Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Casein kinase 1α governs antigen-receptor-induced NF-κB activation and human lymphoma cell survival

Nature volume 458, pages 92–96 (2009)Cite this article

Abstract

The transcription factor NF-κB is required for lymphocyte activation and proliferation as well as the survival of certain lymphoma types1,2. Antigen receptor stimulation assembles an NF-κB activating platform containing the scaffold protein CARMA1 (also called CARD11), the adaptor BCL10 and the paracaspase MALT1 (the CBM complex), linked to the inhibitor of NF-κB kinase complex3,4,5,6,7,8,9,10,11,12, but signal transduction is not fully understood1. We conducted parallel screens involving a mass spectrometry analysis of CARMA1 binding partners and an RNA interference screen for growth inhibition of the CBM-dependent ‘activated B-cell-like’ (ABC) subtype of diffuse large B-cell lymphoma (DLBCL)12. Here we report that both screens identified casein kinase 1α (CK1α) as a bifunctional regulator of NF-κB. CK1α dynamically associates with the CBM complex on T-cell-receptor (TCR) engagement to participate in cytokine production and lymphocyte proliferation. However, CK1α kinase activity has a contrasting role by subsequently promoting the phosphorylation and inactivation of CARMA1. CK1α has thus a dual ‘gating’ function which first promotes and then terminates receptor-induced NF-κB. ABC DLBCL cells required CK1α for constitutive NF-κB activity, indicating that CK1α functions as a conditionally essential malignancy gene—a member of a new class of potential cancer therapeutic targets.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Identification of CK1α as a CARMA1-binding partner.
Figure 2: Requirement of CK1α for NF-κB activation and proliferation in lymphocytes.
Figure 3: CK1α kinase activity contributes to the negative feedback control of the CBM complex and NF-κB activation.
Figure 4: Role of CK1α in ABC DLBCL survival and NF-κB signalling.

Similar content being viewed by others

References

  1. Hacker, H. & Karin, M. Regulation and function of IKK and IKK-related kinases. Sci. STKE 2006, re13 (2006)

    Article  Google Scholar 

  2. Schulze-Luehrmann, J. & Ghosh, S. Antigen-receptor signaling to nuclear factor κB. Immunity 25, 701–715 (2006)

    Article  CAS  Google Scholar 

  3. Egawa, T. et al. Requirement for CARMA1 in antigen receptor-induced NF-κB activation and lymphocyte proliferation. Curr. Biol. 13, 1252–1258 (2003)

    Article  CAS  Google Scholar 

  4. Gaide, O. et al. CARMA1 is a critical lipid raft-associated regulator of TCR-induced NF-κB activation. Nature Immunol. 3, 836–843 (2002)

    Article  CAS  Google Scholar 

  5. Hara, H. et al. The MAGUK family protein CARD11 is essential for lymphocyte activation. Immunity 18, 763–775 (2003)

    Article  CAS  Google Scholar 

  6. Jun, J. E. & Goodnow, C. C. Scaffolding of antigen receptors for immunogenic versus tolerogenic signaling. Nature Immunol. 4, 1057–1064 (2003)

    Article  ADS  CAS  Google Scholar 

  7. Newton, K. & Dixit, V. M. Mice lacking the CARD of CARMA1 exhibit defective B lymphocyte development and impaired proliferation of their B and T lymphocytes. Curr. Biol. 13, 1247–1251 (2003)

    Article  CAS  Google Scholar 

  8. Ruefli-Brasse, A. A., French, D. M. & Dixit, V. M. Regulation of NF-κB-dependent lymphocyte activation and development by paracaspase. Science 302, 1581–1584 (2003)

    Article  ADS  CAS  Google Scholar 

  9. Ruland, J. et al. Bcl10 is a positive regulator of antigen receptor-induced activation of NF-κB and neural tube closure. Cell 104, 33–42 (2001)

