Activation of Ras GTPases is a conserved feature of antigen receptor signaling, including FcεR1 activation of mast cells. Antigenic cross-linking of the FcεR1 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 FcεR1 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 FcεR1 induction of Elk-1. Ras function is required, but not sufficient for FcεR1 induction of NFAT. However, activation or inhibition of Ras markedly shifts the antigen dose-response for FcεR1 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 FcεR1 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.
Distinct Ras Effector Pathways Are Involved in FcεR1 Regulation of the Transcriptional Activity of Elk-1 and NFAT 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.
Helen Turner, Doreen A. Cantrell; Distinct Ras Effector Pathways Are Involved in FcεR1 Regulation of the Transcriptional Activity of Elk-1 and NFAT in Mast Cells. J Exp Med 6 January 1997; 185 (1): 43–54. doi: https://doi.org/10.1084/jem.185.1.43
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