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Negative regulation of Lyn protein‐tyrosine kinase by c‐Cbl ubiquitin‐protein ligase in FcɛRI‐mediated mast cell activation
Author(s) -
Kyo Shinkou,
Sada Kiyonao,
Qu Xiujuan,
Maeno Koichiro,
Miah S. M. Shahjahan,
KawauchiKamata Keiko,
Yamamura Hirohei
Publication year - 2003
Publication title -
genes to cells
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.912
H-Index - 115
eISSN - 1365-2443
pISSN - 1356-9597
DOI - 10.1046/j.1365-2443.2003.00679.x
Subject(s) - lyn , ubiquitin ligase , syk , ubiquitin , tyrosine kinase , biology , degranulation , microbiology and biotechnology , proteasome , signal transduction , receptor , biochemistry , gene
Background: Recent studies have demonstrated that c‐Cbl functions as a ubiquitin‐protein ligase toward immune receptors and non‐receptor protein‐tyrosine kinase Syk by facilitating their ubiquitination and subsequent targeting to proteasomes. However, it was not clear whether Src family kinase Lyn is regulated by the Cbl family of ubiquitin‐protein ligases. Results: Aggregation of the high affinity IgE receptor (FcɛRI) induces the rapid ubiquitination of Lyn in rat basophilic leukaemia RBL‐2H3 cells. Treatment of cells with a proteasome inhibitor enhances the ubiquitination of Lyn. Stimulation of FcɛRI results in the association of Lyn with c‐Cbl and Cbl‐b, both of which then become tyrosine phosphorylated. Co‐transfection study shows that both c‐Cbl and Cbl‐b could induce the ubiquitination of activated Lyn in COS cells. Furthermore, over‐expression of membrane‐anchored form of c‐Cbl inhibits the FcɛRI‐mediated degranulation and cytokine gene production in RBL‐2H3 cells by the down‐regulation of the kinase activity of Lyn through the enhanced ubiquitination. Conclusions: These results demonstrate that Lyn is down‐regulated by c‐Cbl‐mediated ubiquitination and subsequent degradation in proteasome after FcɛRI stimulation in mast cells. Targeting of c‐Cbl in the lipid raft results in the inhibition of FcɛRI‐mediated mast cell activation.