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 '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.
Mesh Terms:
Adaptor Proteins, Signal Transducing, B-Cell CLL-Lymphoma 10 Protein, CARD Signaling Adaptor Proteins, Casein Kinases, Caspases, Cell Proliferation, Cell Survival, Cells, Cultured, Feedback, Physiological, Guanylate Cyclase, Humans, I-kappa B Kinase, Jurkat Cells, Lymphoma, Large B-Cell, Diffuse, Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein, NF-kappa B, Neoplasm Proteins, Protein Binding, Receptors, Antigen, Signal Transduction
Adaptor Proteins, Signal Transducing, B-Cell CLL-Lymphoma 10 Protein, CARD Signaling Adaptor Proteins, Casein Kinases, Caspases, Cell Proliferation, Cell Survival, Cells, Cultured, Feedback, Physiological, Guanylate Cyclase, Humans, I-kappa B Kinase, Jurkat Cells, Lymphoma, Large B-Cell, Diffuse, Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein, NF-kappa B, Neoplasm Proteins, Protein Binding, Receptors, Antigen, Signal Transduction
Nature
Date: Mar. 05, 2009
PubMed ID: 19118383
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