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Science 293 (5534): 1495-1499

Copyright © 2001 by the American Association for the Advancement of Science

Activation by IKKalpha of a Second, Evolutionary Conserved, NF-kappa B Signaling Pathway

Uwe Senftleben,12 Yixue Cao,1 Gutian Xiao,3 Florian R. Greten,1 Gertraud Krähn,14 Giuseppina Bonizzi,1 Yi Chen,1 Yinling Hu,1 Abraham Fong,3 Shao-Cong Sun,3 Michael Karin1*

In mammals, the canonical nuclear factor kappa B (NF-kappa B) signaling pathway activated in response to infections is based on degradation of Ikappa B inhibitors. This pathway depends on the Ikappa B kinase (IKK), which contains two catalytic subunits, IKKalpha and IKKbeta . IKKbeta is essential for inducible Ikappa B phosphorylation and degradation, whereas IKKalpha is not. Here we show that IKKalpha is required for B cell maturation, formation of secondary lymphoid organs, increased expression of certain NF-kappa B target genes, and processing of the NF-kappa B2 (p100) precursor. IKKalpha preferentially phosphorylates NF-kappa B2, and this activity requires its phosphorylation by upstream kinases, one of which may be NF-kappa B-inducing kinase (NIK). IKKalpha is therefore a pivotal component of a second NF-kappa B activation pathway based on regulated NF-kappa B2 processing rather than Ikappa B degradation.

1 Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
2 Clinic for Anesthesiology, University of Ulm, Steinhövelstrasse 9, 89075 Ulm, Germany.
3 Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA.
4 Department of Dermatology, University of Ulm, Oberer Eselsberg 40, 89081 Ulm, Germany.
*   To whom correspondence should be addressed.


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Constitutive Production of NF-{kappa}B2 p52 Is Not Tumorigenic but Predisposes Mice to Inflammatory Autoimmune Disease by Repressing Bim Expression.
Z. Wang, B. Zhang, L. Yang, J. Ding, and H.-F. Ding (2008)
J. Biol. Chem. 283, 10698-10706
   Abstract »    Full Text »    PDF »
Control of canonical NF-{kappa}B activation through the NIK-IKK complex pathway.
B. Zarnegar, S. Yamazaki, J. Q. He, and G. Cheng (2008)
PNAS 105, 3503-3508
   Abstract »    Full Text »    PDF »
Lymphotoxin-{alpha}1{beta}2 and LIGHT Induce Classical and Noncanonical NF-{kappa}B-Dependent Proinflammatory Gene Expression in Vascular Endothelial Cells.
L. A. Madge, M. S. Kluger, J. S. Orange, and M. J. May (2008)
J. Immunol. 180, 3467-3477
   Abstract »    Full Text »    PDF »
IKK/NF-{kappa}B regulates skeletal myogenesis via a signaling switch to inhibit differentiation and promote mitochondrial biogenesis.
N. Bakkar, J. Wang, K. J. Ladner, H. Wang, J. M. Dahlman, M. Carathers, S. Acharyya, M. A. Rudnicki, A. D. Hollenbach, and D. C. Guttridge (2008)
J. Cell Biol. 180, 787-802
   Abstract »    Full Text »    PDF »
Elucidating the Function of an Ancient NF-{kappa}B p100 Homologue, CrRelish, in Antibacterial Defense.
Z. H. Fan, X. W. Wang, J. Lu, B. Ho, and J. L. Ding (2008)
Infect. Immun. 76, 664-670
   Abstract »    Full Text »    PDF »
Signal processing by its coil zipper domain activates IKK{gamma}.
S. Bloor, G. Ryzhakov, S. Wagner, P. J. G. Butler, D. L. Smith, R. Krumbach, I. Dikic, and F. Randow (2008)
PNAS 105, 1279-1284
   Abstract »    Full Text »    PDF »
Phosphorylation of Serine 68 in the I{kappa}B Kinase (IKK)-binding Domain of NEMO Interferes with the Structure of the IKK Complex and Tumor Necrosis Factor-{alpha}-induced NF-{kappa}B Activity.
L. Palkowitsch, J. Leidner, S. Ghosh, and R. B. Marienfeld (2008)
J. Biol. Chem. 283, 76-86
   Abstract »    Full Text »    PDF »
A JNK1/AP-1-Dependent, COX-2 Induction Is Implicated in 12-O-Tetradecanoylphorbol-13-Acetate-Induced Cell Transformation through Regulating Cell Cycle Progression.
D. Zhang, J. Li, L. Song, W. Ouyang, J. Gao, and C. Huang (2008)
Mol. Cancer Res. 6, 165-174
   Abstract »    Full Text »    PDF »
The Human T-Cell Leukemia Virus Type 1 Tax Oncoprotein Requires the Ubiquitin-Conjugating Enzyme Ubc13 for NF-{kappa}B Activation.
N. Shembade, N. S. Harhaj, M. Yamamoto, S. Akira, and E. W. Harhaj (2007)
J. Virol. 81, 13735-13742
   Abstract »    Full Text »    PDF »
Enhancement of NF-{kappa}B Activation in Lymphocytes Prevents T Cell Apoptosis and Improves Survival in Murine Sepsis.
H. V. Groesdonk, F. Wagner, B. Hoffarth, M. Georgieff, and U. Senftleben (2007)
J. Immunol. 179, 8083-8089
   Abstract »    Full Text »    PDF »
Tumor Necrosis Factor-{alpha} Augments Matrix Metalloproteinase-9 Production in Skeletal Muscle Cells through the Activation of Transforming Growth Factor- -activated Kinase 1 (TAK1)-dependent Signaling Pathway.
A. K. Srivastava, X. Qin, N. Wedhas, M. Arnush, T. A. Linkhart, R. B. Chadwick, and A. Kumar (2007)
J. Biol. Chem. 282, 35113-35124
   Abstract »    Full Text »    PDF »
Torque Teno Virus (SANBAN Isolate) ORF2 Protein Suppresses NF-{kappa}B Pathways via Interaction with I{kappa}B Kinases.
H. Zheng, L. Ye, X. Fang, B. Li, Y. Wang, X. Xiang, L. Kong, W. Wang, Y. Zeng, L. Ye, et al. (2007)
J. Virol. 81, 11917-11924
   Abstract »    Full Text »    PDF »
Reduction in I{kappa}B Kinase {alpha} Expression Promotes the Development of Skin Papillomas and Carcinomas.
E. Park, F. Zhu, B. Liu, X. Xia, J. Shen, T. Bustos, S. M. Fischer, and Y. Hu (2007)
Cancer Res. 67, 9158-9168
   Abstract »    Full Text »    PDF »
Lipopolysaccharide from Salmonella enterica Activates NF-{kappa}B through both Classical and Alternative Pathways in Primary B Lymphocytes.
V. Souvannavong, N. Saidji, and R. Chaby (2007)
Infect. Immun. 75, 4998-5003
   Abstract »    Full Text »    PDF »
Bruton's Tyrosine Kinase Mediates NF-{kappa}B Activation and B Cell Survival by B Cell-Activating Factor Receptor of the TNF-R Family.
N. P. Shinners, G. Carlesso, I. Castro, K. L. Hoek, R. A. Corn, R. L. Woodland, M. L. Scott, D. Wang, and W. N. Khan (2007)
J. Immunol. 179, 3872-3880
   Abstract »    Full Text »    PDF »

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