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* Division of Cell Biology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037;
National Research Institute of Vegetables, Tea Science, National Agriculture Research Organization, Shizuoka, Japan; and
Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, Prague, Czech Republic
EL mice have been used as a model of epilepsy, whereas ASK mice are an epilepsy-resistant variant originating from a colony of EL mice. Mast cell-dependent anaphylaxis is easily inducible by stimulation with IgE and Ag in ASK mice, whereas EL mice are resistant to such stimuli. In this study we have characterized mast cells derived from these two strains. ASK mast cells proliferated more vigorously than EL cells in response to IL-3 and stem cell factor. Although ASK mast cells degranulated less vigorously than EL mast cells upon stimulation with IgE and Ag, ASK cells produced and secreted several-fold more TNF-
and IL-2 than EL cells. Consistent with the similarities of these ASK and EL mast cell responses with phenotypes of lyn–/– and wild-type mast cells, respectively, Lyn activity was reduced in ASK cells. In addition to the impaired Lyn activity, ASK cells just like lyn–/– cells exhibited reduced Syk activity, prolonged activation of ERK and JNK, and enhanced activation of Akt. Furthermore, the lipid raft-resident transmembrane adaptor protein Cbp/PAG that associates with Lyn was hypophosphorylated in ASK cells. Importantly, similar to lyn–/– cells, Fyn was hyperactivated in ASK cells. Therefore, these results are consistent with the notion that Lyn-dependent phosphorylation of Cbp/PAG negatively regulates Src family kinases. This study also suggests that reduced activity of Lyn, a negative regulator of mast cell activation, underlies the susceptibility of ASK mice to anaphylaxis and implies that dysregulation of Lyn and other Src family kinases contributes to epileptogenesis.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This study was supported by Grants AI38348 and AI50209 from the National Institutes of Health (to T.K.) and by Grant 1M 0506 from the Center of Molecular and Cellular Immunology (to V.H.). This is Publication No. 766 from the La Jolla Institute for Allergy and Immunology.
2 Current address: Division of Cellular Therapy, Advanced Clinical Research Center, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
3 Address correspondence and reprint requests to Dr. Toshiaki Kawakami, Division of Cell Biology, La Jolla Institute for Allergy and Immunology, 9420 Athena Circle, La Jolla, CA 92037. E-mail address: toshi{at}liai.org
4 Abbreviations used in this paper: PTK, protein-tyrosine kinase; SFK, Src family PTK; Csk, C-terminal Src kinase; Cbp, Csk-binding protein; PAG, phosphoprotein associated with glycosphingolipid-enriched microdomain; BMMC, bone marrow-derived mast cell; SCF, stem cell factor; NMDA, glutamate N-methyl-D-aspartate; HSA, human serum albumin.
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