Casein Kinase 1alpha Governs Antigen-Receptor-Induced NF-KappaB Activation and Human Lymphoma Cell Survival

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 \u27activated B-cell-like\u27 (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 \u27gating\u27 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

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

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/CARD11, the adaptor BCL10, and the paracaspase MALT1 (CBM complex), linked to the inhibitor of NF-κB kinase (IKK) complex3–12, but signal transduction is not fully understood1. We conducted parallel screens involving a mass spectrometry analysis of CARMA1 binding partners and an RNAi 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 upon T cell receptor (TCR) engagement to augment cytokine production and lymphocyte proliferation. However, CK1α kinase activity plays a counterposing 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” (CEMal) gene - a member of a new class of potential cancer therapeutic targets