Cbl-b Positively Regulates Btk-mediated Activation of Phospholipase C-γ2 in B Cells

Yasuda , Tomoharu; Tezuka , Tohru; Maeda , Akito; Inazu , Tetsuya; Yamanashi , Yuji; Gu , Hua; Kurosaki , Tomohiro; Yamamoto , Tadashi

doi:10.1084/jem.20020068

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Article| June 24 2002

Cbl-b Positively Regulates Btk-mediated Activation of Phospholipase C-γ2 in B Cells

Tomoharu Yasuda,

Tomoharu Yasuda

1Department of Oncology, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo 108-8639, Japan

4Department of Cell Regulation, Medical Research Institute, Tokyo Medical Dental University, Bunkyo-ku, Tokyo 113-8510, Japan

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Tohru Tezuka,

Tohru Tezuka

1Department of Oncology, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo 108-8639, Japan

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Akito Maeda,

Akito Maeda

2Department of Molecular Genetics, Institute for Liver Research, Kansai Medical University, Moriguchi, Osaka 570-8506, Japan

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Tetsuya Inazu,

Tetsuya Inazu

3Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852

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Yuji Yamanashi,

Yuji Yamanashi

4Department of Cell Regulation, Medical Research Institute, Tokyo Medical Dental University, Bunkyo-ku, Tokyo 113-8510, Japan

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Hua Gu,

Hua Gu

3Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852

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Tomohiro Kurosaki,

Tomohiro Kurosaki

2Department of Molecular Genetics, Institute for Liver Research, Kansai Medical University, Moriguchi, Osaka 570-8506, Japan

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Tadashi Yamamoto

1Department of Oncology, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo 108-8639, Japan

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Author and Article Information

Tomoharu Yasuda

1Department of Oncology, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo 108-8639, Japan

4Department of Cell Regulation, Medical Research Institute, Tokyo Medical Dental University, Bunkyo-ku, Tokyo 113-8510, Japan

Tohru Tezuka

1Department of Oncology, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo 108-8639, Japan

Akito Maeda

2Department of Molecular Genetics, Institute for Liver Research, Kansai Medical University, Moriguchi, Osaka 570-8506, Japan

Tetsuya Inazu

3Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852

Yuji Yamanashi

4Department of Cell Regulation, Medical Research Institute, Tokyo Medical Dental University, Bunkyo-ku, Tokyo 113-8510, Japan

Hua Gu

3Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852

Tomohiro Kurosaki

2Department of Molecular Genetics, Institute for Liver Research, Kansai Medical University, Moriguchi, Osaka 570-8506, Japan

Tadashi Yamamoto

1Department of Oncology, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo 108-8639, 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: [email protected]

A. Maeda's present address is Department of Molecular Immunology and Allergy, Kyoto University, Sakyo-ku, Kyoto 606-8315, Japan.

*

Abbreviations used in this paper: BCR, B cell receptor; BLNK, B cell linker protein; Btk, Bruton's tyrosine kinase; EGFR, epidermal growth factor receptor; ERK, extracellular signal-regulated kinase; GEM, glycolipid-enriched microdomain; GST, glutathione S–transferase; IP₃, inositol 1,4,5-trisphosphate; ITAM, immunoreceptor tyrosine-based activation motif; JNK, c-Jun NH₂-terminal kinase; MAPK, mitogen-activated protein kinase; PI3K, phosphatidylinositol 3-kinase; PLC, phospholipase C; PTK, protein tyrosine kinase; RBD, Rap1 binding domain; TKB, tyrosine kinase–binding.

Received: January 15 2002

Revision Received: April 29 2002

Accepted: May 14 2002

Online ISSN: 1540-9538

Print ISSN: 0022-1007

The Rockefeller University Press

2002

J Exp Med (2002) 196 (1): 51–63.

https://doi.org/10.1084/jem.20020068

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)-γ2 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-γ2 and helped the association of PLC-γ2 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-γ2 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-γ2 complex formation.

The Rockefeller University Press

2002

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