as a model to study gammaherpesvirus pathogenesis both in tissue culture systems and in vivo. We used a gene-trapping approach to get insight into cellular factors involved in MHV68 infection. By generating a library of gene-trapped CHO cells, we were able to isolate several clones that exhibited various degrees of resistance to MHV68-induced cytopathic effect. Clones that showed the highest degree of resistance were affected at the early stage of the viral cycle, with the vast majority of these clones being deficient for heparan sulfate (HS) expression at the cell surface. Heparan sulfate expression could be restored in all the HS-deficient clones by expression of EXT1, an enzyme that is essential for the biosynthesis of HS. Consistent with the role of HS in viral entry, HS-deficient CHO cells did not support viral internalization. Cell surface heparan sulfate proteoglycans (HSPG) are mostly composed of HS chains attached to two families of core proteins, the transmembrane syndecans and the GPI-anchored glypicans. Treatment of CHO cells with phosphatidylinositol-specific phospholipase C (PI-PLC) did not significantly affect the level of HS expression, indicating that the glypicans are not a major source of HSPG in CHO cells. By contrast, treatment of CHO cells with PMA, a drug known to accelerate syndecan shedding, resulted in a decrease in both HS expression and susceptibility to MHV68; these effects were abolished by TIMP-3, a specific inhibitor of syndecan shedding. All together, our results confirm the essential role of HS in MHV68 infection and identify the syndecans as a major source of HSPG used by the virus as coreceptors to infect CHO cells.
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PMID:Selection of mutant CHO clones resistant to murine gammaherpesvirus 68 infection. 1819 80

The antiadhesive extracellular matrix molecule tenascin-C abrogates cell spreading on fibronectin through competitive inhibition of syndecan-4, thereby preventing focal adhesion kinase (FAK) activation and triggering enhanced proteolytic degradation of both RhoA and tropomyosin 1 (TM1). Here, we show that simultaneous signaling by lysophosphatidic acid (LPA) and platelet-derived growth factor (PDGF) initiates glioma cell spreading and migration through syndecan-4-independent activation of paxillin and FAK and by stabilizing expression of RhoA, TM1, TM2, and TM3. By using gene silencing methods, we show that paxillin, TM1, TM2, and TM3 are essential for LPA/PDGF-induced cell spreading on a fibronectin/tenascin-C (FN/TN) substratum. LPA/PDGF-induced cell spreading and migration on FN/TN depends on phosphatidylinositol 3-kinase, RhoKinase, and mitogen-activated protein kinase/extracellular signal-regulated kinase kinase 1/2 but is independent of phospholipase C and Jun kinase. RNA microarray data reveal expression of tenascin-C, PDGFs, LPA, and the respective receptors in several types of cancer, suggesting that the TN/LPA/PDGF axis exists in malignant tumors. These findings may in turn be relevant for diagnostic or therapeutic applications targeting cancer.
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PMID:Combined lysophosphatidic acid/platelet-derived growth factor signaling triggers glioma cell migration in a tenascin-C microenvironment. 1875 8

Although phosphatidylinositol 4,5-bisphosphate (PIP(2)) regulates syndecan-4 function, the potential influence of syndecan-4 on PIP(2) remains unknown. GFP containing PIP(2)-binding-PH domain of phospholipase Cdelta (GFP-PHdelta) was used to monitor PIP(2). Syndecan-4 overexpression in COS-7 cells enhanced membrane translocation of GFP-PHdelta, while the opposite was observed when syndecan-4 was knocked-down. PIP(2) levels were higher in total phospholipids extracted from rat embryo fibroblasts expressing syndecan-4. Syndecan-4-induced membrane targeting of GFP-PHdelta was further enhanced by phosphoinositide-3-kinase inhibitor, but not by phospholipase C (PLC) inhibitor. Besides, both ionomycin and epidermal growth factor caused dissociation of GFP-PHdelta from plasma membrane, an effect that was significantly delayed by syndecan-4 over-expression. Collectively, these data suggest that syndecan-4 promotes plasma membrane retention of PIP(2) by negatively regulating PLC-dependent PIP(2) degradation.
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PMID:Syndecan-4 promotes the retention of phosphatidylinositol 4,5-bisphosphate in the plasma membrane. 1956 Apr 61


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