REGULATED SHEDDING OF SYNDECAN-1 AND SYNDECAN-4 ECTODOMAINS BY THROMBIN AND GROWTH-FACTOR RECEPTOR ACTIVATION

The syndecan family of transmembrane heparan sulfate proteoglycans is abundant on the surface of all adherent mammalian cells. Syndecans bin d and modify the action of various growth factors/cytokines, proteases /antiproteases, cell adhesion molecules, and extracellular matrix comp onents. Syndecan expression is highly regulated during wound repair, a process orchestrated by many of these effecters. Each syndecan ectodo main is shed constitutively by cultured cells, but the mechanism and s ignificance of this shedding are not understood. Therefore, we examine d (i) whether physiological agents active during wound repair influenc e syndecan shedding, and (ii) whether wound fluids contain shed syndec an ectodomains. Using SVEC4-10 endothelial cells we find that certain proteases and growth factors accelerate shedding of the syndecan-1 and -4 ectodomains. Protease-accelerated shedding is completely inhibited by serum-containing media. Thrombin activity is duplicated by the 14- amino acid thrombin receptor agonist peptide that directly activates t he thrombin receptor and is not inhibited by serum. Epidermal growth f actor family members accelerate shedding but FGF-S, platelet-derived g rowth factor-AB, transforming growth factor-beta, tumor necrosis facto r-cu, and vascular endothelial cell growth factor 165 do not. Shed ect odomains are soluble, stable in the conditioned medium, have the same size core proteins regardless whether shed at a basal rate, or acceler ated by thrombin or epidermal growth factor-family members and are fou nd in acute human dermal wound fluids. Thus, shedding is accelerated b y activation of at least two distinct receptor classes, Gr protein-cou pled (thrombin) and protein tyrosine kinase (epidermal growth factor). Proteases and growth factors active during wound repair can accelerat e syndecan shedding from cell surfaces. Regulated shedding of syndecan s suggests physiological roles for the soluble proteoglycan ectodomain s.