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 β (TGFβ) superfamily members, including the distinct and often opposed actions of TGFβs 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 TGFβ-binding residues of this domain overlap and identify individual amino acids essential for binding of each ligand. Mutation of Val⁶¹⁴ to Tyr abolishes both inhibin and TGFβ binding to this domain. Full-length betaglycan V614Y, and other mutations, retain TGFβ binding activity via a distinct site, but are unable to bind inhibin-A. These beta-glycan mutants fail to mediate inhibin antagonism of activin signaling but can present TGFβ to TβRII. Separating the co-receptor actions of betaglycan toward inhibin and TGFβ will allow the clarification of the role of betaglycan in disease states such as renal cell carcinoma and endometrial adenocarcinoma.