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© The Rockefeller University Press, 0022-1007/1997/1/43/ $5.00
The Journal of Experimental Medicine, Volume 185, Number 1, January 6, 1997 43-54

Articles

Distinct Ras Effector Pathways Are Involved in Fc{varepsilon}R1 Regulation of the Transcriptional Activity of Elk-1 and NFAT in Mast Cells

Helen Turner and Doreen A. Cantrell

From the Lymphocyte Activation Laboratory, Imperial Cancer Research Fund, London WC2A 3PX, United Kingdom

Activation of Ras GTPases is a conserved feature of antigen receptor signaling, including Fc{varepsilon}R1 activation of mast cells. Antigenic cross-linking of the Fc{varepsilon}R1 on mast cells results in secretion of allergic mediators and induction of immediate early and cytokine genes. Here we examine the role of Ras in coupling the Fc{varepsilon}R1 to transcriptional regulation. The transcription factors Elk-1, an immediate early gene regulator and the nuclear factor of activated T cells (NFAT), in the context of the IL-4 gene, are identified as Ras targets in mast cells. Ras mediates diverse effects via its diverse effector pathways, which may include other members of the Ras GTPase family such as RhoA and Rac-1. We observe that Elk-1 and NFAT are targeted by distinct Ras effector pathways in mast cells. Activation of the "classical" Ras/Raf-1/MEK/ ERK cascade is necessary and sufficient for Fc{varepsilon}R1 induction of Elk-1. Ras function is required, but not sufficient for Fc{varepsilon}R1 induction of NFAT. However, activation or inhibition of Ras markedly shifts the antigen dose-response for Fc{varepsilon}R1 induction of NFAT. The effector pathway for Ras activation of NFAT is not Raf-1/MEK. We identify that the Rac-1 GTPase is critical in Fc{varepsilon}R1 regulation of NFAT, acting either in parallel with or as an effector of Ras. These data place Ras in a crucial position in mast cells, regulating disparate nuclear targets. Moreover, we identify that two GTPases, Ras and Rac-1, are important regulators of NFAT, and therefore of cytokine expression in mast cells.

Address correspondence to Doreen A. Cantrell, Lymphocyte Activation Laboratory, Imperial Cancer Research Fund, PO Box 123, Lincoln's Inn Fields, London WC2A 3PX, UK.

For gifts of constructs we thank E. Serfling for the IL-4 NFAT reporter and Dr. Richard Treisman for the Elk-1 reporter system. Also, we thank members of the Lymphocyte Activation Laboratory for valuable advice and discussions of the manuscript.

H. Turner is supported by Glaxo-Wellcome (Stevenage, UK).

1Abbreviations used in this paper: CAT, chloramphenicol acetyl transferase; CN, calcineurin; CsA, cyclosporin A; dn, dominant inhibitory; MAP, mitogen-activated protein; MEK, Erk-activating kinase; NFAT, nuclear factor of activated T cells; PKC, protein kinase C; PTK, protein tyrosine kinase.


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