title: The Src family kinase Fgr is critical for activation of mast cells and IgE-mediated anaphylaxis in mice.
abstract: Mast cells are critical for various allergic disorders. Mast cells express Src family kinases, which relay positive and negative regulatory signals by Ag. Lyn, for example, initiates activating signaling events, but it also induces inhibitory signals. Fyn and Hck are reported to be positive regulators, but little is known about the roles of other Src kinases, including Fgr, in mast cells. In this study, we define the role of Fgr. Endogenous Fgr associates with FcεRI and promotes phosphorylation of Syk, Syk substrates, which include linkers for activation of T cells, SLP76, and Gab2, and downstream targets such as Akt and the MAPKs in Ag-stimulated mast cells. As a consequence, Fgr positively regulates degranulation, production of eicosanoids, and cytokines. Fgr and Fyn appeared to act in concert, as phosphorylation of Syk and degranulation are enhanced by overexpression of Fgr and further augmented by overexpression of Fyn but are suppressed by overexpression of Lyn. Moreover, knockdown of Fgr by small interfering RNAs (siRNAs) further suppressed degranulation in Fyn-deficient bone marrow-derived mast cells. Overexpression of Fyn or Fgr restored phosphorylation of Syk and partially restored degranulation in Fyn-deficient cells. Additionally, knockdown of Fgr by siRNAs inhibited association of Syk with FcεRIγ as well as the tyrosine phosphorylation of FcεRIγ. Of note, the injection of Fgr siRNAs diminished the protein level of Fgr in mice and simultaneously inhibited IgE-mediated anaphylaxis. In conclusion, Fgr positively regulates mast cell through activation of Syk. These findings help clarify the interplay among Src family kinases and identify Fgr as a potential therapeutic target for allergic diseases.
authors: Institute of Biomedical Sciences and Technology, College of Medicine, Konkuk University, Chungju 380-701, Korea.
authors: Jun Ho
authors: JH
authors: Lee
authors: Jie Wan
authors: JW
authors: Kim
authors: Do Kyun
authors: DK
authors: Kim
authors: Hyuk Soon
authors: HS
authors: Kim
authors: Hye Jin
authors: HJ
authors: Park
authors: Dong Ki
authors: DK
authors: Park
authors: A-Ram
authors: AR
authors: Kim
authors: Bokyung
authors: B
authors: Kim
authors: Michael A
authors: MA
authors: Beaven
authors: Kui Lea
authors: KL
authors: Park
authors: Young Mi
authors: YM
authors: Kim
authors: Wahn Soo
authors: WS
authors: Choi
mesh_terms: D000707:Anaphylaxis / Q000201:enzymology / Q000235:genetics / Q000276:immunology* / Q000628:therapy; D000818:Animals; D001854:Bone Marrow Cells / Q000201:enzymology / Q000276:immunology* / Q000473:pathology; D015550:Cell Degranulation / Q000235:genetics / Q000276:immunology; D045744:Cell Line, Tumor; D004789:Enzyme Activation / Q000235:genetics / Q000276:immunology; D055785:Gene Knockdown Techniques; D007073:Immunoglobulin E / Q000276:immunology* / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008407:Mast Cells / Q000201:enzymology / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D010766:Phosphorylation / Q000235:genetics / Q000276:immunology; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D051076:Proto-Oncogene Proteins c-fyn / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D034741:RNA, Small Interfering; D051381:Rats; D017455:Receptors, IgE / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D000072377:Syk Kinase; D019061:src-Family Kinases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D017455:Receptors, IgE; D007073:Immunoglobulin E; D011505:Protein-Tyrosine Kinases; C494960:Fyn protein, mouse; C494961:Fyn protein, rat; D051076:Proto-Oncogene Proteins c-fyn; D000072377:Syk Kinase; C000606897:Syk protein, mouse; C000606898:Syk protein, rat; C053102:proto-oncogene proteins c-fgr; D019061:src-Family Kinases