Ligand binding and functional properties of betaglycan, a co-receptor of the transforming growth factor-beta superfamily - Specialized binding regions for transforming growth factor-beta and inhibin A

Betaglycan, also known as the transforming growth factor-beta (TGF-beta) ty pe III receptor, is a membrane-anchored proteoglycan that binds TGF-beta vi a its core protein. Deletion mutagenesis analysis has revealed two regions of betaglycan ectodomain capable of binding TGF-beta: one at the amino-term inal half, the endoglin-related region (Lopez-Casillas, F., Payne, H., Andr es, J. L., and Massague, J. (1994) J. Cell Biol. 124, 557-568), and the oth er at the carboxyl-terminal half, the uromodulin-related region (Pepin, M.- C., Beauchemin, M., Plamondon, J., and O'Connor-McCourt, M. D. (1994) Proc. Natl. Acad. Sci. U. S. A 91, 6997-7001). In the present work we have funct ionally characterized these ligand binding regions. Similar to the wild typ e receptor, both regions bind TGF-beta2 with higher affinity than TGF-beta1 , However, only the endoglin-related region increases the TGF-beta2 labelin g of the TGF-beta type II receptor, the so-called "TGF-beta -presentation" function of the wild type receptor. Despite this preference, both regions a s well as the wild type receptor mediate the TGF-beta2-dependent Smad2 phos phorylation, indicating that they can function indistinguishably as TGF-bet a -enhancing coreceptors, On the other hand, we found that the recently des cribed ability of the wild type betaglycan to bind inhibin A is a property of the core protein that resides in the uromodulin-related region, Binding competition experiments indicate that this region binds inhibin and TGF-bet a with the following relative affinities: TGF-beta2 > inhibin A > TGF-beta1 . All together, the present results suggest that betaglycan ectodomain is e ndowed with two bona fide independent ligand binding domains that can perfo rm specialized functions as co-receptors of distinct members of the TGF-bet a superfamily.