BETAGLYCAN CAN ACT AS A DUAL MODULATOR OF TGF-BETA ACCESS TO SIGNALING RECEPTORS - MAPPING OF LIGAND-BINDING AND GAG ATTACHMENT SITES

Betaglycan, also known as the TGF-beta type III receptor, is a membran e-anchored proteoglycan that presents TGF-beta to the type II signalin g receptor, a transmembrane serine/threonine kinase. The betaglycan ex tracellular region, which can be shed by cells into the medium, contai ns a NH2-terminal domain related to endoglin and a COOH-terminal domai n related to uromodulin, sperm receptors Zp2 and 3, and pancreatic sec retory granule GP-2 protein. We identified residues Ser(535) and Ser(5 46) in the uromodulin-related region as the glycosaminoglycan (GAG) at tachment sites. Their mutation to alanine prevents GAG attachment but does not interfere with betaglycan stability or ability to bind and pr esent TGF-beta to receptor II. Using a panel of deletion mutants, we f ound that TGF-beta binds to the NH2-terminal endoglin-related region o f betaglycan. The remainder of the extracellular domain and the cytopl asmic domain are not required for presentation of TGF-beta to receptor II; however, membrane anchorage is required. Soluble betaglycan can b ind TGF-beta but does not enhance binding to membrane receptors. In fa ct, recombinant soluble betaglycan acts as potent inhibitor of TGF-bet a binding to membrane receptors and blocks TGF-beta action, this effec t being particularly pronounced with the TGF-beta 2 isoform. The resul ts suggest that release of betaglycan into the medium converts this en hancer of TGF-beta action into a TGF-beta antagonist.