Fibroblast growth factor-specific modulation of cellular response by syndecan-4.
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.
Horowitz
Arie
A
Angiogenesis Research Center and Section of Cardiology, Department of Medicine, Dartmouth Medical School, Lebanon, NH 03756, USA. arie.horowitz@dartmouth.edu
Tkachenko
Eugene
E
Simons
Michael
M
D000818:Animals; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism*; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000187:drug effects / Q000254:growth & development* / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism / Q000494:pharmacology; D005346:Fibroblast Growth Factors / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D020929:Mitogen-Activated Protein Kinase Kinases; D016297:Mutagenesis, Site-Directed / Q000235:genetics; D009154:Mutation / Q000235:genetics*; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000502:physiology*; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011108:Polymers / Q000378:metabolism; D011485:Protein Binding / Q000235:genetics; D011493:Protein Kinase C / Q000378:metabolism; D051571:Protein Kinase C-alpha; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary / Q000235:genetics; D011509:Proteoglycans / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D053671:Syndecan-4
D007527:Isoenzymes; D008562:Membrane Glycoproteins; D019269:Phosphatidylinositol 4,5-Diphosphate; D011108:Polymers; D011509:Proteoglycans; C508304:SDC4 protein, human; D053671:Syndecan-4; D016222:Fibroblast Growth Factor 2; D005346:Fibroblast Growth Factors; D017346:Protein Serine-Threonine Kinases; C496628:PRKCA protein, human; D011493:Protein Kinase C; D051571:Protein Kinase C-alpha; D020929:Mitogen-Activated Protein Kinase Kinases; C409022:PDZ-binding kinase