BACKGROUND: NF-kappaB is an ubiquitously expressed transcription factor that plays an important role in the immune, anti-apoptotic and inflammatory responses. NF-kappaB is normally sequestered in the cytoplasm by interacting with inhibitory IkappaB molecules. Upon stimulation, IkappaB is phosphorylated and subsequently degraded by the proteasome, allowing NF-kappaB to translocate into the nucleus where they regulate target gene expression. Two kinases, IKK-alpha and IKK-beta, which are responsible for IkappaB phosphorylation were recently identified. We have recently identified a cytokine inducible IKK-i, a kinase related to IKK-alpha and -beta. IKK-i significantly induced NF-kappaB activation upon over-expression, as did IKK-alpha and IKK-beta. Unlike IKK-alpha and IKK-beta, IKK-i phosphorylated Ser36 but not Ser32 in vitro, suggesting that IKK-i activates NF-kappaB by distinct mechanisms from the conventional IKKs. RESULTS: I-TRAF/TANK was isolated as a molecule that interacts specifically with inducible IkappaB kinase (IKK-i) by the yeast two-hybrid screening procedure. The association of IKK-i and I-TRAF is mediated via the interaction between the N-terminal domain of I-TRAF and the C-terminal portion of IKK-i. In vitro kinase assays demonstrate that IKK-i phosphorylates I-TRAF in the middle portion that associates with TRAF2. Interestingly, TRAF2 is freed from the I-TRAF/TRAF2 complex after I-TRAF phosphorylation. NF-kappaB activation by IKK-i is significantly blocked by coexpression of the N-terminal domain of I-TRAF, dominant negative TRAF2, and dominant negative NIK and IKK-beta. IKK-i over-expression also induced c-Jun N-terminal kinase. These results show that I-TRAF is a substrate of IKK-i. NF-kappaB activation by IKK-i may be mediated through phosphorylation of I-TRAF by IKK-i and subsequent liberation of TRAF2. CONCLUSION: These results indicate that NF-kappaB activation by IKK-i is mediated through phosphorylation of I-TRAF/TANK by IKK-i and subsequent liberation of TRAF2.

This article has been cited by other articles:

				J.-S. Gatot, R. Gioia, T.-L. Chau, F. Patrascu, M. Warnier, P. Close, J.-P. Chapelle, E. Muraille, K. Brown, U. Siebenlist, et al. Lipopolysaccharide-mediated Interferon Regulatory Factor Activation Involves TBK1-IKK{epsilon}-dependent Lys63-linked Polyubiquitination and Phosphorylation of TANK/I-TRAF J. Biol. Chem., October 26, 2007; 282(43): 31131 - 31146. [Abstract] [Full Text] [PDF]

				B. Guo and G. Cheng Modulation of the Interferon Antiviral Response by the TBK1/IKKi Adaptor Protein TANK J. Biol. Chem., April 20, 2007; 282(16): 11817 - 11826. [Abstract] [Full Text] [PDF]

				B. Peant, J.-S. Diallo, L. Lessard, N. Delvoye, C. Le Page, F. Saad, and A.-M. Mes-Masson Regulation of I{kappa}B Kinase {varepsilon} Expression by the Androgen Receptor and the Nuclear Factor-{kappa}B Transcription Factor in Prostate Cancer Mol. Cancer Res., January 1, 2007; 5(1): 87 - 94. [Abstract] [Full Text] [PDF]

				C. Wietek, C. S. Cleaver, V. Ludbrook, J. Wilde, J. White, D. J. Bell, M. Lee, M. Dickson, K. P. Ray, and L. A. J. O'Neill I{kappa}B Kinase {epsilon} Interacts with p52 and Promotes Transactivation via p65 J. Biol. Chem., November 17, 2006; 281(46): 34973 - 34981. [Abstract] [Full Text] [PDF]

				M. Adli and A. S. Baldwin IKK-i/IKK{epsilon} Controls Constitutive, Cancer Cell-associated NF-{kappa}B Activity via Regulation of Ser-536 p65/RelA Phosphorylation J. Biol. Chem., September 15, 2006; 281(37): 26976 - 26984. [Abstract] [Full Text] [PDF]

				J. Harris, S. Oliere, S. Sharma, Q. Sun, R. Lin, J. Hiscott, and N. Grandvaux Nuclear Accumulation of cRel following C-Terminal phosphorylation by TBK1/IKK{epsilon} J. Immunol., August 15, 2006; 177(4): 2527 - 2535. [Abstract] [Full Text] [PDF]

				P. Pontrelli, M. Ursi, E. Ranieri, C. Capobianco, F. P. Schena, L. Gesualdo, and G. Grandaliano CD40L Proinflammatory and Profibrotic Effects on Proximal Tubular Epithelial Cells: Role of NF-{kappa}B and Lyn J. Am. Soc. Nephrol., March 1, 2006; 17(3): 627 - 636. [Abstract] [Full Text] [PDF]

				S. F. Eddy, S. Guo, E. G. Demicco, R. Romieu-Mourez, E. Landesman-Bollag, D. C. Seldin, and G. E. Sonenshein Inducible I{kappa}B Kinase/I{kappa}B Kinase {varepsilon} Expression Is Induced by CK2 and Promotes Aberrant Nuclear Factor-{kappa}B Activation in Breast Cancer Cells Cancer Res., December 15, 2005; 65(24): 11375 - 11383. [Abstract] [Full Text] [PDF]

				S. E. Sweeney, D. Hammaker, D. L. Boyle, and G. S. Firestein Regulation of c-Jun Phosphorylation by the I{kappa}B Kinase-{epsilon} Complex in Fibroblast-Like Synoviocytes J. Immunol., May 15, 2005; 174(10): 6424 - 6430. [Abstract] [Full Text] [PDF]

