The DOI matches its Crossref record; 16 of the 16 references it cites were found in a registry or an index.
Regulation and Function of IKK and IKK-Related Kinases
Abstract
Members of the nuclear factor kappa B (NF-κB) family of dimeric transcription factors (TFs) regulate expression of a large number of genes involved in immune responses, inflammation, cell survival, and cancer. NF-κB TFs are rapidly activated in response to various stimuli, including cytokines, infectious agents, and radiation-induced DNA double-strand breaks. In nonstimulated cells, some NF-κB TFs are bound to inhibitory IκB proteins and are thereby sequestered in the cytoplasm. Activation leads to phosphorylation of IκB proteins and their subsequent recognition by ubiquitinating enzymes. The resulting proteasomal degradation of IκB proteins liberates IκB-bound NF-κB TFs, which translocate to the nucleus to drive expression of target genes. Two protein kinases with a high degree of sequence similarity, IKKα and IKKβ, mediate phosphorylation of IκB proteins and represent a convergence point for most signal transduction pathways leading to NF-κB activation. Most of the IKKα and IKKβ molecules in the cell are part of IKK complexes that also contain a regulatory subunit called IKKγ or NEMO. Despite extensive sequence similarity, IKKα and IKKβ have largely distinct functions, due to their different substrate specificities and modes of regulation. IKKβ (and IKKγ) are essential for rapid NF-κB activation by proinflammatory signaling cascades, such as those triggered by tumor necrosis factor α (TNFα) or lipopolysaccharide (LPS). In contrast, IKKα functions in the activation of a specific form of NF-κB in response to a subset of TNF family members and may also serve to attenuate IKKβ-driven NF-κB activation. Moreover, IKKα is involved in keratinocyte differentiation, but this function is independent of its kinase activity. Several years ago, two protein kinases, one called IKKε or IKK-i and one variously named TBK1 (TANK-binding kinase), NAK (NF-κB–activated kinase), or T2K (TRAF2-associated kinase), were identified that exhibit structural similarity to IKKα and IKKβ. These protein kinases are important for the activation of interferon response factor 3 (IRF3) and IRF7, TFs that play key roles in the induction of type I interferon (IFN-I). Together, the IKKs and IKK-related kinases are instrumental for activation of the host defense system. This Review focuses on the functions of IKK and IKK-related kinases and the molecular mechanisms that regulate their activities.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Differential roles of MDA5 and RIG-I helicases in the recognition of RNA viruses
Kato, H., Takeuchi, O., Sato, S., Yoneyama, M., Yamamoto, M., Matsui, K., Uematsu, S., Jung, A., Kawai, T., Ishii, K. J., et al. (2006) · Nature · doi:10.1038/nature04734 · Cited by 3,888
Hayden, M. S., & Ghosh, S. (2004) · Genes & Development · doi:10.1101/gad.1228704 · Cited by 3,842
IPS-1, an adaptor triggering RIG-I- and Mda5-mediated type I interferon induction
Kawai, T., Takahashi, K., Sato, S., Coban, C., Kumar, H., Kato, H., Ishii, K. J., Takeuchi, O., & Akira, S. (2005) · Nature Immunology · doi:10.1038/ni1243 · Cited by 2,562
Cardif is an adaptor protein in the RIG-I antiviral pathway and is targeted by hepatitis C virus
Meylan, E., Curran, J., Hofmann, K., Moradpour, D., Binder, M., Bartenschlager, R., & Tschopp, J. (2005) · Nature · doi:10.1038/nature04193 · Cited by 2,401
A cytokine-responsive IκB kinase that activates the transcription factor NF-κB
DiDonato, J. A., Hayakawa, M., Rothwarf, D. M., Zandi, E., & Karin, M. (1997) · Nature · doi:10.1038/41493 · Cited by 2,125
Self-citationUbiquitin signalling in the NF-κB pathway
Chen, Z. J. (2005) · Nature Cell Biology · doi:10.1038/ncb0805-758 · Cited by 1,184
TNF-Dependent Recruitment of the Protein Kinase RIP to the TNF Receptor-1 Signaling Complex
Hsu, H., Huang, J., Shu, H.-B., Baichwal, V., & Goeddel, D. V. (1996) · Immunity · doi:10.1016/s1074-7613(00)80252-6 · Cited by 1,182
Lin, R., Heylbroeck, C., Pitha, P. M., & Hiscott, J. (1998) · Molecular and Cellular Biology · doi:10.1128/mcb.18.5.2986 · Cited by 915
Yeh, W.-C., Itie, A., Elia, A. J., Ng, M., Shu, H.-B., Wakeham, A., Mirtsos, C., Suzuki, N., Bonnard, M., Goeddel, D. V., et al. (2000) · Immunity · doi:10.1016/s1074-7613(00)80214-9 · Cited by 515
CARMA1, BCL-10 and MALT1 in lymphocyte development and activation
Thome, M. (2004) · Nature Reviews Immunology · doi:10.1038/nri1352 · Cited by 391
Cited by
Shared Principles in NF-κB Signaling
Hayden, M. S., & Ghosh, S. (2008) · Cell · doi:10.1016/j.cell.2008.01.020 · Cited by 4,494
Molecular mechanisms of necroptosis: an ordered cellular explosion
Vandenabeele, P., Galluzzi, L., Vanden Berghe, T., & Kroemer, G. (2010) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2970 · Cited by 2,382
Crosstalk in NF-κB Signaling Pathways
Oeckinghaus, A., Hayden, M. S., & Ghosh, S. (2011) · Nature Immunology · doi:10.1038/ni.2065 · Cited by 1,942
NF-κB, the first quarter-century: remarkable progress and outstanding questions
Hayden, M. S., & Ghosh, S. (2012) · Genes & Development · doi:10.1101/gad.183434.111 · Cited by 1,693
Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets
Gao, C., Jiang, J., Tan, Y., & Chen, S. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01588-0 · Cited by 1,616
NF-κB links innate immunity to the hypoxic response through transcriptional regulation of HIF-1α
Rius, J., Guma, M., Schachtrup, C., Akassoglou, K., Zinkernagel, A. S., Nizet, V., Johnson, R. S., Haddad, G. G., & Karin, M. (2008) · Nature · doi:10.1038/nature06905 · Cited by 1,614
Self-citationRegulation and cellular roles of ubiquitin-specific deubiquitinating enzymes.
