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Casein kinase 1α governs antigen-receptor-induced NF-B activation and human lymphoma cell survival
Nicolas Bidère1,4,6, Vu N. Ngo2,6, Jeansun Lee1, Cailin Collins2, Lixin Zheng1, Fengyi Wan1, R. Eric Davis2, Georg Lenz2, D. Eric Anderson3, Damien Arnoult4, Aimé Vazquez4, Keiko Sakai1,7, Jun Zhang1, Zhaojing Meng5, Timothy D. Veenstra5, Louis M. Staudt2,6 & Michael J. Lenardo1,6
1 Molecular Development Section, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases
2 Metabolism Branch, Center for Cancer Research, National Cancer Institute,
3 Proteomics and Mass Spectrometry Facility, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA
4 U542, INSERM, Université Paris-Sud, H?pital Paul Brousse, Villejuif 94800, France
5 Laboratory of Proteomics and Analytical Technologies (LPAT), National Cancer Institute, Frederick, Maryland 21702, USA
6 These authors contributed equally to this work.
7 Present address: Division of Viral Immunology, Center for AIDS Research, Kumamoto University, 2-2-1 Honjhou, Kumamoto-shi, Kumamoto-ken 860-0811, Japan.
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 understood1α. 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.
