TGF-β signalling is mediated by two autonomously functioning TβRI:TβRII pairs

Transforming growth factor (TGF)‐βs are dimeric polypeptides that have vital roles in regulating cell growth and differentiation. They signal by assembling a receptor heterotetramer composed of two TβRI:TβRII heterodimers. To investigate whether the two heterodimers bind and signal autonomously, one of the TGF‐β protomers was substituted to block receptor binding. The substituted dimer, TGF‐β3 WD, bound the TβRII extracellular domain and recruited the TβRI with affinities indistinguishable from TGF‐β3, but with one‐half the stoichiometry. TGF‐β3 WD was further shown to retain one‐quarter to one‐half the signalling activity of TGF‐β3 in three established assays for TGF‐β function. Single‐molecule fluorescence imaging with GFP‐tagged receptors demonstrated a measurable increase in the proportion of TβRI and TβRII dimers upon treatment with TGF‐β3, but not with TGF‐β3 WD. These results provide evidence that the two TβRI:TβRII heterodimers bind and signal in an autonomous manner. They further underscore how the TGF‐βs diverged from the bone morphogenetic proteins, the ancestral ligands of the TGF‐β superfamily that signal through a RI:RII:RII heterotrimer. In this study, Andrew Hinck and colleagues differentiate TGF‐β from BMP receptor complexes. Based on various biochemical techniques they report a functional hetero‐dimeric TGF‐β complex that contrasts the hetero‐tetrameric composition of active BMP receptors.