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Molecular and Cellular Biology, December 2004, p. 10757-10765, Vol. 24, No. 24
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.24.10757-10765.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Restoration of NF-B Activation by Tumor Necrosis Factor Alpha Receptor Complex-Targeted MEKK3 in Receptor-Interacting Protein-Deficient Cells

Department of Microbiology and Immunology, School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, New York,¹ Merck Research Laboratories, West Point, Pennsylvania²

Received 26 May 2004/ Returned for modification 6 July 2004/ Accepted 15 September 2004

Receptor-interacting protein (RIP) plays a critical role in tumor necrosis factor alpha (TNF-)-induced NF-B activation. However, the mechanism by which RIP mediates TNF--induced signal transduction is not fully understood. In this study, we reconstituted RIP-deficient Jurkat T cells with a fusion protein composed of full-length MEKK3 and the death domain of RIP (MEKK3-DD). In these cells, MEKK3-DD substitutes for RIP and directly associates with TRADD in TNF receptor complexes following TNF- stimulation. We found that TNF--induced NF-B activation was fully restored by MEKK3-DD in these cells. In contrast, expression of a fusion protein composed of NEMO, a component of the IB kinase complex, and the death domain of RIP (NEMO-DD) cannot restore TNF--induced NF-B activation in RIP-deficient cells. These results indicate that the role of RIP is to specifically recruit MEKK3 to the TNF- receptor complex, whereas the forced recruitment of NEMO to the TNF- receptor complex is insufficient for TNF--induced NF-B activation. Although MEKK2 has a high degree of homology with MEKK3, MEKK2-DD, unlike MEKK3-DD, also fails to restore TNF--induced NF-B activation in RIP-deficient cells, indicating that RIP-dependent recruitment of MEKK3 plays a specific role in TNF- signaling.

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