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

The transcription factor NF-kappa B is required for lymphocyte activation and proliferation as well as the survival of certain lymphoma types(1,2). Antigen receptor stimulation assembles an NF-kappa 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-kappa B kinase complex(3-12), but signal transduction is not fully understood(1). 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 1 alpha (CK1 alpha) as a bifunctional regulator of NF-kappa B. CK1 alpha dynamically associates with the CBM complex on T-cell-receptor (TCR) engagement to participate in cytokine production and lymphocyte proliferation. However, CK1 alpha kinase activity has a contrasting role by subsequently promoting the phosphorylation and inactivation of CARMA1. CK1 alpha has thus a dual 'gating' function which first promotes and then terminates receptor-induced NF-kappa B. ABCDLBCL cells required CK1 alpha for constitutive NF-kappa B activity, indicating that CK1 alpha functions as a conditionally essential malignancy gene-a member of a new class of potential cancer therapeutic targets.