Reyes-Turcu, F. E., Ventii, K. H., & Wilkinson, K. D. (2009) · Annual Review of Biochemistry · doi:10.1146/annurev.biochem.78.082307.091526 · Cited by 1,396
The IRF Family Transcription Factors in Immunity and Oncogenesis
Tamura, T., Yanai, H., Savitsky, D., & Taniguchi, T. (2008) · Annual Review of Immunology · doi:10.1146/annurev.immunol.26.021607.090400 · Cited by 1,259
Epithelial-cell recognition of commensal bacteria and maintenance of immune homeostasis in the gut
Artis, D. (2008) · Nature reviews. Immunology · doi:10.1038/nri2316 · Cited by 1,136
Interdependence of hypoxic and innate immune responses
Nizet, V., & Johnson, R. S. (2009) · Nature Reviews Immunology · doi:10.1038/nri2607 · Cited by 708
Pulsatile Stimulation Determines Timing and Specificity of NF-κB-Dependent Transcription
Ashall, L., Horton, C. A., Nelson, D. E., Paszek, P., Harper, C. V., Sillitoe, K., Ryan, S., Spiller, D. G., Unitt, J. F., Broomhead, D. S., et al. (2009) · Science · doi:10.1126/science.1164860 · Cited by 543
Staudt, L. M. (2010) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a000109 · Cited by 485
Expanding TRAF function: TRAF3 as a tri-faced immune regulator
Häcker, H., Tseng, P.-H., & Karin, M. (2011) · Nature Reviews Immunology · doi:10.1038/nri2998 · Cited by 471
Self-citationApoptosis, necrosis and necroptosis: cell death regulation in the intestinal epithelium
Günther, C., Neumann, H., Neurath, M. F., & Becker, C. (2013) · Gut · doi:10.1136/gutjnl-2011-301364 · Cited by 462
Targeting the NF-κB pathway in asthma and chronic obstructive pulmonary disease
Edwards, M. R., Bartlett, N. W., Clarke, D., Birrell, M., Belvisi, M., & Johnston, S. L. (2009) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2008.09.003 · Cited by 375
JNK1 and IKKβ: molecular links between obesity and metabolic dysfunction
Solinas, G., & Karin, M. (2010) · The FASEB Journal · doi:10.1096/fj.09-151340 · Cited by 347
Self-citationStructural and synaptic plasticity in stress-related disorders
Christoffel, D. J., Golden, S. A., & Russo, S. J. (2011) · Reviews in the Neurosciences · doi:10.1515/rns.2011.044 · Cited by 334
Novel cross-talk within the IKK family controls innate immunity
Clark, K., Peggie, M., Plater, L., Sorcek, R. J., Young, E. R. R., Madwed, J. B., Hough, J., McIver, E. G., & Cohen, P. (2011) · Biochemical Journal · doi:10.1042/bj20101701 · Cited by 326
NF-κB signaling, liver disease and hepatoprotective agents
Sun, B., & Karin, M. (2008) · Oncogene · doi:10.1038/onc.2008.300 · Cited by 307
Self-citationBeck, I. M. E., Vanden Berghe, W., Vermeulen, L., Yamamoto, K. R., Haegeman, G., & De Bosscher, K. (2009) · Endocrine Reviews · doi:10.1210/er.2009-0013 · Cited by 298
Hinz, M., Stilmann, M., Arslan, S. Ç., Khanna, K. K., Dittmar, G., & Scheidereit, C. (2010) · Molecular Cell · doi:10.1016/j.molcel.2010.09.008 · Cited by 280
DNA damage-induced type I interferon promotes senescence and inhibits stem cell function
Yu, Q., Katlinskaya, Y. V., Carbone, C. J., Zhao, B., Katlinski, K. V., Zheng, H., Guha, M., Li, N., Chen, Q., Yang, T., et al. (2015) · Cell Reports · doi:10.1016/j.celrep.2015.03.069 · Cited by 260
Interferons: Signaling, antiviral and viral evasion
Bonjardim, C. A., Ferreira, P. C. P., & Kroon, E. G. (2009) · Immunology Letters · doi:10.1016/j.imlet.2008.11.002 · Cited by 196
Hasan, U. A., Zannetti, C., Parroche, P., Goutagny, N., Malfroy, M., Roblot, G., Carreira, C., Hussain, I., Müller, M., Taylor-Papadimitriou, J., et al. (2013) · Journal of Experimental Medicine · doi:10.1084/jem.20122394 · Cited by 191
