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Molecular and Cellular Biology, June 2002, p. 3892-3904, Vol. 22, No. 11
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.11.3892-3904.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Phosphorylation of NFATc4 by p38 Mitogen-Activated Protein Kinases

Teddy T. C. Yang,1 Qiufang Xiong,1 Hervé Enslen,2 Roger J. Davis,2 and Chi-Wing Chow1*

Department of Molecular Pharmacology, Jack and Pearl Resnick Campus, Albert Einstein College of Medicine, Bronx, New York 10461,1 Department of Biochemistry and Molecular Biology, Program in Molecular Medicine, Howard Hughes Medical Institute, University of Massachusetts Medical School, Worcester, Massachusetts 016052

Received 5 September 2001/ Returned for modification 22 October 2001/ Accepted 25 February 2002

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 {gamma}2 (PPAR{gamma}2) is a target of NFAT. Two distinct NFAT binding elements are located in the PPAR{gamma}2 gene promoter. Stable expression of Ala168,170 NFATc4, but not of wild-type NFATc4, increases the expression of PPAR{gamma}, which contributes in part to increased adipocyte formation. Thus, NFAT regulates PPAR{gamma} gene expression and has a direct role in adipocyte differentiation.

* Corresponding author. Mailing address: Department of Molecular Pharmacology, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY 10461. Phone: (718) 430-2716. Fax: (718) 430-8922. E-mail: cchow{at}aecom.yu.edu.

Molecular and Cellular Biology, June 2002, p. 3892-3904, Vol. 22, No. 11
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.11.3892-3904.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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