Phosphorylation of NFATc4 by p38 mitogen-activated protein kinases.
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 Ser(168) and Ser(170), in the NFAT homology domain of NFATc4. Replacement of Ser(168,170) with Ala promotes nuclear localization of NFATc4 and increases NFAT-mediated transcription activity. Stable expression of Ala(168,170) 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 Ala(168,170) 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.
Yang
Teddy T C
TT
Department of Molecular Pharmacology, Jack and Pearl Resnick Campus, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
Xiong
Qiufang
Q
Enslen
Hervé
H
Davis
Roger J
RJ
Chow
Chi-Wing
CW
D016475:3T3 Cells; D017667:Adipocytes / Q000166:cytology / Q000378:metabolism; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D019556:COS Cells; D002454:Cell Differentiation; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D017124:Conserved Sequence; D006224:Cricetinae; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics; D017386:Sequence Homology, Amino Acid; D012694:Serine / Q000737:chemistry; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D048051:p38 Mitogen-Activated Protein Kinases
D004268:DNA-Binding Proteins; D050778:NFATC Transcription Factors; C494010:NFATC4 protein, human; D009687:Nuclear Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D012694:Serine; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases