THE TRANSFORMING GROWTH-FACTOR BETA-RECEPTORS TYPE-I, TYPE-II, AND TYPE-III FORM HETEROOLIGOMERIC COMPLEXES IN THE PRESENCE OF LIGAND

Transforming growth factors beta (TGF-betas) are disulfide-linked dime rs. In Rat-1 cells both radioiodinated TGF-beta1 and -beta2 bind to an d can be chemically cross-linked to type I and II receptors (which are thought to mediate effects of cell growth suppression and gene activa tion), to type III proteoglycan receptors, and to a novel approximatel y 50-kDa protein. After detergent solubilization of cells that were cr oss-linked with radioiodinated TGF-beta, antibodies specific for the t ype II receptor precipitated labeled receptor types I and III as well as type II. In these cells, the type III receptor is the predominant T GF-beta-binding protein, and antibodies specific for it precipitate ma inly this cross-linked receptor. Thus, in the presence of TGF-beta lig and, receptor types II and III and types II and I form heteromeric com plexes. The majority of the type III receptor does not associate with receptor types I and II, probably reflecting the relative amounts of t he three receptors on the surface of Rat-1 cells. Since TGF-beta1 but not TGF-beta2 binds to the exoplasmic domain of the type II receptor i n the absence of the type III receptor, and since both TGF-beta1 and - beta2 bind with high affinity to the type III receptor, we suggest tha t TGF-beta2, and possibly TGF-beta1, bind initially to the type III re ceptor. The TGF-beta2-type III receptor complex would then interact wi th a type II receptor, thus modulating the affinity of the type II rec eptor for TGF-beta2.