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Papers In Press, published online ahead of print August 5, 2003
Pathology, Upstate Medical Univ-State Univ New York, Syracuse, New York 13210
Corresponding Author: friedmae{at}mail.upstate.edu
The Rho family of small GTPases regulates many aspects of the differentiation of skeletal myoblasts. We now demonstrate that the kinase Mirk/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 to 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 downregulated 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 hours 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 RNAi, which prevented myoblast fusion into myotubes and inhibited induction of myogenin, fast twitch troponin T and muscle myosin heavy chain.
J. Biol. Chem, 10.1074/jbc.M306780200
Submitted on June 25, 2003
Revised on July 30, 2003
Accepted on August 5, 2003
Mirk/dyrk1B is a Rho-induced kinase active in skeletal muscle differentiation
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