The transforming growth factor β receptors types I, II, and III form hetero-oligomeric complexes in the presence of ligand

Transforming growth factors β (TGF-βs) are disulfide-linked dimers. In Rat-1 cells both radioiodinated TGF-β1 and -β2 bind to and can be chemically cross-linked to type I and II receptors (which are thought to mediate effects of cell growth suppression and gene activation), to type III proteoglycan receptors, and to a novel ~50-kDa protein. After detergent solubilization of cells that were cross-linked with radioiodinated TGF-β, antibodies specific for the type II receptor precipitated labeled receptor types I and III as well as type II. In these cells, the type III receptor is the predominant TGF-β-binding protein, and antibodies specific for it precipitate mainly this cross-linked receptor. Thus, in the presence of TGF- β ligand, receptor types II and III and types II and I form heteromeric complexes. The majority of the type III receptor does not associate with receptor types I and II, probably reflecting the relative amounts of the three receptors on the surface of Rat-1 cells. Since TGF-β1 but not TGF-β2 binds to the exoplasmic domain of the type II receptor in the absence of the type III receptor, and since both TGF-β1 and -β2 bind with high affinity to the type III receptor, we suggest that TGF-β2, and possibly TGF-β1, bind initially to the type III receptor. The TGF-β2-type III receptor complex would then interact with a type II receptor, thus modulating the affinity of the type II receptor for TGF-β2.