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Molecular and Cellular Biology, June 2001, p. 3986-3994, Vol. 21, No. 12
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.12.3986-3994.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

The alpha  and beta  Subunits of Ikappa B Kinase (IKK) Mediate TRAF2-Dependent IKK Recruitment to Tumor Necrosis Factor (TNF) Receptor 1 in Response to TNF

Anne Devin,1 Yong Lin,1 Shoji Yamaoka,2 Zhiwei Li,3 Michael Karin,3 and Zheng-gang Liu1,*

Department of Cell and Cancer Biology, Medicine Branch, Division of Clinical Sciences, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 208921; Department of Microbiology, School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan2; and Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, University of California, San Diego, La Jolla, California 920933

Received 7 December 2000/Returned for modification 26 January 2001/Accepted 26 March 2001

The activation of Ikappa B kinase (IKK) is a key step in the nuclear translocation of the transcription factor NF-kappa B. IKK is a complex composed of three subunits: IKKalpha , IKKbeta , and IKKgamma (also called NEMO). In response to the proinflammatory cytokine tumor necrosis factor (TNF), IKK is activated after being recruited to the TNF receptor 1 (TNF-R1) complex via TNF receptor-associated factor 2 (TRAF2). We found that the IKKalpha and IKKbeta catalytic subunits are required for IKK-TRAF2 interaction. This interaction occurs through the leucine zipper motif common to IKKalpha , IKKbeta , and the RING finger domain of TRAF2, and either IKKalpha or IKKbeta alone is sufficient for the recruitment of IKK to TNF-R1. Importantly, IKKgamma is not essential for TNF-induced IKK recruitment to TNF-R1, as this occurs efficiently in IKKgamma -deficient cells. Using TRAF2-/- cells, we demonstrated that the TNF-induced interaction between IKKgamma and the death domain kinase RIP is TRAF2 dependent and that one possible function of this interaction is to stabilize the IKK complex when it interacts with TRAF2.

* Corresponding author. Mailing address: Medicine Branch, NCI, NIH, Bldg. 10, Rm. 6N105, 9000 Rockville Pike, Bethesda, MD 20892. Phone: (301) 435-6351. Fax: (301) 402-1997. E-mail: zgliu{at}helix.nih.gov.

Molecular and Cellular Biology, June 2001, p. 3986-3994, Vol. 21, No. 12
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.12.3986-3994.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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