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J. Biol. Chem., Vol. 280, Issue 22, 21329-21336, June 3, 2005

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Nuclear Targeting of Transforming Growth Factor--activated Smad Complexes^*

Hong Bing Chen, Jonathan G. Rud, Kai Lin, and Lan Xu¶

From the Program in Molecular Medicine, Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts 01605

Upon stimulation by the transforming growth factor (TGF-), Smad2 and Smad3 are phosphorylated at their C termini and assemble into stable heteromeric complexes with Smad4. These complexes are the functional entities that translocate into the nucleus and regulate the expression of TGF- target genes. Here we report that the TGF--activated phospho-Smad3/Smad4 complex utilizes an importin-independent mechanism for nuclear import and engages different nucleoporins for nuclear import compared with the monomeric Smad4. Within the heteromeric complex, phospho-Smad3 appears to dominate over Smad4 in the nuclear import process and guides the complex to its nuclear destination. We also demonstrate that the binding of phospho-Smad3 to Smad4 prevents Smad4 from interacting with the nuclear export receptor chromosome region maintenance 1. In this way, TGF- signaling suppresses nuclear export of Smad4 by chromosome region maintenance 1 and thereby targets Smad4 into the nucleus. Indeed tumorigenic mutations in Smad4 that affect its interaction with Smad2 or Smad3 impair nuclear accumulation of Smad4 in response to TGF-.

Received for publication, January 11, 2005 , and in revised form, March 22, 2005.

^* This work was supported by National Institutes of Health Grant R01CA108509 (to L. X.). 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.

The on-line version of this article (available at http://www.jbc.org) contains Supplemental Fig. 1.

^¶ To whom correspondence should be addressed: Program in Molecular Medicine, University of Massachusetts Medical School, 373 Plantation St., Rm. 308, Worcester, MA 01605. Tel.: 508-856-4273; Fax: 508-856-6662; E-mail: lan.xu{at}umassmed.edu.

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