The transcription factor NF-॔B is required for lymphocyte activation and proliferation as well as the survival of certain lymphoma types . Antigen receptor stimulation assembles an NF-॔B 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-॔B 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 1ॅ (CK1ॅ) as a bifunctional regulator of NF-॔B. CK1ॅ dynamically associates with the CBM complex on T-cell-receptor (TCR) engagement to participate in cytokine production and lymphocyte proliferation. However, CK1ॅ kinase activity has a contrasting role by subsequently promoting the phosphorylation and inactivation of CARMA1. CK1ॅ has thus a dual ‘gating’ function which first promotes and then terminates receptor-induced NF-॔B. ABC DLBCL cells required CK1ॅ for constitutive NF-॔B activity, indicating that CK1ॅ functions as a conditionally essential malignancy gene—a member of a new class of potential cancer therapeutic targets. For a
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Casein kinase 1ॅ governs antigen-receptor-induced NF-॔B activation and human lymphoma cell survival
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.
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, Volume 458 (7234)
Nature Publishing Group (NPG) – Dec 31, 2008
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