PIM-1 phosphorylates NFATc1 (nuclear factor of activated T cells, cytoplasmic, calcineurin-dependent 1) and enhances NFAT-dependent transcription.
The PIM family of serine/threonine kinases consists of at least three members that can cooperate with the myc or bcl-2 oncogenes to induce the development of lymphoid malignancies. To date, however, the precise function and physiological substrates of PIM-1 have not been well characterized. Now, reporting in the Journal of Immunology, Koskinen and colleagues show that PIM-1 phosphorylates NFATc1 (nuclear factor of activated T cells, cytoplasmic, calcineurin-dependent 1) and enhances NFAT-dependent transcription.
PIM-1 expression is upregulated during T-cell activation. When T cells are activated, AP-1 (induced by protein kinase C and Ras) and calcium-dependent signalling cause the dephosphorylation of NFATc, which translocates to the nucleus and, together with AP-1, activates genes such as interleukin-2 (IL-2).
The authors first looked at the role of PIM-1 kinase in signalling for NFAT activation. Jurkat T cells were transfected with a PIM-1 expression vector and a reporter construct containing NFAT binding sites. When the T cells were activated with phorbol 12-myristate 13-acetate and the calcium ionophore ionomycin, endogenous NFAT activity was enchanced by PIM-1. To assess whether PIM-1 targets NFATc in a physiological setting, Jurkat T cells were stimulated and the amount of IL-2 secreted into the medium was measured. PIM-1 transfection of stimulated Jurkat cells significantly enhanced IL-2 production compared with non-transfected cells. Kinase-deficient mutants of PIM-1 were unable to enhance NFAT activity or IL-2 production. Co-immunoprecipitation experiments showed that PIM-1 can physically interact with NFATc1 and is likely to be able to phosphorylate it in vivo.
This study provides the first evidence that a kinase can positively regulate NFAT activity — phosphorylation by other kinases inhibits NFATc translocation to the nucleus. The results suggest that PIM-1 acts downstream of Ras to induce phosphorylation of NFATc1 and IL-2 production in Jurkat T cells.
Elaine Bell
References
ORIGINAL RESEARCH PAPER Rainio, E-M., Sandholm, J. & Koskinen, P. J. Transcriptional activity of NFATc1 is enhanced by the Pim-1 kinase. J. Immunol.168, 1524–1527 (2002). | PubMed |
