TGF-Beta and Bmp Receptors: Distinct Modes of Oligomeric Interactions and Implications for Signaling

Abstract

Transforming growth factor-β (TGF-β) and bone morphogenetic protein (BMP) signal via two Ser-Thr kinase receptors, type I type II (TβRI and II, BMPRI and II for the TGF-β and BMP receptors, respectively), which appear at the cell surface as monomers, homomeric and heteromeric complexes. their extracellular domains (EDs) complexed with ligands were shown to form heterotetramers. However, the interaction dynamics among the full-length receptors in live cell membranes, the domains involved, and the potential roles of receptor homodimerization were largely unexplored. Using patch/FRAP and computerized immunofluorescence co-patching of epitope-tagged receptors [wild-type (wt) or mutants] in live cells, we show that the oligomerizaiton dynamics are distinctly different for the two receptor systems. For TGF-β receptors, we find clear differences between TβRII and TβRI oligomeric interactions: (1) the homodimerization of TβRII, but not TβRI, depends on a cytoplasmic juxtamembrane region; and (2) TβRI/TβRII hetero-oligomerization depends on the cytoplasmic domain of TβRI and on a C-terminal region of TβRII, distinct from the region involved in TβRII homodimerization. TGF-β1 binding mildly elevated TβRII homodimerization, and strongly enhanced TβRI/TβRII heteromeric complex formation. Notably, both homomeric and heteromeric TGF-β receptor complexes were stable on the patch/FRAP time-scale (minutes).In contrast, the BMP receptors display stable interactions on the same timescale only for homomeric complexes, while the heterocomplexes are transient. Interestingly, the BMPR heterocmplexes appear to form at the expense of homodimers, and stabilization of BMPRII/BMPRIb heteromeric (but not homomeric) complexes by IgG binding elevates phospho-Smad formation both without and with BMP-2. Based on these findings, we propose two mechanisms that can suppress the tendency of preformed BMP receptor hetero-oligomers to signal without ligand.