Pharmaceutical Sciences Faculty Publications

Title

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

Document Type

Article

Publication Date

3-5-2009

Journal Title

Nature

ISSN

1476-4687

Volume

458

Issue

7234

First Page

92

Last Page

96

DOI

10.1038/nature07613

PubMed ID

19118383

PubMed Central® ID

PMC2688735

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.

Keywords

Adaptor proteins, signal transducing, casein kinases, caspases, cell proliferation, cell survival, cells, cultured, feedback, physiological, guanylate cyclase, jurkat cells, lymphoma, diffuse, neoplasm proteins, protein binding, receptors, antigen, signal transduction

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