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PI3K and Btk differentially regulate B cell antigen receptor-mediated signal transduction

Nature Immunology volume 4, pages 280–286 (2003)Cite this article

Abstract

Phosphoinositide-3 kinase (PI3K) is thought to activate the tyrosine kinase Btk. However, through analysis of PI3K−/− and Btk−/− mice, B cell antigen receptor (BCR)-induced activation of Btk in mouse B cells was found to be unaffected by PI3K inhibitors or by a lack of PI3K. Consistent with this observation, PI3K−/− Btk−/− double-deficient mice had more severe defects than either single-mutant mouse. NF-κB activation along with Bcl-xL and cyclin D2 induction were severely blocked in both PI3K−/− and Btk−/− single-deficient B cells. Transgenic expression of Bcl-xL restored the development and BCR-induced proliferation of B cells in PI3K−/− mice. Our results indicate that PI3K and Btk have unique roles in proximal BCR signaling and that they have a common target further downstream in the activation of NF-κB.

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Figure 1: The Akt, but not the Btk, pathway is dependent on PI3K in B cells.
Figure 2: Phenotypes of PI3K and Btk double-deficient mice.
Figure 3: Restoration of B cell numbers and proliferative response of PI3K−/− mice by transgenic expression of Bcl-xL.

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Acknowledgements

We thank N. Watanabe and M. Handa for help in some experiments; C. Maki for technical assistance; A. Sakurai, M. Motouchi and K. Furuichi for animal care; and Y. Fukui, T. Kurosaki and L.K. Clayton for suggestions and critical reading of the manuscript. This work was supported in part by a Grant-in-Aid for Creative Scientific Research (13GS0015), a Grant-in-Aid for Scientific Research (A) (13307012), (B) (14370116) and (C) (13670322), and a Grant-in-Aid for Scientific Research on Priority Areas (13037028) from the Japan Society for the Promotion of Science, a National Grant-in-Aid for the Establishment of a High-Tech Research Center in a private University, a grant for the Promotion of the Advancement of Education and Research in Graduate Schools, and a Scientific Frontier Research Grant from the Ministry of Education, Culture, Sports, Science and Technology, Japan.

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Author notes

  1. Harumi Suzuki

    Present address: Department of Microbiology and Immunology, Yamaguchi University School of Medicine, Ube, Yamaguchi, 755-8580, Japan

  2. Toshiaki Ohteki

    Present address: Department of Parasitology, Akita University School of Medicine, Hondo, Akita, 010-8543, Japan

  3. Harumi Suzuki and Satoshi Matsuda: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo, 160-8582, Japan

    Harumi Suzuki, Satoshi Matsuda, Mari Fujiwara, Toshiaki Ohteki & Shigeo Koyasu

  2. Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Corporation (JST), Kawaguchi, 332-0012, Japan

    Satoshi Matsuda, Yasuo Terauchi, Mari Fujiwara, Takashi Kadowaki & Shigeo Koyasu

  3. Department of Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo, 113-8655, Japan

    Yasuo Terauchi, Tomoichiro Asano & Takashi Kadowaki

  4. Department of Medicine, Center for Immunology, University of Minnesota, Minneapolis, 55455, MN, USA

    Timothy W. Behrens

  5. Department of Immunology, Institute of Medical Science, University of Tokyo, Tokyo, 108-8639, Japan

    Taku Kouro & Kiyoshi Takatsu

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Suzuki, H., Matsuda, S., Terauchi, Y. et al. PI3K and Btk differentially regulate B cell antigen receptor-mediated signal transduction. Nat Immunol 4, 280–286 (2003). https://doi.org/10.1038/ni890

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