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Science 9 April 1999:
Vol. 284. no. 5412, pp. 309 - 313
DOI: 10.1126/science.284.5412.309
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Reports

Positive and Negative Regulation of Ikappa B Kinase Activity Through IKKbeta Subunit Phosphorylation

Mireille Delhase, Makio Hayakawa, Yi Chen, Michael Karin *

Ikappa B [inhibitor of nuclear factor kappa B (NF-kappa B)] kinase (IKK) phosphorylates Ikappa B inhibitory proteins, causing their degradation and activation of transcription factor NF-kappa B, a master activator of inflammatory responses. IKK is composed of three subunits--IKKalpha and IKKbeta , which are highly similar protein kinases, and IKKgamma , a regulatory subunit. In mammalian cells, phosphorylation of two sites at the activation loop of IKKbeta was essential for activation of IKK by tumor necrosis factor and interleukin-1. Elimination of equivalent sites in IKKalpha , however, did not interfere with IKK activation. Thus, IKKbeta , not IKKalpha , is the target for proinflammatory stimuli. Once activated, IKKbeta autophosphorylated at a carboxyl-terminal serine cluster. Such phosphorylation decreased IKK activity and may prevent prolonged activation of the inflammatory response.

Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0636, USA.
*   To whom correspondence should be addressed. E-mail: karinoffice{at}ucsd.edu

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J. Biol. Chem. 278, 38566-38570
   Abstract »    Full Text »    PDF »
A Role for NF-{kappa}B Essential Modifier/I{kappa}B Kinase-{gamma} (NEMO/IKK{gamma}) Ubiquitination in the Activation of the I{kappa}B Kinase Complex by Tumor Necrosis Factor-{alpha}.
E. D. Tang, C.-Y. Wang, Y. Xiong, and K.-L. Guan (2003)
J. Biol. Chem. 278, 37297-37305
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Apparently Normal Tumor Necrosis Factor Receptor 1 Signaling in the Absence of the Silencer of Death Domains.
R. Endres, G. Hacker, I. Brosch, and K. Pfeffer (2003)
Mol. Cell. Biol. 23, 6609-6617
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Heat Shock Protein 27 Association with the I{kappa}B Kinase Complex Regulates Tumor Necrosis Factor {alpha}-induced NF-{kappa}B Activation.
K.-J. Park, R. B. Gaynor, and Y. T. Kwak (2003)
J. Biol. Chem. 278, 35272-35278
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A Selective IKK-2 Inhibitor Blocks NF-{kappa}B-dependent Gene Expression in Interleukin-1{beta}-stimulated Synovial Fibroblasts.
N. Kishore, C. Sommers, S. Mathialagan, J. Guzova, M. Yao, S. Hauser, K. Huynh, S. Bonar, C. Mielke, L. Albee, et al. (2003)
J. Biol. Chem. 278, 32861-32871
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Differential Phosphorylation of the Signal-responsive Domain of I{kappa}B{alpha} and I{kappa}B{beta} by I{kappa}B Kinases.
C. Wu and S. Ghosh (2003)
J. Biol. Chem. 278, 31980-31987
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NF-{kappa}B1 p105 Negatively Regulates TPL-2 MEK Kinase Activity.
S. Beinke, J. Deka, V. Lang, M. P. Belich, P. A. Walker, S. Howell, S. J. Smerdon, S. J. Gamblin, and S. C. Ley (2003)
Mol. Cell. Biol. 23, 4739-4752
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Regulation of Airway Epithelial Cell NF-{kappa}B-Dependent Gene Expression by Protein Kinase C{delta}.
K. Page, J. Li, L. Zhou, S. Iasvoyskaia, K. C. Corbit, J.-W. Soh, I. B. Weinstein, A. R. Brasier, A. Lin, and M. B. Hershenson (2003)
J. Immunol. 170, 5681-5689
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In Vivo Identification of Inducible Phosphoacceptors in the IKK{gamma}/NEMO Subunit of Human I{kappa}B Kinase.
R. S. Carter, K. N. Pennington, B. J. Ungurait, and D. W. Ballard (2003)
J. Biol. Chem. 278, 19642-19648
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Tyrosine Phosphorylation of I-{kappa}B Kinase {alpha}/{beta} by Protein Kinase C-Dependent c-Src Activation Is Involved in TNF-{alpha}-Induced Cyclooxygenase-2 Expression.
W.-C. Huang, J.-J. Chen, H. Inoue, and C.-C. Chen (2003)
J. Immunol. 170, 4767-4775
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Combined Deficiency of p50 and cRel in CD4+ T Cells Reveals an Essential Requirement for Nuclear Factor {kappa}B in Regulating Mature T Cell Survival and In Vivo Function.
Y. Zheng, M. Vig, J. Lyons, L. Van Parijs, and A. A. Beg (2003)
J. Exp. Med. 197, 861-874
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Ceramide-induced and Age-associated Increase in Macrophage COX-2 Expression Is Mediated through Up-regulation of NF-kappa B Activity.
D. Wu, M. Marko, K