Multiple p21ras effector pathways regulate nuclear factor of activated T cells

Elisabeth Genot (Lead / Corresponding author), Steve Cleverley, Stefan Henning, Doreen Cantrell

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    147 Citations (Scopus)

    Abstract

    The transcription factor, Nuclear Factor of Activated T cells (NFAT) is a major target for p21ras and calcium signalling pathways in the IL-2 gene and is induced by p21ras signals acting in synergy with calcium/calcineurin signals. One p21ras effector pathway involves the MAP kinase ERK-2, and we have examined its role in NFAT regulation. Expression of dominant negative MAPKK-1, prevents NFAT induction. Constitutively active MAPKK-1 fully activates ERK-2 and the transcription factor Elk-1, but does not substitute for activated p21ras and synergize with calcium/calcineurin signals to induce NFAT. Expression of dominant negative N17Rac also prevents TCR and p21ras activation of NFAT, but without interfering with the ERK-2 pathway. The transcriptional activity of the NFAT binding site is mediated by a complex comprising a member of the NFAT group and AP-1 family proteins. The induction of AP-1 by p21ras also requires Rac-1 function. Activated Rac-1 could mimic activated p21ras to induce AP-1 but not to induce NFAT. Moreover, the combination of activated MAPKK-1 and Rac-1 could not substitute for activated p21ras and synergize with calcium signals to induce NFAT. Thus, p21ras regulation of NEAT in T cells requires the activity of multiple effector pathways including those regulated by MAPKK-1/ERK-2 and Rac-1.

    Original languageEnglish
    Pages (from-to)3923-3933
    Number of pages11
    JournalEMBO Journal
    Volume15
    Issue number15
    Publication statusPublished - 1 Aug 1996

    Keywords

    • MAPKK-1
    • NFAT
    • Rac-1
    • Ras
    • TCR
    • Transduction

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