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Blood, 1 March 2004, Vol. 103, No. 5, pp. 1779-1786. Prepublished online as a Blood First Edition Paper on November 6, 2003; DOI 10.1182/blood-2003-07-2260. This Article Full Text Full Text (PDF) All Versions of this Article: 2003-07-2260v1 103/5/1779    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 HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Qu, X. Articles by Yamamura, H. Search for Related Content PubMed PubMed Citation Articles by Qu, X. Articles by Yamamura, H. Related Collections Immunobiology Signal Transduction Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  IMMUNOBIOLOGY Negative regulation of FcRI-mediated mast cell activation by a ubiquitin-protein ligase Cbl-b Xiujuan Qu, Kiyonao Sada, Shinkou Kyo, Koichiro Maeno, S. M. Shahjahan Miah, and Hirohei Yamamura From the Division of Proteomics, Department of Genome Sciences, Kobe University Graduate School of Medicine, Kobe, Japan. Aggregation of the high-affinity immunoglobulin E (IgE) receptor (FcRI) on mast cells induces a number of biochemical events, including protein-tyrosine phosphorylation leading to degranulation and multiple cytokine gene transcription. Here, we have demonstrated that a second member of the Cbl family of ubiquitin-protein ligase Cbl-b translocates into the lipid raft after FcRI engagement. Overexpression of Cbl-b in the lipid raft inhibits FcRI-mediated degranulation and cytokine gene transcription through the distinct mechanism. A point mutation of Cys373 in the RING finger domain of Cbl-b abrogates the suppression of FcRI-mediated degranulation but not cytokine gene transcription. The antigen-induced tyrosine phosphorylation of FcRI, Syk, phospholipase C- (PLC-), activation of c-Jun N-terminal kinase (JNK), extracellular signal regulated kinase (ERK), inhibitor of nuclear factor B kinase (IKK), and Ca++ influx were all suppressed in the cells overexpressing Cbl-b in the lipid raft. In particular, the expression amount of Gab2 protein and thereby its FcRI-mediated tyrosine phosphorylation were dramatically down-regulated by ubiquitin-protein ligase activity of Cbl-b. These results suggest that Cbl-b is a negative regulator of both Lyn-Syk-LAT and Gab2mediated complementary signaling pathways in FcRI-mediated mast cell activation. 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