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.
Bidère
Nicolas
N
Molecular Development Section, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
Ngo
Vu N
VN
Lee
Jeansun
J
Collins
Cailin
C
Zheng
Lixin
L
Wan
Fengyi
F
Davis
R Eric
RE
Lenz
Georg
G
Anderson
D Eric
DE
Arnoult
Damien
D
Vazquez
Aimé
A
Sakai
Keiko
K
Zhang
Jun
J
Meng
Zhaojing
Z
Veenstra
Timothy D
TD
Staudt
Louis M
LM
Lenardo
Michael J
MJ
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000074018:B-Cell CLL-Lymphoma 10 Protein; D053468:CARD Signaling Adaptor Proteins / Q000378:metabolism; D047388:Casein Kinases / Q000378:metabolism*; D020169:Caspases / Q000378:metabolism; D049109:Cell Proliferation; D002470:Cell Survival; D002478:Cells, Cultured; D025461:Feedback, Physiological; D006162:Guanylate Cyclase / Q000378:metabolism; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D019169:Jurkat Cells; D016403:Lymphoma, Large B-Cell, Diffuse / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein; D016328:NF-kappa B / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000378:metabolism; D011485:Protein Binding; D011946:Receptors, Antigen / Q000378:metabolism*; D015398:Signal Transduction
D048868:Adaptor Proteins, Signal Transducing; D000074018:B-Cell CLL-Lymphoma 10 Protein; C118591:BCL10 protein, human; D053468:CARD Signaling Adaptor Proteins; D016328:NF-kappa B; D009363:Neoplasm Proteins; D011946:Receptors, Antigen; D047388:Casein Kinases; D051550:I-kappa B Kinase; D020169:Caspases; C400109:MALT1 protein, human; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein; C426242:CARD11 protein, human; D006162:Guanylate Cyclase