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J. Biol. Chem., Vol. 282, Issue 11, 8380-8392, March 16, 2007

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RSK2 Mediates Muscle Cell Differentiation through Regulation of NFAT3^*

Yong-Yeon Cho, Ke Yao, Ann M. Bode, H. Robert Bergen, III, Benjamin J. Madden, Sang-Muk Oh, Svetlana Ermakova, Bong Seok Kang, Hong Seok Choi, Jung-Hyun Shim, and Zigang Dong¹

From the Hormel Institute, University of Minnesota, Austin, Minnesota 55912 and the Mayo Proteomics Research Center, Mayo Clinic College of Medicine, Rochester, Minnesota 55905

RSK2, an ERK downstream kinase, is a novel mediator of skeletal muscle cell differentiation through its regulation of NFAT3 activity. We found that the N-terminal (amino acids (aa) 1-68) and C-terminal (aa 416-674) kinase domains of RSK2 directly interacted with nuclear localization signal 1, the Ser/Pro repeat, and the polyproline domains (aa 261-365) of NFAT3. Upon A23187 [GenBank] stimulation, RSK2 induced nuclear localization of NFAT3. RSK2 phosphorylated NFAT3 in vitro (K_m = 3.559 µM), and activation of NFAT3 by RSK2 enhanced the promoter activity of NFAT3 downstream target genes in vivo. Furthermore, nuclear accumulation of NFAT3 was attenuated markedly in RSK2^-/- cells compared with wild-type RSK2^+/+ cells. Notably, RSK2 and NFAT3 induced a significant differentiation of C2C12 myoblasts to multinucleated myotubes. Multinucleated myotube differentiation was inhibited by small interfering RNA against RSK2, ERK1/2, or NFAT3. These results demonstrate that RSK2 is an important kinase for NFAT3 in mediating myotube differentiation.

Received for publication, December 11, 2006 , and in revised form, December 21, 2006.

^* This work was supported in part by the Hormel Foundation and National Institutes of Health Grants CA77646, CA88961, CA81064, and CA27502. 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.

¹ To whom correspondence should be addressed: Hormel Inst., University of Minnesota, 801 16th Ave. NE, Austin, MN 55912. Tel.: 507-437-9600; Fax: 507-437-9606; E-mail: zgdong{at}hi.umn.edu.

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