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Science 291 (5511): 2162-2165

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

Defective Lymphotoxin-beta Receptor-Induced NF-kappa B Transcriptional Activity in NIK-Deficient Mice

Li Yin,1 Lin Wu,2 Holger Wesche,2 Cora D. Arthur,1 J. Michael White,1 David V. Goeddel,2 Robert D. Schreiber1*

The role of NF-kappa B-inducing kinase (NIK) in cytokine signaling remains controversial. To identify the physiologic functions of NIK, we disrupted the NIK locus by gene targeting. Although NIK-/- mice displayed abnormalities in both lymphoid tissue development and antibody responses, NIK-/- cells manifested normal NF-kappa B DNA binding activity when treated with a variety of cytokines, including tumor necrosis factor (TNF), interleukin-1 (IL-1), and lymphotoxin-beta (LTbeta ). However, NIK was selectively required for gene transcription induced through ligation of LTbeta receptor but not TNF receptors. These results reveal that NIK regulates the transcriptional activity of NF-kappa B in a receptor-restricted manner.

1 Center for Immunology, Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
2 Tularik Inc., 2 Corporate Drive, South San Francisco, CA 94080, USA.
*   To whom correspondence should be addressed. E-mail: schreiber{at}

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S. Tegethoff, J. Behlke, and C. Scheidereit (2003)
Mol. Cell. Biol. 23, 2029-2041
   Abstract »    Full Text »    PDF »
Ikappa B kinase 2 but not NF-kappa B-inducing kinase is essential for effective DC antigen presentation in the allogeneic mixed lymphocyte reaction.
E. Andreakos, C. Smith, C. Monaco, F. M. Brennan, B. M. Foxwell, and M. Feldmann (2003)
Blood 101, 983-991
   Abstract »    Full Text »    PDF »
The NF-kappa B Activation in Lymphotoxin beta Receptor Signaling Depends on the Phosphorylation of p65 at Serine 536.
X. Jiang, N. Takahashi, N. Matsui, T. Tetsuka, and T. Okamoto (2003)
J. Biol. Chem. 278, 919-926
   Abstract »    Full Text »    PDF »
RelB is required for Peyer's patch development: differential regulation of p52-RelB by lymphotoxin and TNF.
Z. B. Yilmaz, D. S. Weih, V. Sivakumar, and F. Weih (2003)
EMBO J. 22, 121-130
   Abstract »    Full Text »    PDF »
NF-{kappa}B activation by protein kinase C isoforms and B-cell function.
J. Moscat, M. T. Diaz-Meco, and P. Rennert (2003)
EMBO Rep. 4, 31-36
   Abstract »    Full Text »
Lymphotoxin and lipopolysaccharide induce NF-{kappa}B-p52 generation by a co-translational mechanism.
B. Mordmuller, D. Krappmann, M. Esen, E. Wegener, and C. Scheidereit (2003)
EMBO Rep. 4, 82-87
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The Drosophila Atypical Protein Kinase C-Ref(2)P Complex Constitutes a Conserved Module for Signaling in the Toll Pathway.
A. Avila, N. Silverman, M. T. Diaz-Meco, and J. Moscat (2002)
Mol. Cell. Biol. 22, 8787-8795
   Abstract »    Full Text »    PDF »
Molecular Mechanisms for Lipopolysaccharide-induced Biphasic Activation of Nuclear Factor-kappa B (NF-kappa B).
S.-J. Han, H.-M. Ko, J.-H. Choi, K. H. Seo, H.-S. Lee, E.-K. Choi, I.-W. Choi, H.-K. Lee, and S.-Y. Im (2002)
J. Biol. Chem. 277, 44715-44721
   Abstract »    Full Text »    PDF »
