RAC-1 REGULATES NUCLEAR FACTOR OF ACTIVATED T-CELLS (NFAT) C1 NUCLEARTRANSLOCATION IN RESPONSE TO FC-EPSILON 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 lym phocytes by controlling induction of a wide variety of cytokine genes. The GTPases Ras and Rac-1 have essential functions in regulation of N FAT transcriptional activity in the mast cell system, where Fc epsilon receptor type 1 (Fc epsilon R1) ligation results in induction of mult iple NFAT target genes. This report examines the precise biochemical b asis for the Rac-1 dependency of Fc epsilon R1 activation of NFAT in m ast cells. We are able to place Rac-1 in two positions in the signalin g network that regulates the assembly and activation of NFAT transcrip tional complexes in lymphocytes. First, we show that activity of Rac-1 is required for Fc epsilon R1-mediated NFATC1 dephosphorylation and n uclear import. Regulation of NFAT localization by the Fc epsilon R1 is a Rac-dependent but Ras-independent process. This novel signaling rol e for Rac-1 is distinct from its established regulation of the actin c ytoskeleton. Our data also reveal a second GTPase signaling pathway re gulating NFAT transcriptional activity, in which Rac-1 mediates a Ras signal. These data illustrate that the GTPase Rac-1 should now be cons idered as a component of the therapeutically important pathways contro lling NFATC1 subcellular localization. They also reveal that GTPases m ay serve multiple functions in cellular responses to antigen receptor ligation.