The Journal of Experimental Medicine
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© The Rockefeller University Press, 0022-1007/1998/8/527/ $5.00
The Journal of Experimental Medicine, Volume 188, Number 3, August 3, 1998 527-537

Articles

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

Helen Turner*, Manuel Gomez*, Edward McKenzie{ddagger}, Antje Kirchem*, Andrew Lennard{ddagger}, and Doreen A. Cantrell*

From the * Lymphocyte Activation Laboratory, Imperial Cancer Research Fund, London WC2A 3PX, United Kingdom; and the {ddagger} 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{varepsilon} receptor type 1 (Fc{varepsilon}R1) ligation results in induction of multiple NFAT target genes. This report examines the precise biochemical basis for the Rac-1 dependency of Fc{varepsilon}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{varepsilon}R1-mediated NFATC1 dephosphorylation and nuclear import. Regulation of NFAT localization by the Fc{varepsilon}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.

Key Words: Ras • nuclear factor of activated T cells • Rac-1 • Fc{varepsilon} receptor type 1 • mast cells

Address correspondence to Doreen A. Cantrell, Lymphocyte Activation Laboratory, Imperial Cancer Research Fund, P.O. Box 123, Lincoln's Inn Fields, London WC2A 3PX, UK. Phone: 44-171-269-3307; Fax: 44-171-269-3479; E-mail: cantrell{at}icrf.icnet.uk

H. Turner was supported by Glaxo-Wellcome and Imperial Cancer Research Fund.

H. Turner's present address is Laboratory of Allergy and Immunology, Beth Israel Hospital, Harvard Medical School, 99 Brookline Ave., Boston, MA 02215.

Abbreviations used: AP-1, activator protein 1; CAT, chloramphenicol acetyl transferase; CN, calcineurin; CsA, Cyclosporin A; GEF, guanine nucleotide exchange factor; GFP, green fluorescent protein; GSK, glycogen synthase kinase; PI, propidium iodide; NFAT, nuclear factor of activated T cells; NLS, nuclear localization sequences.


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