專題：Nature報導
在淋巴細胞激發過程中，CBM蛋白複合物（由支架蛋白CARMA1、銜接蛋白BCL10和Paracaspase酶MALT1組成）在將來自T細胞和B細胞中抗原受體的信號傳導給轉錄因子NF-kappaB當中起一個關鍵作用。
這一重要蛋白複合物是怎樣被調控的仍然不清楚，但現在Bidère等人發現，CBM複合物是由酪蛋白激酶1alpha (CK1alpha)以兩種相反方式調控的，先是促進、然後是終止由受體誘導的NF-kappaB活性及淋巴細胞激發。CK1alpha是淋巴細胞中所發現的內在性NF-kappaB信號作用所必需的。這種雙重「門控」功能表明，CK1在一定條件下可充當一個必要的惡性基因，有可能代表新的一類癌症治療目標。（生物谷Bioon.com）
生物谷推薦原始出處：
Nature 458, 92-96 (5 March 2009) | doi:10.1038/nature07613
Casein kinase 1α governs antigen-receptor-induced NF-B activation and human lymphoma cell survival
Nicolas Bidère1,4,6, Vu N. Ngo2,6, Jeansun Lee1, Cailin Collins2, Lixin Zheng1, Fengyi Wan1, R. Eric Davis2, Georg Lenz2, D. Eric Anderson3, Damien Arnoult4, Aimé Vazquez4, Keiko Sakai1,7, Jun Zhang1, Zhaojing Meng5, Timothy D. Veenstra5, Louis M. Staudt2,6 & Michael J. Lenardo1,6
1 Molecular Development Section, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases
2 Metabolism Branch, Center for Cancer Research, National Cancer Institute,
3 Proteomics and Mass Spectrometry Facility, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA
4 U542, INSERM, Université Paris-Sud, H?pital Paul Brousse, Villejuif 94800, France
5 Laboratory of Proteomics and Analytical Technologies (LPAT), National Cancer Institute, Frederick, Maryland 21702, USA
6 These authors contributed equally to this work.
7 Present address: Division of Viral Immunology, Center for AIDS Research, Kumamoto University, 2-2-1 Honjhou, Kumamoto-shi, Kumamoto-ken 860-0811, Japan.
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 (also called CARD11), the adaptor BCL10 and the paracaspase MALT1 (the CBM complex), linked to the inhibitor of NF-κB kinase complex3, 4, 5, 6, 7, 8, 9, 10, 11, 12, but signal transduction is not fully understood1α. 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 1α (CK1α) as a bifunctional regulator of NF-κB. CK1α dynamically associates with the CBM complex on T-cell-receptor (TCR) engagement to participate in cytokine production and lymphocyte proliferation. However, CK1α kinase activity has a contrasting 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 gene—a member of a new class of potential cancer therapeutic targets.