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

Nicolas Bidère, Vu N. Ngo, Jeansun Lee, Cailin Collins, Lixin Zheng, Fengyi Wan, R. Eric Davis, Georg Lenz, D. Eric Anderson, Damien Arnoult, Aimé Vazquez, Keiko Sakai, Jun Zhang, Zhaojing Meng, Timothy D. Veenstra, Louis M. Staudt, Michael J. Lenardo

Research output: Contribution to journalArticle

100 Scopus citations

Abstract

The transcription factor NF-κB is required for lymphocyte activation and proliferation as well as the survival of certain lymphoma types. 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 complex, but signal transduction is not fully understood. 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). 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.

Original languageEnglish (US)
Pages (from-to)92-96
Number of pages5
JournalNature
Volume458
Issue number7234
DOIs
StatePublished - Mar 5 2009

ASJC Scopus subject areas

  • General

Fingerprint Dive into the research topics of 'Casein kinase 1α governs antigen-receptor-induced NF-κB activation and human lymphoma cell survival'. Together they form a unique fingerprint.

  • Cite this

    Bidère, N., Ngo, V. N., Lee, J., Collins, C., Zheng, L., Wan, F., Davis, R. E., Lenz, G., Anderson, D. E., Arnoult, D., Vazquez, A., Sakai, K., Zhang, J., Meng, Z., Veenstra, T. D., Staudt, L. M., & Lenardo, M. J. (2009). Casein kinase 1α governs antigen-receptor-induced NF-κB activation and human lymphoma cell survival. Nature, 458(7234), 92-96. https://doi.org/10.1038/nature07613