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J. Biol. Chem., Vol. 281, Issue 25, 17156-17163, June 23, 2006

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A Dishevelled-1/Smad1 Interaction Couples WNT and Bone Morphogenetic Protein Signaling Pathways in Uncommitted Bone Marrow Stromal Cells^*

From the Division of Molecular and Cellular Pathology, Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama 35294-0019

Genetic evidence from both humans and mice suggests that Wnt/-catenin and bone morphogenetic protein (BMP) signaling pathways are essential for bone marrow mesenchymal stem cells to differentiate into osteoblasts. Here we describe a mechanism through which BMPs antagonize Wnt signaling and retard bone marrow mesenchymal stem cell proliferation. Treatment with Wnt3a, but not BMP-2, stimulated Lef1-mediated transcriptional activity, whereas co-stimulation with both Wnt3a and BMP-2 markedly reduced Wnt3a-induced reporter activity. Immunoprecipitation assays in 293T cells transfected with individual Smads and Wnt pathway components revealed a specific interaction between Dvl-1 and Smad1 that was dependent on the presence of Wnt3a or BMP-2. Under unstimulated conditions, Dvl-1 and Smad1 are co-immunoprecipitated and form a complex through the linker region of Smad1. Wnt3a treatment transiently disrupted the Dvl-1/Smad1 interaction coincident with nuclear accumulation of -catenin. In contrast, when cells were exposed to both Wnt3a and BMP-2, there was an enhanced accumulation of the Dvl-1-Smad1 complex and a decreased nuclear accumulation of -catenin. Expression of a mutant Smad1 protein, which cannot be phosphorylated in response to BMP, eliminated the inhibitory effect of BMP on Wnt-induced-catenin accumulation and transcriptional activity. These results identify a potential mechanism whereby BMP-2 antagonizes Wnt signaling in osteoblast progenitors by promoting an interaction between Smad1 and Dvl-1 that restricts -catenin activation.

Received for publication, December 27, 2005 , and in revised form, March 31, 2006.

^* This work was supported by National Institutes of Health Grants AR49410 (to T. L. C.) and DK57501 (to X. C.). 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 To whom correspondence should be addressed: Division of Molecular and Cellular Pathology, Dept. of Pathology, University of Alabama at Birmingham, 1670 University Blvd., VH G001, Birmingham, AL 35294-0019. Tel.: 205-934-2726; Fax: 205-934-0043; E-mail: tclemens{at}path.uab.edu.

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