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PKC-β controls IκB kinase lipid raft recruitment and activation in response to BCR signaling

Nature Immunology volume 3, pages 780–786 (2002)Cite this article

Abstract

NF-κB signaling is required for the maintenance of normal B lymphocytes, whereas dysregulated NF-κB activation contributes to B cell lymphomas. The events that regulate NF-κB signaling in B lymphocytes are poorly defined. Here, we demonstrate that PKC-β is specifically required for B cell receptor (BCR)-mediated NF-κB activation. B cells from protein kinase C-β (PKC-β)-deficient mice failed to recruit the IκB kinase (IKK) complex into lipid rafts, activate IKK, degrade IκB or up-regulate NF-κB–dependent survival signals. Inhibition of PKC-β promoted cell death in B lymphomas characterized by exaggerated NF-κB activity. Together, these data define an essential role for PKC-β in BCR survival signaling and highlight PKC-β as a key therapeutic target for B-lineage malignancies.

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Figure 1: PKC-β is required for BCR-dependent survival signaling.
Figure 2: PKC-β−/− mice have a reduced percentage of recirculating BM B cells.
Figure 3: PKC-β is required for BCR- and FcεRI-dependent NF-κB activation.
Figure 4: PKC-β is required for BCR-dependent recruitment of IKK into lipid raft compartments and for generation of the BCR-signalosome.
Figure 5: PKC-β is not required for BCR-mediated differentiation signals.
Figure 6: PKC-β inhibition leads to cell death in PKC-β–expressing DLBCL lines.
Figure 7: PKC-β expression profile and response to PKC-β inhibition in a panel of DLBCL lines.

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Acknowledgements

We thank C. Sawyers, G. Cheng and A. Scharenberg for critical reading of the manuscript and members of the Rawlings lab for technical assistance and thoughtful discussions. Supported in part by NIH grants HD37091, CA81140, AI38348, AI33617 and CA74929 and the American Cancer Society. Also supported by the MSTP (GM08042) and Tumor Immunology (CA09120) Training Grants at UCLA (to T. T. S.); a Lymphoma Research Foundation Faculty Award (to M. T.); and a McDonnell Scholar Award, Leukemia and Lymphoma Society Scholar Award and the Joan J. Drake Grant for Excellence in Cancer Research (to D. J. R.).

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  1. Thomas T. Su and Beichu Guo: These authors contributed equally to this work.

Authors and Affiliations

  1. The Molecular Biology Institute, University of California, Los Angeles, 90095, CA, USA

    Thomas T. Su, Lisa A. Humphries, Randolph Wall & Michael Teitell

  2. Department of Immunology and University of Washington School of Medicine, Seattle, 98195, WA, USA

    Beichu Guo

  3. La Jolla Institute for Allergy and Immunology, San Diego, 92121, CA, USA

    Yuko Kawakami & Toshiaki Kawakami

  4. Department of Pediatrics, University of Washington School of Medicine, Seattle, 98195, WA, USA

    Karen Sommer, Keun Chae, Roberta M. Kato, Shin Kang & David J. Rawlings

  5. Department of Microbiology and Immunology and University of California, Los Angeles, 90095, CA, USA

    Lisa Patrone & Randolph Wall

  6. Department of Pathology and Laboratory Medicine, University of California, Los Angeles, 90095, CA, USA

    Michael Teitell

  7. Max Planck Institute, Hannover, Germany

    Michael Leitges

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Su, T., Guo, B., Kawakami, Y. et al. PKC-β controls IκB kinase lipid raft recruitment and activation in response to BCR signaling. Nat Immunol 3, 780–786 (2002). https://doi.org/10.1038/ni823

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