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Genes & Dev. 16 (15): 1950-1963

Copyright © 2002 by Cold Spring Harbor Laboratory Press.

Vol. 16, No. 15, pp. 1950-1963, August 1, 2002

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

Bin Y. Qin,1 Suvana S. Lam,1 John J. Correia,2 and Kai Lin1,3

1 Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts 01655, USA; 2 Department of Biochemistry, University of Mississippi Medical Center, Jackson, Mississippi 39216, USA

Smad3 transduces the signals of TGF-beta s, 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-beta 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.

[Key Words: TGF-beta ; Smad; phosphorylation; signaling; allosteric]

3 Corresponding author.

GENES & DEVELOPMENT 16:1950-1963 © 2002 by Cold Spring Harbor Laboratory Press  ISSN 0890-9369/02 $5.00

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