TGF-? signalling is mediated by two autonomously functioning T?RI:T?RII pairs.

ABSTRACT: Transforming growth factor (TGF)-?s are dimeric polypeptides that have vital roles in regulating cell growth and differentiation. They signal by assembling a receptor heterotetramer composed of two T?RI:T?RII heterodimers. To investigate whether the two heterodimers bind and signal autonomously, one of the TGF-? protomers was substituted to block receptor binding. The substituted dimer, TGF-?3 WD, bound the T?RII extracellular domain and recruited the T?RI with affinities indistinguishable from TGF-?3, but with one-half the stoichiometry. TGF-?3 WD was further shown to retain one-quarter to one-half the signalling activity of TGF-?3 in three established assays for TGF-? function. Single-molecule fluorescence imaging with GFP-tagged receptors demonstrated a measurable increase in the proportion of T?RI and T?RII dimers upon treatment with TGF-?3, but not with TGF-?3 WD. These results provide evidence that the two T?RI:T?RII heterodimers bind and signal in an autonomous manner. They further underscore how the TGF-?s diverged from the bone morphogenetic proteins, the ancestral ligands of the TGF-? superfamily that signal through a RI:RII:RII heterotrimer.

SUBMITTER: Huang T 

PROVIDER: S-EPMC3094126 | biostudies-literature | 2011 Apr

REPOSITORIES: biostudies-literature