RSK2 mediates muscle cell differentiation through regulation of NFAT3

J Biol Chem. 2007 Mar 16;282(11):8380-92. doi: 10.1074/jbc.M611322200. Epub 2007 Jan 9.


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 stimulation, RSK2 induced nuclear localization of NFAT3. RSK2 phosphorylated NFAT3 in vitro (Km=3.559 microM), 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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Cell Differentiation
  • Enzyme Inhibitors / pharmacology
  • Gene Expression Regulation*
  • Humans
  • Mice
  • Molecular Sequence Data
  • Muscles / cytology*
  • NFATC Transcription Factors / physiology*
  • Protein Binding
  • Protein Structure, Tertiary
  • Ribosomal Protein S6 Kinases, 90-kDa / metabolism*
  • Sequence Homology, Amino Acid


  • Enzyme Inhibitors
  • NFATC Transcription Factors
  • NFATC4 protein, human
  • Ribosomal Protein S6 Kinases, 90-kDa
  • ribosomal protein S6 kinase, 90kDa, polypeptide 3