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J. Biol. Chem., Vol. 282, Issue 28, 20603-20611, July 13, 2007

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Selective Inhibitory Effects of Smad6 on Bone Morphogenetic Protein Type I Receptors^*

Kouichiro Goto, Yuto Kamiya, Takeshi Imamura, Kohei Miyazono¹, and Keiji Miyazawa

From the Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan and the Department of Biochemistry, The Cancer Institute of the Japanese Foundation of Cancer Research, Koto-ku, Tokyo 135-8550, Japan

The inhibitory Smads, Smad6 and Smad7, play pivotal roles in negative regulation of transforming growth factor- (TGF-) family signaling as feedback molecules as well as mediators of cross-talk with other signaling pathways. Whereas Smad7 acts as a ubiquitous inhibitor of Smad signaling, Smad6 has been shown to effectively inhibit bone morphogenetic protein (BMP) signaling but only weakly TGF-/activin signaling. In the present study, we have found that Smad6 inhibits signaling from the activin receptor-like kinase (ALK)-3/6 subgroup in preference to that from the ALK-1/2 subgroup of BMP type I receptors. The difference is attributable to the interaction of Smad6 with these BMP type I receptors. The amino acid residues responsible for Smad6 sensitivity of ALK-3 were identified as Arg-238, Phe-264, Thr-265, and Ala-269, which map to the N-terminal lobe of the ALK-3 kinase domain. Although Smad6 regulates BMP signaling through multiple mechanisms, our findings suggest that interaction with type I receptors is a critical step in the function of Smad6.

Received for publication, March 12, 2007 , and in revised form, May 8, 2007.

^* This research was supported by KAKENHI (Grants-in-aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan). 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 Figs. 1–3 and a supplemental table.

¹ To whom correspondence should be addressed: Dept. of Molecular Pathology, Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan. Tel.: 81-3-5841-3345; Fax: 81-3-5841-3354; E-mail: miyazono-ind{at}umin.ac.jp.

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