title: Phospholipase C-β3 regulates FcɛRI-mediated mast cell activation by recruiting the protein phosphatase SHP-1.
abstract: Mast cells are major effectors in high-affinity IgE receptor (FcɛRI)-dependent allergic reactions. Here we show that phospholipase C (PLC)-β3 is crucial for FcɛRI-mediated mast cell activation. Plcb3(-/-) mice showed blunted FcɛRI-dependent late-phase, but not acute, anaphylactic responses and airway inflammation. Accordingly, FcɛRI stimulation of Plcb3(-/-) mast cells exhibited reduced cytokine production but normal degranulation. Reduced cytokine production in Plcb3(-/-) cells could be accounted for by increased activity of the negative regulatory Src family kinase Lyn and reduced activities of the positive regulatory protein kinases MAPKs. Mechanistically, PLC-β3 constitutively interacts with FcɛRI, Lyn, and SHP-1 (protein phosphatase). SHP-1 probably recognizes its substrates Lyn and MAPKs via the recently described kinase tyrosine-based inhibitory motif, KTIM. Consistent with PLC-β3- and SHP-1-mediated repression of Lyn activity by dephosphorylation at Tyr396, FcɛRI-mediated phenotypes were similar in Plcb3(-/-) and SHP-1 mutant mast cells. Thus, we have defined a PLC-β3- and SHP-1-mediated signaling pathway for FcɛRI-mediated cytokine production.
authors.affiliation: Division of Cell Biology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA.
authors.forename: Wenbin
authors.initials: W
authors.lastname: Xiao
authors.forename: Jun-Ichi
authors.initials: J
authors.lastname: Kashiwakura
authors.forename: Hong
authors.initials: H
authors.lastname: Hong
authors.forename: Hiroki
authors.initials: H
authors.lastname: Yasudo
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Ando
authors.forename: Mari
authors.initials: M
authors.lastname: Maeda-Yamamoto
authors.forename: Dianqing
authors.initials: D
authors.lastname: Wu
authors.forename: Yuko
authors.initials: Y
authors.lastname: Kawakami
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Kawakami
mesh_terms: D000818:Animals; D002465:Cell Movement; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D008407:Mast Cells / Q000166:cytology / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D054799:Phospholipase C beta / Q000172:deficiency / Q000276:immunology*; D019000:Phosphotyrosine / Q000378:metabolism; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000235:genetics / Q000276:immunology*; D017455:Receptors, IgE / Q000276:immunology*; D015398:Signal Transduction; D019061:src-Family Kinases / Q000276:immunology
chemical_list: D016207:Cytokines; D017455:Receptors, IgE; D019000:Phosphotyrosine; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D054799:Phospholipase C beta