BINDING AND DEGRADATION OF THROMBOSPONDIN-1 MEDIATED THROUGH HEPARAN-SULFATE PROTEOGLYCANS AND LOW-DENSITY-LIPOPROTEIN RECEPTOR-RELATED PROTEIN - LOCALIZATION OF THE FUNCTIONAL-ACTIVITY TO THE TRIMERIC N-TERMINAL HEPARIN-BINDING REGION OF THROMBOSPONDIN-1

Thrombospondin-l (TSP-1) is a multimodular trimeric protein involved i n cell adhesion, motility and growth. TSP-1 binds to cells and is inte rnalized and degraded in a process that requires the presence of hepar an sulphate proteoglycan; the process is inhibited by heparin or recep tor-associated protein (RAP), an antagonist of the low-density-lipopro tein receptor (LDLR) family. We characterized the attributes of TSP-I that mediate the process. TSP277, which is truncated at Gln-277 of TSP -1 and contains the heparin-binding domain and the heptad repeat regio n that mediates trimerization, bound to and was degraded by a variety of cells with kinetics similar to those of the binding and degradation of intact TSP-1. Degradation of TSP277 was inhibited by heparin or RA P with dose responses similar to those for inhibition of degradation o f TSP-1. Binding and degradation of TSP277 were decreased in Chinese h amster ovary cells lacking heparan sulphate. These results indicate th at the N-terminal heparin-binding domain in a trivalent configuration is sufficient to mediate binding and degradation of TSP-1 via the prot eoglycan-LDLR family pathway.