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Essential role of Src-family protein tyrosine kinases in NF-κB activation during B cell development

Nature Immunology volume 4, pages 274–279 (2003)Cite this article

Abstract

The nature of signals that govern the development of immunoglobulin heavy chain-dependent B cells is largely unknown. Using mice deficient for the B cell-expressed Src-family protein tyrosine kinases (SFKs) Blk, Fyn and Lyn, we show an essential role of these kinases in pre-B cell receptor (pre-BCR)– mediated NF-κB activation and B cell development. This signaling defect is SFK specific, as a deficiency in Syk, which controls pre-B cell development, does not affect NF-κB induction. Impaired NF-κB induction was overcome by the activation of protein kinase C (PKC)-λ, thus suggesting the involvement of PKC-λ in pre-BCR–mediated SFK-dependent activation of NF-κB. Our data show the existence of a functionally distinct SFK signaling module responsible for pre-BCR–mediated NF-κB activation and B cell development.

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Figure 1: Impaired B cell development in Blk−/−Fyn−/−Lyn−/− mice.
Figure 2: Increased cell death in pre-B cells from Blk−/−Fyn−/−Lyn−/− mice.
Figure 3: Impaired B cell development in Blk−/−Fyn−/−Lyn−/− mice is B cell autonomous.
Figure 4: Igβ-mediated tyrosine phosphorylation in Blk−/−Fyn−/−Lyn−/− pro-B cells.
Figure 5: Impaired anti-Igβ–induced NF-κB activation in Blk−/−Fyn−/−Lyn−/−, but not Syk−/−, pro-B cells.
Figure 6: PKC-λ is involved in SFK-mediated signaling.

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Acknowledgements

We thank M.C. Nussenzweig, K. Rajewsky and S. Desiderio for helpful discussions, M. Clark for reagents and Y. Yang for help with statistical analysis. This work is supported by grants from the National Institutes of Health (AI053545-01 to A.T. and DK58066 and HL54476 to C.A.L), the S.L.E. Foundation (to K.S.), the Irene Diamond foundation (to A.T.), the Boehringer Ingelheim Fonds (to A.P.), the Japanese Ministry of Education, Culture, Sports, Science and Technology (Grant-in-aid to H.K.), and the Deutsche Forschungsgemeinschaft (to M.R.).

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Author notes

  1. Takahiro Adachi

    Present address: Department of Immunology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, 113-8510, Japan

  2. Kaoru Saijo and Christian Schmedt: These authors contributed equally to this work.

Authors and Affiliations

  1. Laboratory of Lymphocyte Signaling, The Rockefeller University, New York, 10021, NY, USA

    Kaoru Saijo, Christian Schmedt, I-hsin Su, Alina Patke, Angela Santana & Alexander Tarakhovsky

  2. Department of Immune Regulation, Tokyo Medical and Dental University Graduate School, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan

    Hajime Karasuyama

  3. Department of Laboratory Medicine, University of California, San Francisco, 94143, CA, USA

    Clifford A. Lowell

  4. Department of Molecular Immunology, Biology III, University of Freiburg and Max-Planck Institute of Immunology, Stuebeweg 51, Freiburg, 79108, Germany

    Michael Reth & Takahiro Adachi

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Saijo, K., Schmedt, C., Su, Ih. et al. Essential role of Src-family protein tyrosine kinases in NF-κB activation during B cell development. Nat Immunol 4, 274–279 (2003). https://doi.org/10.1038/ni893

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