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Blood, 1 October 2007, Vol. 110, No. 7, pp. 2511-2519. Prepublished online as a Blood First Edition Paper on May 18, 2007; DOI 10.1182/blood-2007-01-066092. This Article Full Text Full Text (PDF) Supplemental Methods and Figures Erratum (v111,p3299) All Versions of this Article: blood-2007-01-066092v1 110/7/2511    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Hong, H. Articles by Kawakami, T. Search for Related Content PubMed PubMed Citation Articles by Hong, H. Articles by Kawakami, T. Related Collections Immunobiology Signal Transduction Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  IMMUNOBIOLOGY The Src family kinase Hck regulates mast cell activation by suppressing an inhibitory Src family kinase Lyn Hong Hong1, Jiro Kitaura1, Wenbin Xiao1, Vaclav Horejsi2, Chisei Ra3, Clifford A. Lowell4, Yuko Kawakami1, and Toshiaki Kawakami1 1 Division of Cell Biology, La Jolla Institute for Allergy and Immunology, CA; 2 Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, Prague, Czech Republic; 3 Division of Molecular Cell Immunobiology and Allergology, Advanced Medical Research Center, Nihon University Graduate School of Medical Science, Tokyo, Japan; 4 Department of Laboratory Medicine, University of California, San Francisco IgE/antigen-dependent mast cell activation plays a central role in immediate hypersensitivity and other allergic reactions. The Src family tyrosine kinase (SFK) Lyn is activated by the cross-linking of high-affinity IgE receptors (FcRI). Activated Lyn phosphorylates the FcRI subunits, ß and , leading to subsequent activation of various signaling pathways. Lyn also plays a negative regulatory function by activating negative regulatory molecules. Another SFK, Fyn, also contributes to mast cell degranulation by inducing Gab2-dependent microtubule formation. Here we show that a third SFK, Hck, plays a critical role in mast cell activation. Degranulation and cytokine production are reduced in FcRI-stimulated hck–/– mast cells. The reduced degranulation can be accounted for by defects in Gab2 phosphorylation and microtubule formation. Importantly, Lyn activity is elevated in hck–/– cells, leading to increased phosphorylation of several negative regulators. However, positive regulatory events, such as activation of Syk, Btk, JNK, p38, Akt, and NF-B, are substantially reduced in hck–/– mast cells. Analysis of lyn–/–hck–/–, lyn–/–FcRIß–/–, and hck–/–FcRIß–/– cells shows that Hck exerts these functions via both Lyn-dependent and Lyn-independent mechanisms. Thus, this study has revealed a hierarchical regulation among SFK members to fine-tune mast cell activation. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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