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

Tao Huang, Laurent David, Valentín Mendoza, Yong Yang, Maria Villarreal, Keya De, Luzhe Sun, Xiaohong Fang, Fernando López-Casillas, Jeffrey L. Wrana, Andrew P. Hinck

Research output: Contribution to journalArticle

72 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1263-1276
Number of pages14
JournalEMBO Journal
Volume30
Issue number7
DOIs
StatePublished - Apr 6 2011

Keywords

  • TGF-β
  • TβRI
  • TβRII
  • signal transduction
  • signalling

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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