The Journal of Experimental Medicine
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Published online 24 June 2002 doi:10.1084/jem.20020068
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© Rockefeller University Press, 0022-1007/2002/7/51/ $5.00
The Journal of Experimental Medicine, Volume 196, Number 1, July 1, 2002 51-63

Cbl-b Positively Regulates Btk-mediated Activation of Phospholipase C-{gamma}2 in B Cells

Tomoharu Yasuda1,4, Tohru Tezuka1, Akito Maeda2, Tetsuya Inazu3, Yuji Yamanashi4, Hua Gu3, Tomohiro Kurosaki2 and Tadashi Yamamoto1

1 Department of Oncology, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo 108-8639, Japan
2 Department of Molecular Genetics, Institute for Liver Research, Kansai Medical University, Moriguchi, Osaka 570-8506, Japan
3 Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852
4 Department of Cell Regulation, Medical Research Institute, Tokyo Medical Dental University, Bunkyo-ku, Tokyo 113-8510, Japan

Address correspondence to Tadashi Yamamoto, Department of Oncology, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan. Phone: 81-3-5449-5301; Fax: 81-3-5449-5413; E-mail: tyamamot{at}ims.u-tokyo.ac.jp

Genetic studies have revealed that Cbl-b plays a negative role in the antigen receptor–mediated proliferation of lymphocytes. However, we show that Cbl-b–deficient DT40 B cells display reduced phospholipase C (PLC)-{gamma}2 activation and Ca2+ mobilization upon B cell receptor (BCR) stimulation. In addition, the overexpression of Cbl-b in WEHI-231 mouse B cells resulted in the augmentation of BCR-induced Ca2+ mobilization. Cbl-b interacted with PLC-{gamma}2 and helped the association of PLC-{gamma}2 with Bruton's tyrosine kinase (Btk), as well as B cell linker protein (BLNK). Cbl-b was indispensable for Btk-dependent sustained increase in intracellular Ca2+. Both NH2-terminal tyrosine kinase-binding domain and COOH-terminal half region of Cbl-b were essential for its association with PLC-{gamma}2 and the regulation of Ca2+ mobilization. These results demonstrate that Cbl-b positively regulates BCR-mediated Ca2+ signaling, most likely by influencing the Btk/BLNK/PLC-{gamma}2 complex formation.

Key Words: BCR • Cbl family • calcium • GEMs • adaptor protein


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