J. Exp. Med., Volume 188, Number 3, August 3, 1998 527-537

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

By Helen Turner,^* Manuel Gomez,^* Edward McKenzie, Antje Kirchem,^* Andrew Lennard, and Doreen A. Cantrell^*

From the ^* Lymphocyte Activation Laboratory, Imperial Cancer Research Fund, London WC2A 3PX, United Kingdom; and the  Yamanouchi Research Institute, Littlemore Park, Oxford OX4 4SX, United Kingdom

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 receptor type 1 (FcR1) ligation results in induction of multiple NFAT target genes. This report examines the precise biochemical basis for the Rac-1 dependency of FcR1 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 FcR1-mediated NFATC1 dephosphorylation and nuclear import. Regulation of NFAT localization by the FcR1 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.

Ras;  nuclear factor of activated T cells;  Rac-1;  Fc receptor type 1;  mast cells

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