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J. Biol. Chem., Vol. 278, Issue 42, 41347-41354, October 17, 2003

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Mirk/dyrk1B Is a Rho-induced Kinase Active in Skeletal Muscle Differentiation^*

Xiaobing Deng , Daina Z. Ewton , Brad Pawlikowski , Margaret Maimone  and Eileen Friedman   ¶

From the Departments of Pathology and Cell & Developmental Biology, Upstate Medical University, State University of New York, Syracuse, New York 13210

The Rho family of small GTPases regulates numerous signaling pathways that control the organization of the cytoskeleton, transcription factor activity, and many aspects of the differentiation of skeletal myoblasts. We now demonstrate that the kinase Mirk (minibrain-related kinase)/dyrk1B is induced by members of the Rho-family in myoblasts and that Mirk is active in skeletal muscle differentiation. Mirk is an arginine-directed serine/threonine kinase which is expressed at elevated levels in skeletal muscle compared with other normal tissues. A Mirk promoter construct was activated when C2C12 myoblasts were switched from growth to differentiation medium and was also activated by the Rho family members RhoA, Cdc42, and to a lesser degree Rac1, but not by MyoD or Myf5. Mirk protein levels increased following transient expression of constitutively active Cdc42-QL, RhoA-QL, or Rac1-QL in C2C12 cells. High concentrations of serum mitogens down-regulated Mirk through activation of the Ras-MEK-Erk pathway. As a result, Mirk transcription was induced by the MEK1 inhibitor PD98059 and by the switch from growth to differentiation medium. Mirk was induced with similar kinetics to another Rho-induced differentiation gene, myogenin. Mirk protein levels increased 10-fold within 24–48 h after primary cultured muscle cells; C2C12 mouse myoblasts or L6 rat myoblasts were induced to differentiate. Thus Mirk was induced following the commitment stage of myogenesis. Stable overexpression of Mirk enabled myoblasts to fuse more rapidly when placed in differentiation medium. The function of Mirk in muscle differentiation was established by depletion of endogenous Mirk by small interfering RNA, which prevented myoblast fusion into myotubes and inhibited induction of markers of differentiation, including myogenin, fast twitch troponin T, and muscle myosin heavy chain. Other members of the dyrk/minibrain/HIPK family of kinases in lower organisms have been shown to regulate the transition from growth to differentiation, and Mirk is now shown to participate in skeletal muscle development.

Received for publication, June 25, 2003 , and in revised form, July 30, 2003.

^* This work was supported by Public Health Service Award RO1 CA67405 (to E. F.) and American Heart Association, New York State Affliliate Award 0256199T (to M. M.). 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.

^¶ To whom all correspondence should be addressed at: Upstate Medical University, Pathology Dept., 2303 Weiskotten Hall, 750 East Adams St., Syracuse, NY 13210. Tel.: 315-464-7138; Fax: 315-464-8419; E-mail: friedmae{at}mail.upstate.edu.

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