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J. Biol. Chem., Vol. 280, Issue 16, 15992-16001, April 22, 2005

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The Integral Inner Nuclear Membrane Protein MAN1 Physically Interacts with the R-Smad Proteins to Repress Signaling by the Transforming Growth Factor- Superfamily of Cytokines^*

Deng Pan¶, Luis D. Estévez-Salmerón¶, Shannon L. Stroschein||, Xueliang Zhu**, Jun He¶, Sharleen Zhou, and Kunxin Luo¶

From the Department of Molecular and Cell Biology, University of California, Berkeley and ^¶Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California 94720

Smad proteins are critical intracellular mediators of the transforming growth factor-, bone morphogenic proteins (BMPs), and activin signaling. Upon ligand binding, the receptor-associated R-Smads are phosphorylated by the active type I receptor serine/threonine kinases. The phosphorylated R-Smads then form heteromeric complexes with Smad4, translocate into the nucleus, and interact with various transcription factors to regulate the expression of downstream genes. Interaction of Smad proteins with cellular partners in the cytoplasm and nucleus is a critical mechanism by which the activities and expression of the Smad proteins are modulated. Here we report a novel step of regulation of the R-Smad function at the inner nuclear membrane through a physical interaction between the integral inner nuclear membrane protein MAN1 and R-Smads. MAN1, through the RNA recognition motif, associates with R-Smads but not Smad4 at the inner nuclear membrane in a ligand-independent manner. Overexpression of MAN1 results in inhibition of R-Smad phosphorylation, heterodimerization with Smad4 and nuclear translocation, and repression of transcriptional activation of the TGF, BMP2, and activin-responsive promoters. This repression of TGF, BMP2, and activin signaling is dependent on the MAN1-Smad interaction because a point mutation that disrupts this interaction abolishes the transcriptional repression by MAN1. Thus, MAN1 represents a new class of R-Smad regulators and defines a previously unrecognized regulatory step at the nuclear periphery.

Received for publication, October 1, 2004 , and in revised form, January 12, 2005.

^* This work was supported by National Institutes of Health Grant CA87940 (to K. L.) and Dean's start-up fund. 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.

Both authors contributed equally to this work.

^|| Present address: University of California, Genentech Hall, Rm. N374, 600 16th St., San Francisco, CA 94143.

^** Present address: Institute of Biochemistry and Cell Biology, SIBS, Chinese Academy of Sciences, 320 Yue Yang Rd., Shanghai 200031, China.

To whom correspondence should be addressed: Dept. of Molecular and Cell Biology, University of California, Berkeley, 237 Hildebrand Hall, mail code 3206, Berkeley, CA 94720-3206. Tel.: 510-486-5178; Fax: 510-486-6488; E-mail: kluo{at}uclink.berkeley.edu.

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