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J. Biol. Chem., Vol. 279, Issue 42, 43646-43653, October 15, 2004

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Differential Regulation of the B Cell Receptor-mediated Signaling by the E3 Ubiquitin Ligase Cbl^*

Yuan Shao, Chun Yang, Chris Elly, and Yun-Cai Liu

From the Division of Cell Biology, La Jolla Institute for Allergy and Immunology, San Diego, California 92121

The E3 ubiquitin ligase Cbl has been implicated in intracellular signaling pathways induced by the engagement of the B cell antigen receptor (BCR) as a negative regulator. Here we showed that Cbl deficiency results in a reduction of B cell proliferation. Cbl^–/– B cells show impaired tyrosine phosphorylation, reduced Erk activation, and attenuated calcium mobilization in response to BCR engagement. The phosphorylation of Syk and Btk is also down-modulated. Interestingly, Cbl^–/– B cells display enhanced BCR-induced phosphorylation of CD19 and its association with phosphatidylinositol 3-kinase. Importantly, Lyn kinase activity is up-regulated in Cbl^–/– B cells, which correlates inversely with the Cblmediated ubiquitination of Lyn. Because Lyn has both negative and positive roles in B cells, our results suggested that Cbl differentially modulates the BCR-mediated signaling pathways through targeting Lyn ubiquitination, which affects B cell development and activation.

Received for publication, April 13, 2004 , and in revised form, August 3, 2004.

^* This work is supported by National Institutes of Health Grant RO1DK-56558 (to Y.-C. L.). The costs of publication of this article were defrayed in part by the payment of page charges. This 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: La Jolla Institute for Allergy and Immunology, 10355 Science Center Dr., San Diego, CA 92121. Tel.: 858-678-4604; Fax: 858-558-3525; E-mail: yuncail{at}liai.org.

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