Activation of Syk tyrosine kinase is required for c-Cbl-mediated ubiquitination of FcεRI and Syk in RBL cells

Rossella Paolini, Rosa Molfetta, Laurie O. Beitz, Juan Zhang, Andrew M. Scharenberg, Mario Piccoli, Luigi Frati, Reuben Siraganian, Angela Santoni

Research output: Contribution to journalArticlepeer-review


Engagement of the high affinity receptor for IgE (FcεRI) on mast cells and basophils results in FcεRI β and γ subunits ubiquitination by an as yet undefined mechanism. Here we show that, upon FcεRI engagement on RBL-2H3 cells Syk undergoes ubiquitination and Syk kinase activity is required for its own ubiquitination and that of FcεRI β and γ chains. This requirement was demonstrated by overexpression of Syk wild-type or its kinase-dead mutant in RBL cells or using an Syk-deficient RBL-derived cell line transfected with wild-type or a kinase inactive form of Syk. We also identify c-Cbl as the E3 ligase responsible for both Syk and receptor ubiquitination. Furthermore, we demonstrate that Syk controls tyrosine phosphorylation of Syk-associated Cbl induced after receptor engagement. These data suggest a mutual regulation between Syk and Cbl activities. Finally, we show that a selective inhibitor of proteasome degradation induces persistence of tyrosine-phosphorylated receptor complexes, of activated Syk, and of FcεRI-triggered degranulation. Our results provide a molecular mechanism for down-regulation of engaged receptor complexes by targeting ubiquitinated FcεRI and activated Syk to the proteasome for degradation.

Original languageEnglish
Pages (from-to)36940-36947
Number of pages8
JournalJournal of Biological Chemistry
Issue number40
Publication statusPublished - Oct 4 2002

ASJC Scopus subject areas

  • Biochemistry


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