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- Title
Casein kinase 1alpha governs antigen-receptor-induced NF-kappaB activation and human lymphoma cell survival.
- Authors
Bidère, Nicolas; Ngo, Vu N; Lee, Jeansun; Collins, Cailin; Zheng, Lixin; Wan, Fengyi; Davis, R Eric; Lenz, Georg; Anderson, D Eric; Arnoult, Damien; Vazquez, Aimé; Sakai, Keiko; Zhang, Jun; Meng, Zhaojing; Veenstra, Timothy D; Staudt, Louis M; Lenardo, Michael J
- 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.
- Publication
Nature, 2009, Vol 458, Issue 7234, p92
- ISSN
1476-4687
- Publication type
Journal Article
- DOI
10.1038/nature07613