title: Casein kinase 1alpha governs antigen-receptor-induced NF-kappaB activation and human lymphoma cell survival.
abstract: The transcription factor NF-kappaB is required for lymphocyte activation and proliferation as well as the survival of certain lymphoma types. Antigen receptor stimulation assembles an NF-kappaB 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-kappaB 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 1alpha (CK1alpha) as a bifunctional regulator of NF-kappaB. CK1alpha dynamically associates with the CBM complex on T-cell-receptor (TCR) engagement to participate in cytokine production and lymphocyte proliferation. However, CK1alpha kinase activity has a contrasting role by subsequently promoting the phosphorylation and inactivation of CARMA1. CK1alpha has thus a dual 'gating' function which first promotes and then terminates receptor-induced NF-kappaB. ABC DLBCL cells required CK1alpha for constitutive NF-kappaB activity, indicating that CK1alpha functions as a conditionally essential malignancy gene-a member of a new class of potential cancer therapeutic targets.
authors.affiliation: Molecular Development Section, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Bidère
authors.forename: Vu N
authors.initials: VN
authors.lastname: Ngo
authors.forename: Jeansun
authors.initials: J
authors.lastname: Lee
authors.forename: Cailin
authors.initials: C
authors.lastname: Collins
authors.forename: Lixin
authors.initials: L
authors.lastname: Zheng
authors.forename: Fengyi
authors.initials: F
authors.lastname: Wan
authors.forename: R Eric
authors.initials: RE
authors.lastname: Davis
authors.forename: Georg
authors.initials: G
authors.lastname: Lenz
authors.forename: D Eric
authors.initials: DE
authors.lastname: Anderson
authors.forename: Damien
authors.initials: D
authors.lastname: Arnoult
authors.forename: Aimé
authors.initials: A
authors.lastname: Vazquez
authors.forename: Keiko
authors.initials: K
authors.lastname: Sakai
authors.forename: Jun
authors.initials: J
authors.lastname: Zhang
authors.forename: Zhaojing
authors.initials: Z
authors.lastname: Meng
authors.forename: Timothy D
authors.initials: TD
authors.lastname: Veenstra
authors.forename: Louis M
authors.initials: LM
authors.lastname: Staudt
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Lenardo
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000074018:B-Cell CLL-Lymphoma 10 Protein; D053468:CARD Signaling Adaptor Proteins / Q000378:metabolism; D047388:Casein Kinases / Q000378:metabolism*; D020169:Caspases / Q000378:metabolism; D049109:Cell Proliferation; D002470:Cell Survival; D002478:Cells, Cultured; D025461:Feedback, Physiological; D006162:Guanylate Cyclase / Q000378:metabolism; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D019169:Jurkat Cells; D016403:Lymphoma, Large B-Cell, Diffuse / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein; D016328:NF-kappa B / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000378:metabolism; D011485:Protein Binding; D011946:Receptors, Antigen / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000074018:B-Cell CLL-Lymphoma 10 Protein; C118591:BCL10 protein, human; D053468:CARD Signaling Adaptor Proteins; D016328:NF-kappa B; D009363:Neoplasm Proteins; D011946:Receptors, Antigen; D047388:Casein Kinases; D051550:I-kappa B Kinase; D020169:Caspases; C400109:MALT1 protein, human; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein; C426242:CARD11 protein, human; D006162:Guanylate Cyclase