期刊
YAKUGAKU ZASSHI-JOURNAL OF THE PHARMACEUTICAL SOCIETY OF JAPAN
卷 133, 期 4, 页码 413-418出版社
PHARMACEUTICAL SOC JAPAN
DOI: 10.1248/yakushi.12-00227-1
关键词
mast cell; degranulation; anaphylaxis; Gab2; signal transduction
Mast cells are major players in allergic responses. IgE-dependent activation through Fc epsilon RI leads to degranulation and cytokine production, both of which require Gab2. To clarify how the signals diverge at Gab2, we established Gab2 knock-in mice that express Gab2 mutated at either the PI-3K- or SHP-2-binding sites. Examination of these mutants showed that both binding sites were required for the degranulation and anaphylaxis response, but not for cytokine production or contact hypersensitivity. Furthermore, the PI-3K- but not the SHP-2-binding site was important for granule translocation during degranulation. We also identified a small GTPase, ARF1, as the downstream target of PI-3K that regulates granule translocation. Fe epsilon RI-stimulation induced ARF1 activation, and this response was dependent on Fyn and the PI-3K-binding site of Gab2. ARF1 activity was required for the Fe epsilon RI-mediated granule translocation. These results indicate that Fyn/Gab2/PI-3K/ARF1-mediated signaling is specifically involved in granule translocation and the anaphylaxis response. In this review, I discussed how Gab2 controls biological events especially for mast cell degranulation and allergy response.
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