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Science 24 August 2001:
Vol. 293. no. 5534, pp. 1495 - 1499
DOI: 10.1126/science.1062677
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Reports

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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Regulation of I{kappa}B Kinase (IKK) Complex by IKK{gamma}-dependent Phosphorylation of the T-loop and C Terminus of IKKbeta.
B. Schomer-Miller, T. Higashimoto, Y.-K. Lee, and E. Zandi (2006)
J. Biol. Chem. 281, 15268-15276
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Rapid TNFR1-dependent lymphocyte depletion in vivo with a selective chemical inhibitor of IKKbeta.
K. Nagashima, V. G. Sasseville, D. Wen, A. Bielecki, H. Yang, C. Simpson, E. Grant, M. Hepperle, G. Harriman, B. Jaffee, et al. (2006)
Blood 107, 4266-4273
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Constitutive NF-{kappa}B and NFAT activation leads to stimulation of the BLyS survival pathway in aggressive B-cell lymphomas.
L. Fu, Y.-C. Lin-Lee, L. V. Pham, A. Tamayo, L. Yoshimura, and R. J. Ford (2006)
Blood 107, 4540-4548
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Rac1, but Not Rac1B, Stimulates RelB-mediated Gene Transcription in Colorectal Cancer Cells.
P. Matos and P. Jordan (2006)
J. Biol. Chem. 281, 13724-13732
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An Alternative Splice Product of I{kappa}B Kinase (IKK{gamma}), IKK{gamma}-{Delta}, Differentially Mediates Cytokine and Human T-Cell Leukemia Virus Type 1 Tax-Induced NF-{kappa}B Activation.
T. Hai, M.-L. Yeung, T. G. Wood, Y. Wei, S. Yamaoka, Z. Gatalica, K.-T. Jeang, and A. R. Brasier (2006)
J. Virol. 80, 4227-4241
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Diabetes-Induced Activation of Canonical and Noncanonical Nuclear Factor-{kappa}B Pathways in Renal Cortex..
J. M. Starkey, S. J. Haidacher, W. S. LeJeune, X. Zhang, B. C. Tieu, S. Choudhary, A. R. Brasier, L. A. Denner, and R. G. Tilton (2006)
Diabetes 55, 1252-1259
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Cross-regulation between Notch and p63 in keratinocyte commitment to differentiation.
B.-C. Nguyen, K. Lefort, A. Mandinova, D. Antonini, V. Devgan, G. Della Gatta, M. I. Koster, Z. Zhang, J. Wang, A. T. di Vignano, et al. (2006)
Genes & Dev. 20, 1028-1042
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Drosophila Ik2, a member of the I{kappa}B kinase family, is required for mRNA localization during oogenesis.
R. S. Shapiro and K. V. Anderson (2006)
Development 133, 1467-1475
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Mechanisms of Liver Injury. I. TNF-{alpha}-induced liver injury: role of IKK, JNK, and ROS pathways.
R. F. Schwabe and D. A. Brenner (2006)
Am J Physiol Gastrointest Liver Physiol 290, G583-G589
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Essential Role of I{kappa}B Kinase {alpha} in Thymic Organogenesis Required for the Establishment of Self-Tolerance.
D. Kinoshita, F. Hirota, T. Kaisho, M. Kasai, K. Izumi, Y. Bando, Y. Mouri, A. Matsushima, S. Niki, H. Han, et al. (2006)
J. Immunol. 176, 3995-4002
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Antianoikis Effect of Nuclear Factor-{kappa}B through Up-regulated Expression of Osteoprotegerin, BCL-2, and IAP-1.
M. Toruner, M. Fernandez-Zapico, J. J. Sha, L. Pham, R. Urrutia, and L. J. Egan (2006)
J. Biol. Chem. 281, 8686-8696
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IKK{alpha} Regulates Estrogen-induced Cell Cycle Progression by Modulating E2F1 Expression.
Z. Tu, S. Prajapati, K.-J. Park, N. J. Kelly, Y. Yamamoto, and R. B. Gaynor (2006)
J. Biol. Chem. 281, 6699-6706
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Helicobacter pylori Induces I{kappa}B Kinase {alpha} Nuclear Translocation and Chemokine Production in Gastric Epithelial Cells.
Y. Hirata, S. Maeda, T. Ohmae, W. Shibata, A. Yanai, K. Ogura, H. Yoshida, T. Kawabe, and M. Omata (2006)
Infect. Immun. 74, 1452-1461
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Inhibition of Human Immunodeficiency Virus Type 1 Replication in Latently Infected Cells by a Novel I{kappa}B Kinase Inhibitor.
A. F. B. Victoriano, K. Asamitsu, Y. Hibi, K. Imai, N. G. Barzaga, and T. Okamoto (2006)
Antimicrob. Agents Chemother. 50, 547-555
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Coordination between NF-{kappa}B family members p50 and p52 is essential for mediating LTbetaR signals in the development and organization of secondary lymphoid tissues.
J. C. Lo, S. Basak, E. S. James, R. S. Quiambo, M. C. Kinsella, M.-L. Alegre, F. Weih, G. Franzoso, A. Hoffmann, and Y.-X. Fu (2006)
Blood 107, 1048-1055
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The C-terminal Activating Region 2 of the Epstein-Barr Virus-encoded Latent Membrane Protein 1 Activates NF-{kappa}B through TRAF6 and TAK1.
L. Wu, H. Nakano, and Z. Wu (2006)
J. Biol. Chem. 281, 2162-2169
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Stabilization of Basally Translated NF-{kappa}B-inducing Kinase (NIK) Protein Functions as a Molecular Switch of Processing of NF-{kappa}B2 p100.
G. Qing, Z. Qu, and G. Xiao (2005)
J. Biol. Chem. 280, 40578-40582
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RelB/p52 NF-{kappa}B Complexes Rescue an Early Delay in Mammary Gland Development in Transgenic Mice with Targeted Superrepressor I{kappa}B-{alpha} Expression and Promote Carcinogenesis of the Mammary Gland.
E. G. Demicco, K. T. Kavanagh, R. Romieu-Mourez, X. Wang, S. R. Shin, E. Landesman-Bollag, D. C. Seldin, and G. E. Sonenshein (2005)
Mol. Cell. Biol. 25, 10136-10147
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TAK1, but not TAB1 or TAB2, plays an essential role in multiple signaling pathways in vivo.
J.-H. Shim, C. Xiao, A. E. Paschal, S. T. Bailey, P. Rao, M. S. Hayden, K.-Y. Lee, C. Bussey, M. Steckel, N. Tanaka, et al. (2005)
Genes & Dev. 19, 2668-2681
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