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Originally published In Press as doi:10.1074/jbc.M204948200 on July 26, 2002

J. Biol. Chem., Vol. 277, Issue 40, 36940-36947, October 4, 2002
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Activation of Syk Tyrosine Kinase Is Required for c-Cbl-mediated Ubiquitination of Fcepsilon RI and Syk in RBL Cells*

Rossella PaoliniDagger §, Rosa MolfettaDagger , Laurie O. Beitz||, Juan Zhang**, Andrew M. Scharenberg||, Mario PiccoliDagger , Luigi FratiDagger §, Reuben Siraganian**, and Angela SantoniDagger §

From the Dagger  Department of Experimental Medicine and Pathology, Institute Pasteur-Fondazione Cenci Bolognetti, University La Sapienza, Rome 00161, Italy, the || Departments of Pediatric Rheumatology and Immunology, University of Washington, Seattle, Washington 98195, the ** Receptors and Signal transduction Section, Oral Infection and Immunity Branch, NIDCR, National Institutes of Health, Bethesda, Maryland 20892, and the § Mediterranean Institute for Neurosciences Neuromed, Pozzilli (IS) 86077, Italy

Engagement of the high affinity receptor for IgE (Fcepsilon RI) on mast cells and basophils results in Fcepsilon RI beta  and gamma  subunits ubiquitination by an as yet undefined mechanism. Here we show that, upon Fcepsilon RI engagement on RBL-2H3 cells Syk undergoes ubiquitination and Syk kinase activity is required for its own ubiquitination and that of Fcepsilon RI beta  and gamma  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 Fcepsilon RI-triggered degranulation. Our results provide a molecular mechanism for down-regulation of engaged receptor complexes by targeting ubiquitinated Fcepsilon RI and activated Syk to the proteasome for degradation.

* This work was supported by grants from the Italian Association for Cancer Research, CNR special project on Biotechnologies, Ministero dell'Università e della Ricerca Scientifica e Tecnologica, 40 and 60%, respectively, and the Center for Excellence in Molecular Biology and Medicine.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Dept. of Experimental Medicine and Pathology, University La Sapienza, Viale Regina Elena 324, Rome 00161, Italy. Tel.:/Fax: 39-06-446-8448; E-mail: rossella.paolini@uniroma1.it.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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