A SINGLE HETEROMERIC RECEPTOR COMPLEX IS SUFFICIENT TO MEDIATE BIOLOGICAL EFFECTS OF TRANSFORMING GROWTH-FACTOR-BETA LIGANDS

Transforming growth factor beta (TGF-beta), a multifunctional cytokine that regulates a variety of biological functions, signals through a h eteromeric receptor complex of the type I and type II TGF-beta recepto rs. The type II receptor, a transmembrane serine-threonine kinase, was cloned based on its ability to directly bind TGF-beta. Recently, a nu mber of candidate type I TGF-beta receptors have been isolated. Althou gh only one of these transmembrane kinases (R4) has been shown to medi ate TGF-beta-dependent gene activation, others bind TGF-beta when over expressed in COS cells. Consequently, it has been postulated that the diversity of TGF-beta responses is generated through the association o f distinct type I receptors with the type II TGF-beta receptor, thus c reating receptor complexes of differential signaling capacities. In co ntrast to this model, we demonstrate that stable expression of only th e R4 type I TGF-beta receptor in a mutant cell line lacking endogenous type I TGF-beta receptor was able to complex with the endogenous type II TGF-beta receptor and restore the effects of TGF-beta on inhibitio n of cell proliferation and activation of specific genes, regardless o f which of the three mammalian isoforms of TGF-beta was used as the li gand. Therefore, R4 acts as a fully functional type I TGF-beta recepto r and the differential effects of TGF-beta are likely mediated by a si ngle receptor complex consisting of R4 and the type II receptor.