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J. Biol. Chem., Vol. 280, Issue 29, 27271-27283, July 22, 2005

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Transforming Growth Factor--activated Kinase-1 (TAK1), a MAP3K, Interacts with Smad Proteins and Interferes with Osteogenesis in Murine Mesenchymal Progenitors^*

Andrea Hoffmann, Olena Preobrazhenska, Claas Wodarczyk, Yvonne Medler, Andreas Winkel, Sandra Shahab, Danny Huylebroeck, Gerhard Gross¶, and Kristin Verschueren

From the Gesellschaft für Biotechnologische Forschung, "Signal Transduction and Gene Regulation," Mascheroder Weg 1, 38124 Braunschweig, Germany and the Department of Developmental Biology (VIB7), Flanders Interuniversity Institute for Biotechnology and Laboratory of Molecular Biology (Celgen), University of Leuven, Herestraat 49, 3000 Leuven, Belgium

TAK1 (transforming growth factor--activated kinase-1), a MAP3K with considerable sequence similarity to Raf-1 and MEKK-1, has been identified as a transforming growth factor-/bone morphogenetic protein (BMP)-activated cytosolic component of the MAPK pathways. In this investigation, the molecular interactions between TAK1 and Smad proteins were characterized as well as their influence on BMP-mediated mesenchymal cell differentiation along the osteogenic/chondrogenic pathway. In co-immunoprecipitations we found an interaction of TAK1 with all Smads tested, R-Smads Smads1-5, the co-Smad Smad4, and the inhibitory Smads (I-Smad6 and I-Smad7). Smad interaction with TAK1 takes place through their MH2 domain. This interaction is dependent on the presence of an active kinase domain in TAK1. TAK1 dramatically interferes with R-Smad transactivation in reporter assays and affects subcellular distribution of Smad proteins. Activated TAK1 also interferes with BMP-dependent osteogenic development in murine mesenchymal progenitor cells (C3H10T). A potential TAK1-mediated apoptosis process could be excluded for these cells. Both synergistic and interfering influences of TAK1 on BMP-mediated Smad-signaling have been reported previously. We suggest that TAK1 is a factor that is involved in the fine-tuning of BMP effects during osteogenic development.

Received for publication, March 28, 2005 , and in revised form, May 11, 2005.

^* This work was supported by the Gesellschaft für Biotechnologische Forschung, Deutsche Forschungsgemeinschaft Grants Ho2058/1-1, SFB578, and SFB599, VIB Grant VIB07, the University of Leuven Grants IUAP 5-35 and OT/00/41 (to D. H.), and the Fund of Scientific Research-Flanders Grant G.0105.02 (to D. H.). 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 Experimental Procedures, Results, and Fig. 10.

^¶ To whom correspondence should be addressed. Tel.: 49-531-6181-212; Fax: 49-531-6181-202; E-mail: ggr{at}gbf.de.

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