title: Phosphorylation of the cytoplasmic tail of syndecan-4 regulates activation of protein kinase Calpha.
abstract: Syndecans are transmembrane proteoglycans capable of carrying both heparan and chondroitin sulfate chains. The cytoplasmic tail of syndecan-4 was recently reported to undergo in vivo phosphorylation on Ser183 in the membrane-proximal part of the tail (Horowitz, A., and Simons, M. (1998) J. Biol. Chem. 273, 10914-10918). However, the functional consequences of this event remain unknown. The cytoplasmic tail of syndecan-4 is known to undergo multimerization and to activate protein kinase Calpha (PKCalpha), with both events depending on the presence of the commonly occurring phospholipid phosphatidylinositol 4,5-bisphosphate (PIP2). In the present investigation we found that phosphorylation of Ser183 produced a 10-fold reduction in the ability of syndecan-4 to activate PKCalpha, without affecting its ability to bind the PKC. Because Ser183 is adjacent to positively charged lysine groups that resemble PIP2-binding regions in several other proteins, phosphorylation of this serine may affect the binding affinity of the syndecan-4 cytoplasmic tail to PIP2. We found that the Ser183-phosphorylated cytoplasmic tail of syndecan-4 has indeed a significantly lower affinity to PIP2 compared with the nonphosphorylated tail. Furthermore, Ser183 phosphorylation abolished PIP2-dependent oligomerization of syndecan-4 cytoplasmic tails. We conclude that Ser183 phosphorylation regulates syndecan-4-dependent activation of PKCalpha by reducing the affinity to PIP2 and inhibiting the oligomerization of syndecan-4 cytoplasmic tails. These results further support the role of syndecan-4 in signal transduction in endothelial cells.
authors.affiliation: Angiogenesis Research Center, Cardiovascular Division, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: A
authors.initials: A
authors.lastname: Horowitz
authors.forename: M
authors.initials: M
authors.lastname: Simons
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D002850:Chromatography, Gel; D004789:Enzyme Activation / Q000502:physiology; D008562:Membrane Glycoproteins / Q000737:chemistry* / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000201:enzymology; D010446:Peptide Fragments / Q000494:pharmacology; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000378:metabolism; D010766:Phosphorylation; D010768:Phosphoserine / Q000378:metabolism; D011485:Protein Binding / Q000502:physiology; D011487:Protein Conformation; D011493:Protein Kinase C / Q000378:metabolism*; D011509:Proteoglycans / Q000737:chemistry*; D051381:Rats; D015398:Signal Transduction / Q000502:physiology; D053671:Syndecan-4
chemical_list: D008562:Membrane Glycoproteins; D010446:Peptide Fragments; D019269:Phosphatidylinositol 4,5-Diphosphate; D011509:Proteoglycans; C508307:Sdc4 protein, rat; D053671:Syndecan-4; D010768:Phosphoserine; D011493:Protein Kinase C