Abstract
Proteoglycans participate in growth factor interaction with the cell surface through their heparan sulfate chains (HS), but it is not known if they are otherwise involved in growth factor signaling. It appears now that the syndecan-4 core protein, a transmembrane proteoglycan shown previously to bind phosphatidylinositol 4,5-bisphosphate (PIP(2)) and activate PKC alpha, participates in mediating the effects of fibroblast growth factor (FGF)2 on cell function. Mutations in the cytoplasmic tail of syndecan-4 that either reduced its affinity to PIP(2) (PIP(2)(-)) or disrupted its postsynaptic density 95, disk large, zona occludens-1 (PDZ)-dependent binding (PDZ(-)) produced a FGF2-specific dominant negative phenotype in endothelial cells as evidenced by the marked decline of their migration and proliferation rates and the impairment of their capacity to form tubes. In both cases, the molecular mechanism was determined to consist of a decrease in the syndecan-4-dependent activation of PKC alpha. This decrease was caused either by inhibition of FGF2-induced syndecan-4 dephosphorylation in the case of the PDZ(-) mutation or by disruption of basolateral targeting of syndecan-4 and its associated PDZ-dependent complex in the case of the PIP(2)(-) mutation. These results suggest that PKCalpha activation and PDZ-mediated formation of a serine/threonine phosphatase-containing complex by syndecan-4 are downstream events of FGF2 signaling.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Cell Membrane / drug effects
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Cell Membrane / metabolism*
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Cells, Cultured
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Endothelium, Vascular / drug effects
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Endothelium, Vascular / growth & development*
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Endothelium, Vascular / metabolism
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Fibroblast Growth Factor 2 / metabolism
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Fibroblast Growth Factor 2 / pharmacology
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Fibroblast Growth Factors / metabolism*
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Fibroblast Growth Factors / pharmacology
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Humans
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Isoenzymes / metabolism
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Membrane Glycoproteins / drug effects
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Membrane Glycoproteins / genetics
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Membrane Glycoproteins / metabolism*
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Mitogen-Activated Protein Kinase Kinases
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Mutagenesis, Site-Directed / genetics
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Mutation / genetics*
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Neovascularization, Physiologic / drug effects
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Neovascularization, Physiologic / physiology*
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Phosphatidylinositol 4,5-Diphosphate / genetics
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Phosphatidylinositol 4,5-Diphosphate / metabolism
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Phosphorylation / drug effects
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Polymers / metabolism
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Protein Binding / genetics
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Protein Kinase C / metabolism
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Protein Kinase C-alpha
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism
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Protein Structure, Tertiary / genetics
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Proteoglycans / drug effects
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Proteoglycans / genetics
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Proteoglycans / metabolism*
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Signal Transduction / drug effects
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Signal Transduction / physiology*
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Syndecan-4
Substances
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Isoenzymes
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Membrane Glycoproteins
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Phosphatidylinositol 4,5-Diphosphate
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Polymers
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Proteoglycans
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SDC4 protein, human
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Syndecan-4
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Fibroblast Growth Factor 2
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Fibroblast Growth Factors
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Protein Serine-Threonine Kinases
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PRKCA protein, human
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Protein Kinase C
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Protein Kinase C-alpha
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Mitogen-Activated Protein Kinase Kinases
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PDZ-binding kinase