Phosphorylation of NFATc4 by p38 mitogen-activated protein kinases

Teddy T C Yang, Qiufang Xiong, Hervé Enslen, Roger J. Davis, Chi Wing Chow

Research output: Contribution to journalArticle

128 Citations (Scopus)

Abstract

Nuclear factor of activated T cells (NFAT) is implicated in multiple biological processes, including cytokine gene expression, cardiac hypertrophy, and adipocyte differentiation. A conserved NFAT homology domain is identified in all NFAT members. Dephosphorylation of the NFAT homology region is critical for NFAT nuclear translocation and transcriptional activation. Here we demonstrate that NFATc4 is phosphorylated by p38 mitogen-activated protein (MAP) kinase but not by JNK. The p38 MAP kinase phosphorylates multiple residues, including Ser168 and Ser170, in the NFAT homology domain of NFATc4. Replacement of Ser168,170 with Ala promotes nuclear localization of NFATc4 and increases NFAT-mediated transcription activity. Stable expression of Ala168,170 NFATc4, but not of wild-type NFATc4, in NIH 3T3 cells promotes adipocyte formation under differentiation conditions. Molecular analysis indicates that peroxisome proliferator-activated receptor γ2 (PPARγ2) is a target of NFAT. Two distinct NFAT binding elements are located in the PPARγ2 gene promoter. Stable expression of Ala168,170 NFATc4, but not of wild-type NFATc4, increases the expression of PPARγ, which contributes in part to increased adipocyte formation. Thus, NFAT regulates PPAReγ gene expression and has a direct role in adipocyte differentiation.

Original languageEnglish (US)
Pages (from-to)3892-3904
Number of pages13
JournalMolecular and Cellular Biology
Volume22
Issue number11
DOIs
StatePublished - 2002

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NFATC Transcription Factors
p38 Mitogen-Activated Protein Kinases
Phosphorylation
Adipocytes
Peroxisome Proliferator-Activated Receptors
Biological Phenomena
Gene Expression
NIH 3T3 Cells
Cardiomegaly
Transcriptional Activation
Cytokines

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cell Biology

Cite this

Yang, T. T. C., Xiong, Q., Enslen, H., Davis, R. J., & Chow, C. W. (2002). Phosphorylation of NFATc4 by p38 mitogen-activated protein kinases. Molecular and Cellular Biology, 22(11), 3892-3904. https://doi.org/10.1128/MCB.22.11.3892-3904.2002

Phosphorylation of NFATc4 by p38 mitogen-activated protein kinases. / Yang, Teddy T C; Xiong, Qiufang; Enslen, Hervé; Davis, Roger J.; Chow, Chi Wing.

In: Molecular and Cellular Biology, Vol. 22, No. 11, 2002, p. 3892-3904.

Research output: Contribution to journalArticle

Yang, TTC, Xiong, Q, Enslen, H, Davis, RJ & Chow, CW 2002, 'Phosphorylation of NFATc4 by p38 mitogen-activated protein kinases', Molecular and Cellular Biology, vol. 22, no. 11, pp. 3892-3904. https://doi.org/10.1128/MCB.22.11.3892-3904.2002
Yang, Teddy T C ; Xiong, Qiufang ; Enslen, Hervé ; Davis, Roger J. ; Chow, Chi Wing. / Phosphorylation of NFATc4 by p38 mitogen-activated protein kinases. In: Molecular and Cellular Biology. 2002 ; Vol. 22, No. 11. pp. 3892-3904.
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