Abstract
Mast cell activation induced by aggregation of FcεRI receptors with immunoglobulin E and antigen is mediated through the activation of multiple protein kinase cascades. Here we report that the regulatory protein RabGEF1 bound to Ras and negatively regulated Ras activation and its 'downstream' effector pathways in FcεRI-dependent mast cell activation. RabGEF1-deficient mast cells showed enhanced degranulation and release of lipid mediators and cytokines in response to FcεRI aggregation. RabGEF1-deficient mice developed severe skin inflammation and had increased numbers of mast cells. Thus, RabGEF1 is a negative regulator of FcεRI-dependent mast cell activation, and a lack of RabGEF1 results in the development of skin inflammation in vivo.
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Acknowledgements
We thank B.H. Koller for support; M. Miyamoto, A. Xu, M. Liebersbach and Z.-S. Wang for technical assistance; O. Kocher, C.J. Der, A. Sidow and J. Binkley for advice; and S. Kohler for review of the skin histology. Supported by Fondation pour la Recherche Medicale (D.S.) and United States Public Health Service (AI-23990, CA-72074 and HL-67674 to S.J.G.).
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Authors of this manuscript (S.-Y.T., M.T. and S.J.G.) have filed the following patents regarding this research: US Patents 5,965,707 and 6,500,942 (RIN2, a novel inhibitor of Ras-mediated signaling) and US Patent Provisional Application (in vivo models for RabGEF1-dependent signaling and functions).
Supplementary information
Supplementary Fig. 1
Generation and characterization of anti-RabGEF1 antibody (Ac-KSER) (PDF 403 kb)
Supplementary Fig. 2
Generation of Rabgef1−/− mice on WB/Re x C57BL/6F2 background (PDF 450 kb)
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Tam, SY., Tsai, M., Snouwaert, J. et al. RabGEF1 is a negative regulator of mast cell activation and skin inflammation. Nat Immunol 5, 844–852 (2004). https://doi.org/10.1038/ni1093
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DOI: https://doi.org/10.1038/ni1093
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