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TGF‐β signalling is mediated by two autonomously functioning TβRI:TβRII pairs
Author(s) -
Huang Tao,
David Laurent,
Mendoza Valentín,
Yang Yong,
Villarreal Maria,
De Keya,
Sun LuZhe,
Fang Xiaohong,
LópezCasillas Fernando,
Wrana Jeffrey L,
Hinck Andrew P
Publication year - 2011
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/emboj.2011.54
Subject(s) - biology , signalling , signal transduction , microbiology and biotechnology , genetics
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.