Identification of distinct inhibin and transforming growth factor β-binding sites on betaglycan -: Functional separation of betaglycan co-receptor actions

Betaglycan is a co-receptor that mediates signaling by transforming growth factor beta (TGF beta) superfamily members, including the distinct and often opposed actions of TGF beta s and inhibins. Loss of betaglycan expression, or abrogation of betaglycan function, is implicated in several human and animal diseases, although both betaglycan actions and the ligands involved in these disease states remain unclear. Here we identify a domain spanning amino acids 591-700 of the betaglycan extracellular domain as the only inhibin-binding region in betaglycan. This binding site is within the betaglycan ZP domain, but inhibin binding is not integral to the ZP motif of other proteins. We show that the inhibin and TGF beta-binding residues of this domain overlap and identify individual amino acids essential for binding of each ligand. Mutation of Val(614) to Tyr abolishes both inhibin and TGF beta binding to this domain. Full-length betaglycan V614Y, and other mutations, retain TGF beta binding activity via a distinct site, but are unable to bind inhibin-A. These betaglycan mutants fail to mediate inhibin antagonism of activin signaling but can present TGF beta to T beta RII. Separating the co-receptor actions of betaglycan toward inhibin and TGF beta will allow the clarification of the role of betaglycan in disease states such as renal cell carcinoma and endometrial adenocarcinoma.