RSK2 mediates muscle cell differentiation through regulation of NFAT3.
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.
Cho
Yong-Yeon
YY
Hormel Institute, University of Minnesota, Austin, Minnesota 55912, USA.
Yao
Ke
K
Bode
Ann M
AM
Bergen
H Robert
HR
Madden
Benjamin J
BJ
Oh
Sang-Muk
SM
Ermakova
Svetlana
S
Kang
Bong Seok
BS
Choi
Hong Seok
HS
Shim
Jung-Hyun
JH
Dong
Zigang
Z
D000595:Amino Acid Sequence; D000818:Animals; D002454:Cell Differentiation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D009132:Muscles / Q000166:cytology*; D050778:NFATC Transcription Factors / Q000502:physiology*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid
D004791:Enzyme Inhibitors; D050778:NFATC Transcription Factors; C494010:NFATC4 protein, human; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C069330:ribosomal protein S6 kinase, 90kDa, polypeptide 3