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J. Biol. Chem., Vol. 282, Issue 25, 18327-18338, June 22, 2007

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Activation of Mps1 Promotes Transforming Growth Factor--independent Smad Signaling^*

From the Department of Chemistry and Biochemistry, University of Colorado, Boulder, Colorado 80309

The primary intracellular mediators of TGF- signaling are the Smad proteins. Phosphorylation of R-Smad at the C-terminal SSXS motif by the activated TGF- type I receptor kinase triggers a conformation change in R-Smad and facilitates complex formation between R-Smad and Smad4, which shuttle into the nucleus where they interact with DNA and other transcription factors to regulate gene expression. In an attempt to identify proteins interacting with activated Smad signaling complex, we discovered that Mps1, a protein kinase that plays important roles in normal mitotic progression and mitotic checkpoint signaling, co-purifies with this complex. We demonstrated that Smad2 and Smad3 but not Smad4 are substrates of Mps1 in vitro and in vivo. Mps1 phosphorylates Smad2 and Smad3 at the SSXS motif in their C-terminal regions in vitro and in vivo. Disruption of microtubule networks by nocodazole activates Mps1 and promotes TGF--independent activation of Smad signaling. We found that Mps1 is involved in turning on Smad signaling by phosphorylating R-Smads. Our results reveal a novel functional link between Mps1 and Smads in a non-canonical Smad signaling pathway.

Received for publication, January 23, 2007 , and in revised form, April 23, 2007.

^* This work was supported in part by Grant CA095527 from the National Institutes of Health and a grant from the Elsa Pardee Foundation (to X. L.). 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.

¹ Supported by a postgraduate B scholarship from the Natural Sciences and Engineering Research Council of Canada.

² To whom correspondence should be addressed: Dept. of Chemistry and Biochemistry, UCB 215, University of Colorado-Boulder, Boulder, CO 80309. Tel.: 303-735-6161; Fax: 303-735-6161; E-mail: Xuedong.Liu{at}colorado.edu.

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