Distinct Ras Effector Pathways Are Involved in FcεR1 Regulation of the Transcriptional Activity of Elk-1 and NFAT in Mast Cells

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Abstract
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.