title: c-Jun NH(2)-terminal kinase inhibits targeting of the protein phosphatase calcineurin to NFATc1.
abstract: The protein phosphatase calcineurin is a critical mediator of calcium signals during T-cell activation. One substrate of calcineurin is the transcription factor NFATc1, which is retained in the cytoplasm of quiescent cells. NFATc1 activation requires the translocation of the transcription factor into the nucleus, a process that is mediated by calcineurin. This interaction with calcineurin requires a targeting domain (PxIxIT motif) located in the NH(2)-terminal region of NFATc1. Here we demonstrate that the calcineurin targeting domain of NFATc1 is phosphorylated and inactivated by the c-Jun NH(2)-terminal kinase (JNK). This disruption of calcineurin targeting inhibits the nuclear accumulation and transcription activity of NFATc1 and accounts for the observation that Jnk1(-/-) T cells exhibit greatly increased NFATc1-dependent nuclear responses.
authors.affiliation: Howard Hughes Medical Institute, Program in Molecular Medicine, Department of Biochemistry and Molecular Biology, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.
authors.forename: C W
authors.initials: CW
authors.lastname: Chow
authors.forename: C
authors.initials: C
authors.lastname: Dong
authors.forename: R A
authors.initials: RA
authors.lastname: Flavell
authors.forename: R J
authors.initials: RJ
authors.lastname: Davis
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D019703:Calcineurin / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015759:Ionomycin / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases; D019169:Jurkat Cells / Q000187:drug effects / Q000378:metabolism; D028884:Karyopherins; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D009154:Mutation; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D010766:Phosphorylation; D018160:Receptors, Cytoplasmic and Nuclear; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D000097606:Exportin 1 Protein
chemical_list: D019703:Calcineurin; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D015759:Ionomycin; D048031:JNK Mitogen-Activated Protein Kinases; D028884:Karyopherins; D020928:Mitogen-Activated Protein Kinases; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D011993:Recombinant Fusion Proteins; D013755:Tetradecanoylphorbol Acetate; D014157:Transcription Factors; D000097606:Exportin 1 Protein; C494003:NFATC1 protein, human