title: Gab2, via PI-3K, regulates ARF1 in FcεRI-mediated granule translocation and mast cell degranulation.
abstract: Mast cells are major players in allergic responses. IgE-dependent activation through FcεR 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 PI3K or SH2 domain-containing protein tyrosine phosphatase-2 (SHP2) 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 PI3K, but not the SHP2, binding site was important for granule translocation during degranulation. We also identified a small GTPase, ADP-ribosylation factor (ARF)1, as the downstream target of PI3K that regulates granule translocation. FcεRI stimulation induced ARF1 activation, and this response was dependent on Fyn and the PI3K binding site of Gab2. ARF1 activity was required for FcεRI-mediated granule translocation. These data indicated that Fyn/Gab2/PI3K/ARF1-mediated signaling is specifically involved in granule translocation and the anaphylaxis response.
authors.affiliation: Laboratory for Cytokine Signaling, RIKEN Research Center for Allergy and Immunology, Yokohama, Kanagawa 230-0045, Japan.
authors.forename: Keigo
authors.initials: K
authors.lastname: Nishida
authors.forename: Satoru
authors.initials: S
authors.lastname: Yamasaki
authors.forename: Aiko
authors.initials: A
authors.lastname: Hasegawa
authors.forename: Akihiro
authors.initials: A
authors.lastname: Iwamatsu
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Koseki
authors.forename: Toshio
authors.initials: T
authors.lastname: Hirano
mesh_terms: D020823:ADP-Ribosylation Factor 1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D048868:Adaptor Proteins, Signal Transducing; D000707:Anaphylaxis / Q000235:genetics / Q000276:immunology; D000818:Animals; D001665:Binding Sites / Q000235:genetics / Q000276:immunology; D001854:Bone Marrow Cells / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D015550:Cell Degranulation / Q000235:genetics / Q000276:immunology*; D002460:Cell Line; D002462:Cell Membrane / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D003594:Cytoplasmic Granules / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism*; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D055879:Gene Knock-In Techniques; D008407:Mast Cells / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism / Q000502:physiology*; D010750:Phosphoproteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D021381:Protein Transport / Q000276:immunology; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000378:metabolism / Q000502:physiology; D017455:Receptors, IgE / Q000502:physiology*
chemical_list: D020823:ADP-Ribosylation Factor 1; D048868:Adaptor Proteins, Signal Transducing; D019869:Phosphatidylinositol 3-Kinases; D010750:Phosphoproteins; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D017455:Receptors, IgE; C490894:Gab2 protein, mouse; C516725:Ptpn11 protein, mouse