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R1
Regulation of the Transcriptional Activity of Elk-1 and
NFAT in Mast Cells
By
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
R1 activation of mast cells. Antigenic cross-linking of the FcR1 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 FcR1 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 FcR1 induction of Elk-1. Ras function is required, but not sufficient for FcR1 induction of NFAT. However, activation or inhibition of
Ras markedly shifts the antigen dose-response for FcR1 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 FcR1 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.
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