Interleukin-1 (IL-1) Receptor-Associated Kinase-Dependent IL-1-Induced Signaling Complexes Phosphorylate TAK1 and TAB2 at the Plasma Membrane and Activate TAK1 in the Cytosol.
Z. Jiang, J. Ninomiya-Tsuji, Y. Qian, K. Matsumoto, and X. Li (2002)
Mol. Cell. Biol. 22, 7158-7167
   Abstract »    Full Text »    PDF »
CD40 regulates the processing of NF-{kappa}B2 p100 to p52.
H. J. Coope, P. G. P. Atkinson, B. Huhse, M. Belich, J. Janzen, M. J. Holman, G. G. B. Klaus, L. H. Johnston, and S. C. Ley (2002)
EMBO J. 21, 5375-5385
   Abstract »    Full Text »    PDF »
Constitutive Nuclear Factor-kappa B Activity Is Required for Central Neuron Survival.
A. L. Bhakar, L.-L. Tannis, C. Zeindler, M. P. Russo, C. Jobin, D. S. Park, S. MacPherson, and P. A. Barker (2002)
J. Neurosci. 22, 8466-8475
   Abstract »    Full Text »    PDF »
The Phosphatidylinositol 3-Kinase-Akt Pathway Limits Lipopolysaccharide Activation of Signaling Pathways and Expression of Inflammatory Mediators in Human Monocytic Cells.
M. Guha and N. Mackman (2002)
J. Biol. Chem. 277, 32124-32132
   Abstract »    Full Text »    PDF »
Essential Role of NF-{kappa}B-Inducing Kinase in T Cell Activation Through the TCR/CD3 Pathway.
M. Matsumoto, T. Yamada, S. K. Yoshinaga, T. Boone, T. Horan, S. Fujita, Y. Li, and T. Mitani (2002)
J. Immunol. 169, 1151-1158
   Abstract »    Full Text »    PDF »
Role of NF{kappa}B activator Act1 in CD40-mediated signaling in epithelial cells.
Y. Qian, Z. Zhao, Z. Jiang, and X. Li (2002)
PNAS 99, 9386-9391
   Abstract »    Full Text »    PDF »
Differential requirement for NF-kappa B-inducing kinase in the induction of NF-kappa B by IL-1beta , TNF-alpha , and Fas.
M. P. Russo, B. L. Bennett, A. M. Manning, D. A. Brenner, and C. Jobin (2002)
Am J Physiol Cell Physiol 283, C347-C357
   Abstract »    Full Text »    PDF »
Genetic Evidence for the Essential Role of beta -Transducin Repeat-containing Protein in the Inducible Processing of NF-kappa B2/p100.
A. Fong and S.-C. Sun (2002)
J. Biol. Chem. 277, 22111-22114
   Abstract »    Full Text »    PDF »
Evidence for a Dual Mechanism for IL-10 Suppression of TNF-{alpha} Production That Does Not Involve Inhibition of p38 Mitogen-Activated Protein Kinase or NF-{kappa}B in Primary Human Macrophages.
A. Denys, I. A. Udalova, C. Smith, L. M. Williams, C. J. Ciesielski, J. Campbell, C. Andrews, D. Kwaitkowski, and B. M. J. Foxwell (2002)
J. Immunol. 168, 4837-4845
   Abstract »    Full Text »    PDF »
Postgestational Lymphotoxin/Lymphotoxin {beta} Receptor Interactions Are Essential for the Presence of Intestinal B Lymphocytes.
R. D. Newberry, J. S. McDonough, K. G. McDonald, and R. G. Lorenz (2002)
J. Immunol. 168, 4988-4997
   Abstract »    Full Text »    PDF »
Signaling Molecules of the NF-{kappa}B Pathway Shuttle Constitutively between Cytoplasm and Nucleus.
A. Birbach, P. Gold, B. R. Binder, E. Hofer, R. de Martin, and J. A. Schmid (2002)
J. Biol. Chem. 277, 10842-10851
   Abstract »    Full Text »    PDF »
A Novel NF-kappa B-inducing Kinase-MAPK Signaling Pathway Up-regulates NF-kappa B Activity in Melanoma Cells.
P. Dhawan and A. Richmond (2002)
J. Biol. Chem. 277, 7920-7928
   Abstract »    Full Text »    PDF »

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