OLIGOMERIC STRUCTURE OF TYPE-I AND TYPE-II TRANSFORMING-GROWTH-FACTOR-BETA RECEPTORS - HOMODIMERS FORM IN THE ER AND PERSIST AT THE PLASMA-MEMBRANE

Transforming growth factor beta (TGF-beta) signaling involves interact ions of at least two different receptors, types I (T beta RI) and II ( T beta RII), which form ligand-mediated heteromeric complexes. Althoug h we have shown in the past that T beta RII in the absence of ligand i s a homodimer on the cell surface, T beta RI has not been similarly in vestigated, and the site of complex formation is not known for either receptor. Several studies have indicated that homomeric interactions a re involved in TGF-beta signaling and regulation, emphasizing the impo rtance of a detailed understanding of the homooligomerization of T bet a RI or T beta RII. Here we have combined complementary approaches to study these homomeric interactions in both naturally expressing cell l ines and cells cotransfected with various combinations of epitope-tagg ed type I or type II receptors. We used sedimentation velocity of meta bolically labeled receptors on sucrose gradients to show that both T b eta RI and T beta RII form homodimer-sized complexes in the endoplasmi c reticulum, and we used coimmunoprecipitation studies to demonstrate the existence of type I homooligomers. Using a technique based on anti body-mediated immunofluorescence copatching of receptors carrying diff erent epitope tags, we have demonstrated ligand-independent homodimers of T beta RI on the surface of live cells. Soluble forms of both rece ptors are secreted as monomers, indicating that the ectodomains are no t sufficient to mediate homodimerization, although TGF-beta 1 is able to promote dimerization of the type II receptor ectodomain. These find ings may have important implications for the regulation of TGF-beta si gnaling.