    Article  CAS  Google Scholar 

  10. Ruland, J., Duncan, G. S., Wakeham, A. & Mak, T. W. Differential requirement for Malt1 in T and B cell antigen receptor signaling. Immunity 19, 749–758 (2003)

    Article  CAS  Google Scholar 

  11. Wang, D. et al. A requirement for CARMA1 in TCR-induced NF-κB activation. Nature Immunol. 3, 830–835 (2002)

    Article  CAS  Google Scholar 

  12. Ngo, V. N. et al. A loss-of-function RNA interference screen for molecular targets in cancer. Nature 441, 106–110 (2006)

    Article  ADS  CAS  Google Scholar 

  13. Price, M. A. CKI, there’s more than one: casein kinase I family members in Wnt and Hedgehog signaling. Genes Dev. 20, 399–410 (2006)

    Article  CAS  Google Scholar 

  14. Oeckinghaus, A. et al. Malt1 ubiquitination triggers NF-κB signaling upon T-cell activation. EMBO J. 26, 4634–4645 (2007)

    Article  CAS  Google Scholar 

  15. Bidere, N., Snow, A. L., Sakai, K., Zheng, L. & Lenardo, M. J. Caspase-8 regulation by direct interaction with TRAF6 in T cell receptor-induced NF-κB activation. Curr. Biol. 16, 1666–1671 (2006)

    Article  CAS  Google Scholar 

  16. Matsumoto, R. et al. Phosphorylation of CARMA1 plays a critical role in T cell receptor-mediated NF-κB activation. Immunity 23, 575–585 (2005)

    Article  CAS  Google Scholar 

  17. Sommer, K. et al. Phosphorylation of the CARMA1 linker controls NF-κB activation. Immunity 23, 561–574 (2005)

    Article  CAS  Google Scholar 

  18. Shinohara, H. et al. PKC β regulates BCR-mediated IKK activation by facilitating the interaction between TAK1 and CARMA1. J. Exp. Med. 202, 1423–1431 (2005)

    Article  CAS  Google Scholar 

  19. Shambharkar, P. B. et al. Phosphorylation and ubiquitination of the IκB kinase complex by two distinct signaling pathways. EMBO J. 26, 1794–1805 (2007)

    Article  CAS  Google Scholar 

  20. Davidson, G. et al. Casein kinase 1 γ couples Wnt receptor activation to cytoplasmic signal transduction. Nature 438, 867–872 (2005)

    Article  ADS  CAS  Google Scholar 

  21. Peters, J. M., McKay, R. M., McKay, J. P. & Graff, J. M. Casein kinase I transduces Wnt signals. Nature 401, 345–350 (1999)

    Article  ADS  CAS  Google Scholar 

  22. Wegener, E. et al. Essential role for IκB kinase β in remodeling Carma1-Bcl10-Malt1 complexes upon T cell activation. Mol. Cell 23, 13–23 (2006)

    Article  CAS  Google Scholar 

  23. Alizadeh, A. A. et al. Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature 403, 503–511 (2000)

    Article  ADS  CAS  Google Scholar 

  24. Rosenwald, A. et al. The use of molecular profiling to predict survival after chemotherapy for diffuse large-B-cell lymphoma. N. Engl. J. Med. 346, 1937–1947 (2002)

    Article  Google Scholar 

  25. Davis, R. E., Brown, K. D., Siebenlist, U. & Staudt, L. M. Constitutive nuclear factor κB activity is required for survival of activated B cell-like diffuse large B cell lymphoma cells. J. Exp. Med. 194, 1861–1874 (2001)

    Article  CAS  Google Scholar 

  26. Lenz, G. et al. Oncogenic CARD11 mutations in human diffuse large B cell lymphoma. Science 319, 1676–1679 (2008)

    Article  ADS  CAS  Google Scholar 

  27. Liu, C. et al. Control of β-catenin phosphorylation/degradation by a dual-kinase mechanism. Cell 108, 837–847 (2002)

    Article  CAS  Google Scholar 

  28. Shaffer, A. L. et al. IRF4 addiction in multiple myeloma. Nature 454, 226–231 (2008)

    Article  ADS  CAS  Google Scholar 

  29. Solimini, N. L., Luo, J. & Elledge, S. J. Non-oncogene addiction and the stress phenotype of cancer cells. Cell 130, 986–988 (2007)

