title: FcepsilonRI beta-chain ITAM amplifies PI3K-signaling to ensure synergistic degranulation response via FcepsilonRI and adenosine receptors.
abstract: Simultaneous stimulation with antigen and adenosine in mast cells induces a synergistic degranulation response at a low antigen dose that is insufficient to cause secretion by itself. This kind of stimulation is thought to be relevant to the immediate asthmatic response upon bronchial challenge with low-dose allergen. In this context, FcepsilonRI- and adenosine receptor-mediated signalings cooperate to increase degranulation in mast cells. In the present study, we prepared mast cells that have mutations (Y219F/Y225F/Y229F) in three tyrosine residues of the FcepsilonRI beta-chain (FcRbeta)-ITAM in order to elucidate the molecular mechanisms of degranulation response synergistically elicited by costimulation with low-dose antigen and adenosine. Introduction of mutations in the FcRbeta-ITAM abolished the synergistic degranulation response. Upon costimulation with low-dose antigen and adenosine, tyrosine phosphorylation of Grb2-associated binder 2, which is located upstream of PI3K-signaling, was significantly increased, but severely diminished in FcRbeta-ITAM mutant cells. These findings indicate that FcRbeta acts as a critical element in mast cell synergistic degranulation response through FcepsilonRI and adenosine receptors, and that PI3K-signaling through FcRbeta-ITAM is a crucial participant in augmentation of FcepsilonRI-mediated degranulation by adenosine.
authors.affiliation: Division of Molecular Cell Immunology and Allergology, Nihon University Graduate School of Medical Science, Tokyo, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Nunomura
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Gon
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Yoshimaru
authors.forename: Junichi
authors.initials: J
authors.lastname: Kashiwakura
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Kawakami
authors.forename: Chisei
authors.initials: C
authors.lastname: Ra
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000241:Adenosine / Q000494:pharmacology; D000818:Animals; D020013:Calcium Signaling / Q000502:physiology; D015550:Cell Degranulation / Q000502:physiology*; D007073:Immunoglobulin E / Q000276:immunology; D008407:Mast Cells / Q000502:physiology*; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D016297:Mutagenesis, Site-Directed; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000032:analysis; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary; D020239:Receptor Cross-Talk / Q000502:physiology*; D017455:Receptors, IgE / Q000235:genetics / Q000502:physiology*; D018047:Receptors, Purinergic P1 / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000241:Adenosine; D007073:Immunoglobulin E; D019869:Phosphatidylinositol 3-Kinases; D010750:Phosphoproteins; D019000:Phosphotyrosine; D017455:Receptors, IgE; D018047:Receptors, Purinergic P1; D011993:Recombinant Fusion Proteins; C521907:Fc-epsilon receptor I beta-chain, mouse; C490894:Gab2 protein, mouse