Neurodegeneration in an animal model of Parkinson’s disease is exacerbated by a high-fat diet
Morris, J. K., Bomhoff, G. L., Stanford, J. A., & Geiger, P. C. (2010) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00449.2010 · Cited by 163
Regulation of liver regeneration and hepatocarcinogenesis by suppressor of cytokine signaling 3
Riehle, K. J., Campbell, J. S., McMahan, R. S., Johnson, M. M., Beyer, R. P., Bammler, T. K., & Fausto, N. (2008) · The Journal of Experimental Medicine · doi:10.1084/jem.20070820 · Cited by 161
Functional Dissection of the TBK1 Molecular Network
Goncalves, A., Bürckstümmer, T., Dixit, E., Scheicher, R., Górna, M. W., Karayel, E., Sugar, C., Stukalov, A., Berg, T., Kralovics, R., et al. (2011) · PLoS ONE · doi:10.1371/journal.pone.0023971 · Cited by 136
Wu, X., Yang, Z., Zou, J., Gao, H., Shao, Z., Li, C., & Lei, P. (2025) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-025-02179-x · Cited by 88
Effects of Inhibitor of κB Kinase Activity in the Nucleus Accumbens on Emotional Behavior
Christoffel, D. J., Golden, S. A., Heshmati, M., Graham, A., Birnbaum, S., Neve, R. L., Hodes, G. E., & Russo, S. J. (2012) · Neuropsychopharmacology · doi:10.1038/npp.2012.121 · Cited by 78
Moussaieff, A., Shohami, E., Kashman, Y., Fride, E., Schmitz, M. L., Renner, F., Fiebich, B. L., Munoz, E., Ben-Neriah, Y., & Mechoulam, R. (2007) · Molecular Pharmacology · doi:10.1124/mol.107.038810 · Cited by 75
Signal transduction and Th17 cell differentiation
O'Shea, J. J., Steward-Tharp, S. M., Laurence, A., Watford, W. T., Wei, L., Adamson, A. S., & Fan, S. (2009) · Microbes and Infection · doi:10.1016/j.micinf.2009.04.007 · Cited by 73
NF-κB, IκB, and IRAK Control Glutamate Receptor Density at the Drosophila NMJ
Heckscher, E. S., Fetter, R. D., Marek, K. W., Albin, S. D., & Davis, G. W. (2007) · Neuron · doi:10.1016/j.neuron.2007.08.005 · Cited by 72
Zhou, H.-J., Wang, L.-Q., Xu, Q.-S., Fan, Z.-X., Zhu, Y., Jiang, H., Zheng, X.-J., Ma, Y.-H., & Zhan, R.-Y. (2016) · Experimental Cell Research · doi:10.1016/j.yexcr.2016.09.020 · Cited by 64
The Activation of IL-1-Induced Enhancers Depends on TAK1 Kinase Activity and NF-κB p65
Jurida, L., Soelch, J., Bartkuhn, M., Handschick, K., Müller, H., Newel, D., Weber, A., Dittrich-Breiholz, O., Schneider, H., Bhuju, S., et al. (2015) · Cell Reports · doi:10.1016/j.celrep.2015.01.001 · Cited by 51
AKT Activation by Pdcd4 Knockdown Up-Regulates Cyclin D1 Expression and Promotes Cell Proliferation
Guo, X., Li, W., Wang, Q., & Yang, H.-S. (2011) · Genes & Cancer · doi:10.1177/1947601911431082 · Cited by 40
Overactivation of the NF‐κB pathway impairs molar enamel formation
Yamada, A., Kawasaki, M., Miake, Y., Yamada, Y., Blackburn, J., Kawasaki, K., Trakanant, S., Nagai, T., Nihara, J., Kudo, T., et al. (2020) · Oral Diseases · doi:10.1111/odi.13384 · Cited by 9
Metadata
- Authors
- Häcker, H., & Karin, M.
- Venue
- Science's STKE
- Published
- 2006-10-17
- Volume
- 2006
- Issue
- 357
- Pages
- re13-re13
- ISSN
- 1525-8882 (ISSN-L)
- OpenAlex
- W2098710866
- Cited by
- 1,274
- References
- 16
- FWCI
- 26.78
- Type
- journal article
- Language
- en
- Open access
- closed
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
Data sources
Bibliographic data: Semantic Scholar, OpenAlex, Crossref.
Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
Semantic Scholar’s data is described in: Kinney, R., et al. (2023). The Semantic Scholar Open Data Platform. arXiv:2301.10140.
