title: Btk-dependent Rac activation and actin rearrangement following FcepsilonRI aggregation promotes enhanced chemotactic responses of mast cells.
abstract: Mast cells infiltrate the sites of inflammation associated with chronic atopic disease and during helminth and bacterial infection. This process requires receptor-mediated cell chemotaxis across a concentration gradient of their chemotactic ligands. In vivo, mast cells are likely to be exposed to several such agents, which can cooperate in a synergistic manner to regulate mast cell homing. Here, we report that chemotaxis of mouse bone-marrow-derived mast cells (BMMCs) in response to the chemoattractants stem-cell factor (SCF) and prostaglandin (PG)E(2), is substantially enhanced following antigen-dependent ligation of the high-affinity receptor for IgE (FcεRI). These responses were associated with enhanced activation of phosphoinositide 3-kinase (PI3K), and downstream activation of the tyrosine protein kinase Btk, with subsequent enhanced phospholipase (PL)Cγ-mediated Ca(2+) mobilization, Rac activation and F-actin rearrangement. Antigen-induced chemotaxis, and the ability of antigen to amplify responses mediated by SCF, adenosine and PGE(2) were suppressed following inhibition of PI3K, and were impaired in BMMCs derived from Btk(-/-) mice. There were corresponding decreases in the PLCγ-mediated Ca(2+) signal, Rac activation and F-actin rearrangement, which, as they are essential for BMMC chemotaxis, accounts for the impaired migration of Btk-deficient cells. Taken together, these data demonstrate that, by regulating signaling pathways that control F-actin rearrangement, Btk is crucial for the ability of antigen to amplify mast-cell chemotactic responses.
authors.affiliation: Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 10 Center Drive MSC 1881, Bethesda, MD 20892-1881, USA.
authors.forename: Hye Sun
authors.initials: HS
authors.lastname: Kuehn
authors.forename: Madeleine
authors.initials: M
authors.lastname: Rådinger
authors.forename: Jared M
authors.initials: JM
authors.lastname: Brown
authors.forename: Khaled
authors.initials: K
authors.lastname: Ali
authors.forename: Bart
authors.initials: B
authors.lastname: Vanhaesebroeck
authors.forename: Michael A
authors.initials: MA
authors.lastname: Beaven
authors.forename: Dean D
authors.initials: DD
authors.lastname: Metcalfe
authors.forename: Alasdair M
authors.initials: AM
authors.lastname: Gilfillan
mesh_terms: D000199:Actins / Q000378:metabolism; D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology*; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D002633:Chemotaxis / Q000187:drug effects* / Q000235:genetics; D015232:Dinoprostone; D005434:Flow Cytometry; D015151:Immunoblotting; D008407:Mast Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008856:Microscopy, Fluorescence; D051966:Phospholipase C gamma / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D019089:Stem Cell Factor / Q000494:pharmacology; D020744:rac GTP-Binding Proteins
chemical_list: D000199:Actins; D019089:Stem Cell Factor; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; D051966:Phospholipase C gamma; D020744:rac GTP-Binding Proteins; D015232:Dinoprostone; D002118:Calcium