Cutting edge: Transcriptional activity of NFATc1 is enhanced by the Pim-1 kinase.
Pim-1 is an oncogenic serine/threonine kinase implicated in cytokine-induced signal transduction and in development of lymphoid malignancies. However, its precise function as well as physiological substrates have remained unknown. In this study we demonstrate that Pim-1 can physically interact with the NFATc1 transcription factor and phosphorylate it in vitro on several serine residues. In contrast to previously recognized NFATc kinases, wild-type Pim-1 enhances NFATc-dependent transactivation and IL-2 production in Jurkat T cells, while kinase-deficient Pim-1 mutants inhibit them in a dominant negative fashion. Our results reveal a novel, phosphorylation-dependent regulatory mechanism targeting NFATc1 through which Pim-1 acts as a downstream effector of Ras to facilitate IL-2-dependent proliferation and/or survival of lymphoid cells.
Rainio
Eeva-Marja
EM
Turku Centre for Biotechnology, University of Turku/Abo Akademi University, and Turku Graduate School of Biomedical Sciences, Turku, Finland.
Sandholm
Jouko
J
Koskinen
Päivi J
PJ
D000818:Animals; D019556:COS Cells; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D007376:Interleukin-2 / Q000096:biosynthesis; D019169:Jurkat Cells; D009154:Mutation; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D010766:Phosphorylation; D010768:Phosphoserine / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000502:physiology*; D051573:Proto-Oncogene Proteins c-pim-1; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000201:enzymology / Q000276:immunology*; D014157:Transcription Factors / Q000737:chemistry / Q000378:metabolism*; D015533:Transcriptional Activation
D004268:DNA-Binding Proteins; D007376:Interleukin-2; D050778:NFATC Transcription Factors; C494003:NFATC1 protein, human; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D014157:Transcription Factors; D010768:Phosphoserine; C496634:PIM1 protein, human; D017346:Protein Serine-Threonine Kinases; D051573:Proto-Oncogene Proteins c-pim-1; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)