Smad3 allostery links TGF-β receptor kinase activation to transcriptional control

  1. Bin Y. Qin1,
  2. Suvana S. Lam1,
  3. John J. Correia2, and
  4. Kai Lin1,3
  1. 1Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts 01655, USA; 2Department of Biochemistry, University of Mississippi Medical Center, Jackson, Mississippi 39216, USA

Abstract

Smad3 transduces the signals of TGF-βs, coupling transmembrane receptor kinase activation to transcriptional control. The membrane-associated molecule SARA (Smad Anchor for Receptor Activation) recruits Smad3 for phosphorylation by the receptor kinase. Upon phosphorylation, Smad3 dissociates from SARA and enters the nucleus, in which its transcriptional activity can be repressed by Ski. Here, we show that SARA and Ski recognize specifically the monomeric and trimeric forms of Smad3, respectively. Thus, trimerization of Smad3, induced by phosphorylation, simultaneously activates the TGF-β signal by driving Smad3 dissociation from SARA and sets up the negative feedback mechanism by Ski. Structural models of the Smad3/SARA/receptor kinase complex and Smad3/Ski complex provide insights into the molecular basis of regulation.

Keywords

Footnotes

  • ↵3 Corresponding author.

  • E-MAIL kai.lin{at}umassmed.edu; FAX (508) 856-2398.

  • Article and publication are at http://www.genesdev.org/cgi/doi/10.1101/gad.1002002.

    • Received April 25, 2002.
    • Accepted June 19, 2002.
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  1. doi: 10.1101/gad.1002002 Genes & Dev. 16: 1950-1963 Cold Spring Harbor Laboratory Press

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