				A. Schoenemeyer, B. J. Barnes, Margo. E. Mancl, E. Latz, N. Goutagny, P. M. Pitha, K. A. Fitzgerald, and D. T. Golenbock The Interferon Regulatory Factor, IRF5, Is a Central Mediator of Toll-like Receptor 7 Signaling J. Biol. Chem., April 29, 2005; 280(17): 17005 - 17012. [Abstract] [Full Text] [PDF]

				S.-P. Gravel and M. J. Servant Roles of an I{kappa}B Kinase-related Pathway in Human Cytomegalovirus-infected Vascular Smooth Muscle Cells: A MOLECULAR LINK IN PATHOGEN-INDUCED PROATHEROSCLEROTIC CONDITIONS J. Biol. Chem., March 4, 2005; 280(9): 7477 - 7486. [Abstract] [Full Text] [PDF]

				M. Sasai, H. Oshiumi, M. Matsumoto, N. Inoue, F. Fujita, M. Nakanishi, and T. Seya Cutting Edge: NF-{kappa}B-Activating Kinase-Associated Protein 1 Participates in TLR3/Toll-IL-1 Homology Domain-Containing Adapter Molecule-1-Mediated IFN Regulatory Factor 3 Activation J. Immunol., January 1, 2005; 174(1): 27 - 30. [Abstract] [Full Text] [PDF]

				D. M. Kokkinakis, X. Liu, S. Chada, M. M. Ahmed, M. M. Shareef, U. K. Singha, S. Yang, and J. Luo Modulation of Gene Expression in Human Central Nervous System Tumors under Methionine Deprivation-induced Stress Cancer Res., October 15, 2004; 64(20): 7513 - 7525. [Abstract] [Full Text] [PDF]

				H. Hemmi, O. Takeuchi, S. Sato, M. Yamamoto, T. Kaisho, H. Sanjo, T. Kawai, K. Hoshino, K. Takeda, and S. Akira The Roles of Two I{kappa}B Kinase-related Kinases in Lipopolysaccharide and Double Stranded RNA Signaling and Viral Infection J. Exp. Med., June 21, 2004; 199(12): 1641 - 1650. [Abstract] [Full Text] [PDF]

				M. Mori, M. Yoneyama, T. Ito, K. Takahashi, F. Inagaki, and T. Fujita Identification of Ser-386 of Interferon Regulatory Factor 3 as Critical Target for Inducible Phosphorylation That Determines Activation J. Biol. Chem., March 12, 2004; 279(11): 9698 - 9702. [Abstract] [Full Text] [PDF]

				S. Sato, M. Sugiyama, M. Yamamoto, Y. Watanabe, T. Kawai, K. Takeda, and S. Akira Toll/IL-1 Receptor Domain-Containing Adaptor Inducing IFN-{beta} (TRIF) Associates with TNF Receptor-Associated Factor 6 and TANK-Binding Kinase 1, and Activates Two Distinct Transcription Factors, NF-{kappa}B and IFN-Regulatory Factor-3, in the Toll-Like Receptor Signaling J. Immunol., October 15, 2003; 171(8): 4304 - 4310. [Abstract] [Full Text] [PDF]

				M. Yamamoto, S. Sato, H. Hemmi, K. Hoshino, T. Kaisho, H. Sanjo, O. Takeuchi, M. Sugiyama, M. Okabe, K. Takeda, et al. Role of Adaptor TRIF in the MyD88-Independent Toll-Like Receptor Signaling Pathway Science, August 1, 2003; 301(5633): 640 - 643. [Abstract] [Full Text] [PDF]

				S. Sharma, B. R. tenOever, N. Grandvaux, G.-P. Zhou, R. Lin, and J. Hiscott Triggering the Interferon Antiviral Response Through an IKK-Related Pathway Science, May 16, 2003; 300(5622): 1148 - 1151. [Abstract] [Full Text] [PDF]

				D. Cappellen, N.-H. Luong-Nguyen, S. Bongiovanni, O. Grenet, C. Wanke, and M. Susa Transcriptional Program of Mouse Osteoclast Differentiation Governed by the Macrophage Colony-stimulating Factor and the Ligand for the Receptor Activator of NFkappa B J. Biol. Chem., June 7, 2002; 277(24): 21971 - 21982. [Abstract] [Full Text] [PDF]

				N. Kishore, Q. K. Huynh, S. Mathialagan, T. Hall, S. Rouw, D. Creely, G. Lange, J. Caroll, B. Reitz, A. Donnelly, et al. IKK-i and TBK-1 are Enzymatically Distinct from the Homologous Enzyme IKK-2. COMPARATIVE ANALYSIS OF RECOMBINANT HUMAN IKK-i, TBK-1, AND IKK-2 J. Biol. Chem., April 12, 2002; 277(16): 13840 - 13847. [Abstract] [Full Text] [PDF]

				U. Schonbeck and P. Libby CD40 Signaling and Plaque Instability Circ. Res., December 7, 2001; 89(12): 1092 - 1103. [Abstract] [Full Text] [PDF]

				G. Valen, Z.-q. Yan, and G.o. K. Hansson Nuclear factor kappa-B and the heart J. Am. Coll. Cardiol., August 1, 2001; 38(2): 307 - 314. [Abstract] [Full Text] [PDF]

				B. S. Miller and E. Zandi Complete Reconstitution of Human Ikappa B Kinase (IKK) Complex in Yeast. ASSESSMENT OF ITS STOICHIOMETRY AND THE ROLE OF IKKgamma ON THE COMPLEX ACTIVITY IN THE ABSENCE OF STIMULATION J. Biol. Chem., September 21, 2001; 276(39): 36320 - 36326. [Abstract] [Full Text] [PDF]