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J. Exp. Med.,
Volume 188, Number 3, August 3, 1998 527-537
Receptor Type 1 Stimulation of Mast Cells
By


From the * Lymphocyte Activation Laboratory, Imperial Cancer Research Fund, London WC2A 3PX,
United Kingdom; and the 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 Fc
Yamanouchi Research Institute, Littlemore Park, Oxford OX4 4SX,
United Kingdom
receptor type 1 (Fc
R1) ligation results in induction of multiple NFAT target genes. This report examines the precise biochemical basis for the Rac-1 dependency of Fc
R1 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 Fc
R1-mediated NFATC1 dephosphorylation and nuclear import. Regulation of NFAT localization by the Fc
R1 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.
receptor type 1;
mast cells
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