Rac-1 regulates nuclear factor of activated T cells (NFAT) C1 nuclear translocation in response to Fcε receptor type 1 stimulation of mast cells

Helen Turner, Manuel Gomez, Edward McKenzie, Antje Kirchem, Andrew Lennard, Doreen A. Cantrell (Lead / Corresponding author)

    Research output: Contribution to journalArticle

    42 Citations (Scopus)

    Abstract

    Transcription factors of the nuclear factor of activated T cells (NFAT) family play a key role in antigen receptor-mediated responses in lymphocytes by controlling induction of a wide variety of cytokine genes. The GTPases Ras and Rac-1 have essential functions in regulation of NFAT transcriptional activity in the mast cell system, where Fcε receptor type 1 (FcεR1) ligation results in induction of multiple NFAT target genes. This report examines the precise biochemical basis for the Rac-1 dependency of FcεR1 activation of NFAT in mast cells. We are able to place Rac-1 in two positions in the signaling network that regulates the assembly and activation of NFAT transcriptional complexes in lymphocytes. First, we show that activity of Rac-1 is required for FcεR1-mediated NFATC1 dephosphorylation and nuclear import. Regulation of NFAT localization by the FcεR1 is a Rac-dependent but Ras-independent process. This novel signaling role for Rac-1 is distinct from its established regulation of the actin cytoskeleton. Our data also reveal a second GTPase signaling pathway regulating NFAT transcriptional activity, in which Rac-1 mediates a Ras signal. These data illustrate that the GTPase Rac- 1 should now be considered as a component of the therapeutically important pathways controlling NFATC1 subcellular localization. They also reveal that GTPases may serve multiple functions in cellular responses to antigen receptor ligation.

    Original languageEnglish
    Pages (from-to)527-537
    Number of pages11
    JournalJournal of Experimental Medicine
    Volume188
    Issue number3
    DOIs
    Publication statusPublished - 3 Aug 1998

    Keywords

    • Fcε receptor type 1
    • Mast cells
    • Nuclear factor of activated T cells
    • Rac-1
    • Ras

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