    Article  CAS  Google Scholar 

  30. Su, H. et al. Requirement for caspase-8 in NF-κB activation by antigen receptor. Science 307, 1465–1468 (2005)

    Article  ADS  CAS  Google Scholar 

  31. Wan, F. et al. Ribosomal protein S3: a KH domain subunit in NF-κB complexes that mediates selective gene regulation. Cell 131, 927–939 (2007)

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by the Intramural Research Program of the NIH, NIAID, NCI, NIDDK and by the Agence Nationale de la Recherche (ANR). We thank M.-T. Auffredou for technical assistance; X. Lin and J. Gavard for reagents; R. Germain, R. Schwartz, U. Siebenlist, P. Schwartzberg, J. Bosco de Oliveira, L. Yu, D. Baltimore, P. Sharp, H. Varmus and A. Snow for discussions and comments; and S. Porcella and the DNA sequencing core facility of the Rocky Mountain Laboratories, NIAID.

Author Contributions N.B., V.N.N., J.L., C.C., L.Z., F.W., R.E.D., G.L., L.M.S. and M.J.L. carried out experimental design/discussion; N.B., V.N.N., J.L., C.C., L.Z., F.W., R.E.D., G.L., D.E.A., D.A., A.V., K.S., J.Z., Z.M. and T.D.V. carried out preparation and performance of experiments; N.B., V.N.N., L.M.S. and M.J.L. carried out manuscript preparation. All authors discussed the results and commented on the manuscript.

Author information

Author notes

  1. Keiko Sakai

    Present address: Present address: Division of Viral Immunology, Center for AIDS Research, Kumamoto University, 2-2-1 Honjhou, Kumamoto-shi, Kumamoto-ken 860-0811, Japan.,

  2. Nicolas Bidère, Vu N. Ngo, Louis M. Staudt and Michael J. Lenardo: These authors contributed equally to this work.

Authors and Affiliations

  1. Molecular Development Section, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases,

    Nicolas Bidère, Jeansun Lee, Lixin Zheng, Fengyi Wan, Keiko Sakai, Jun Zhang & Michael J. Lenardo

  2. Metabolism Branch, Center for Cancer Research, National Cancer Institute,,

    Vu N. Ngo, Cailin Collins, R. Eric Davis, Georg Lenz & Louis M. Staudt

  3. Proteomics and Mass Spectrometry Facility, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA ,

    D. Eric Anderson

  4. U542, INSERM, Université Paris-Sud, Hôpital Paul Brousse, Villejuif 94800, France ,

    Nicolas Bidère, Damien Arnoult & Aimé Vazquez

  5. Laboratory of Proteomics and Analytical Technologies (LPAT), National Cancer Institute, Frederick, Maryland 21702, USA ,

    Zhaojing Meng & Timothy D. Veenstra

Authors
  1. Nicolas Bidère
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Vu N. Ngo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jeansun Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Cailin Collins
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Lixin Zheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Fengyi Wan
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. R. Eric Davis
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Georg Lenz
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. D. Eric Anderson
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Damien Arnoult
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Aimé Vazquez
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Keiko Sakai
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Jun Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Zhaojing Meng
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Timothy D. Veenstra
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Louis M. Staudt
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Michael J. Lenardo
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Louis M. Staudt or Michael J. Lenardo.

Supplementary information

Supplementary Figures

This file contains Supplementary Figures S1-S11 with Legends (PDF 1732 kb)

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bidère, N., Ngo, V., Lee, J. et al. Casein kinase 1α governs antigen-receptor-induced NF-κB activation and human lymphoma cell survival. Nature 458, 92–96 (2009). https://doi.org/10.1038/nature07613

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature07613

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing