Rac-1 Regulates Nuclear Factor of Activated T Cells (NFAT) C1 Nuclear Translocation in Response to Fcε Receptor Type 1 Stimulation of Mast Cells

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...

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Bibliographic Details
Published in:The Journal of experimental medicine 1998-08, Vol.188 (3), p.527-537
Main Authors: Turner, Helen, Gomez, Manuel, McKenzie, Edward, Kirchem, Antje, Lennard, Andrew, Cantrell, Doreen A.
Format: Article
Language:English
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Summary: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.
ISSN:0022-1007
1540-9538
DOI:10.1084/jem.188.3.527