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J. Biol. Chem., Vol. 278, Issue 28, 26249-26257, July 11, 2003

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The Oncoprotein Ski Acts as an Antagonist of Transforming Growth Factor- Signaling by Suppressing Smad2 Phosphorylation^*

Céline Prunier , Marcia Pessah , Nathalie Ferrand , Su Ryeon Seo , Philip Howe  and Azeddine Atfi  ¶

From the Department of Cell Biology, Lerner Research Institute, Cleveland Clinic Foundation Cleveland, Ohio 44195 and INSERM U482, Hôpital Saint-Antoine, 184 Rue du Faubourg Saint-Antoine, 75571, Paris Cedex 12, France

The phosphorylation of Smad2 and Smad3 by the transforming growth factor (TGF)--activated receptor kinases and their subsequent heterodimerization with Smad4 and translocation to the nucleus form the basis for a model how Smad proteins work to transmit TGF- signals. The transcriptional activity of Smad2-Smad4 or Smad3-Smad4 complexes can be limited by the corepressor Ski, which is believed to interact with Smad complexes on TGF--responsive promoters and represses their ability to activate TGF- target genes by assembling on DNA a repressor complex containing histone deacetylase. Here we show that Ski can block TGF- signaling by interfering with the phosphorylation of Smad2 and Smad3 by the activated TGF- type I receptor. Furthermore, we demonstrate that overexpression of Ski induces the assembly of Smad2-Smad4 and Smad3-Smad4 complexes independent of TGF- signaling. The ability of Ski to engage Smad proteins in nonproductive complexes provides new insights into the molecular mechanism used by Ski for disabling TGF- signaling.

Received for publication, April 29, 2003

^* This work was supported by INSERM, CNRS, la Ligue contre le Cancer Comité de Paris, and l' Association pour la Recherche sur le Cancer. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed. Tel.: 33-1-49-28-46-11; Fax: 33-1-40-19-90-62; E-mail: atfi{at}pop.st-antoine.inserm.fr.

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