Nemo-like kinase (NLK) negatively regulates NF-kappa B activity through disrupting the interaction of TAK1 with IKKβ
Open accessAbstract
Stringent negative regulation of the transcription factor NF-κB is essential for maintaining cellular stress responses and homeostasis. However, the tight regulation mechanisms of IKKβ are still not clear. Here, we reported that nemo-like kinase (NLK) is a suppressor of tumor necrosis factor (TNFα)-induced NF-κB signaling by inhibiting the phosphorylation of IKKβ. Overexpression of NLK largely blocked TNFα-induced NF-κB activation, p65 nuclear localization and IκBα degradation; whereas genetic inactivation of NLK showed opposing results. Mechanistically, we identified that NLK interacted with IκB kinase (IKK)-associated complex, which in turn inhibited the assembly of the TAK1/IKKβ and thereby, diminished the IκB kinase phosphorylation. Our results indicate that NLK functions as a pivotal negative regulator in TNFα-induced activation of NF-κB via disrupting the interaction of TAK1 with IKKβ.
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
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.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
NLK has the ability to inhibit NFκB signalling via the IKK-complex and inhibition of p65 translocation.
“NLK has the ability to inhibit NFκB signalling via IKK-complex and inhibition of p65 translocation [25].”
From Nemo-Like Kinase in Development and Diseases: Insights from Mouse Studies (2020) · cites this paper as [25]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Ishitani, T., Ninomiya-Tsuji, J., Nagai, S.-I., Nishita, M., Meneghini, M., Barker, N., Waterman, M., Bowerman, B., Clevers, H., Shibuya, H., et al. (1999) · Nature · doi:10.1038/21674 · Cited by 624 · see citing works
Flagged first, then by citations
Research works printed but not linked: 30
- [1]Baldwin AS Control of oncogenesis and cancer therapy resistance by the transcription factor NF-kappaB J. Clin. Invest 2001 107 241 246 11160144 PMC199203
- [2]Karin M Greten FR NF-κB: linking inflammation and immunity to cancer development and progression Nat. Rev. Immunol 2005 5 749 759 16175180
- [3]Hinz M Scheidereit C The IkappaB kinase complex in NF-kappaB regulation and beyond EMBO Rep 2014 15 46 461 24375677 PMC4303448
- [4]Wan F Lenardo MJ The nuclear signaling of NF-kappaB: current knowledge, new insights, and future perspectives Cell Res 2010 20 24 33 19997086 PMC3052775
- [5]Zandi E Chen Y Karin M Direct phosphorylation of IkappaB by IKKalpha and IKKbeta: discrimination between free and NF-kappaB-bound substrate Science 1998 281 1360 1363 9721103
- [6]Shambharkar PB Blonska M Pappu BP Li H You Y Sakurai H Darnay BG Hara H Penninger J Lin X Phosphorylation and ubiquitination of the IkappaB kinase complex by two distinct signaling pathways EMBO J 2007 26 1794 1805 17363905 PMC1847656
- [7]Li Q Verma IM NF-κB regulation in the immune system Nat. Rev. Immunol 2002 2 725 734 12360211
- [8]Li D Selective degradation of the IkappaB kinase (IKK) by autophagy Cell Res 2006 16 855 856 17109011
- [9]Tergaonkar V Bottero V Ikawa M Li Q Verma IM IkappaB kinase-independent IkappaBalpha degradation pathway: functional NF-kappaB activity and implications for cancer therapy Mol. Cell. Biol 2003 23 8070 8083 14585967 PMC262380
- [10]Baker RG Hayden MS Ghosh S NF-kappaB, inflammation, and metabolic disease Cell Metab 2011 13 11 22 21195345 PMC3040418
- [11]Cao X Pobezinskaya YL Morgan MJ Liu ZG The role of TRADD in TRAIL-induced apoptosis and signaling FASEB J 2011 25 1353 1358 21187341 PMC3058711
- [12]Lin WJ Su YW Lu YC Hao Z Chio II Chen NJ Brustle A Li WY Mak TW Crucial role for TNF receptor-associated factor 2 (TRAF2) in regulating NFkappaB2 signaling that contributes to autoimmunity Proc. Natl. Acad. Sci. U. S. A 2011 108 18354 18359 22042853 PMC3215017
- [13]Chen ZJ Ubiquitination in signaling to and activation of IKK Immunol. Rev 2012 246 95 106 22435549 PMC3549672
- [14]Hayden MS Ghosh S Shared principles in NF-kappaB signaling Cell 2008 132 344 362 18267068
- [15]Israel A The IKK complex, a central regulator of NF-kappaB activation Cold Spring Harb. Perspect. Biol 2010 2 a000158 20300203 PMC2829958
- [16]DiDonato JA Hayakawa M Rothwarf DM Zandi E Karin M A cytokine-responsive IκB kinase that activates the transcription factor NF-κB Nature 1997 388 548 554 9252186
- [17]Zandi E Rothwarf DM Delhase M Hayakawa M Karin M The IκB kinase complex (IKK) contains two kinase subunits, IKKα and IKKβ, necessary for IκB phosphorylation and NF-κB activation Cell 1997 91 243 252 9346241
- [18]Li Q Estepa G Memet S Israel A Verma IM Complete lack of NF-κB activity in IKK1 and IKK2 double-deficient mice: additional defect in neurulation Gene Dev 2000 14 1729 1733 10898787 PMC316792
- [19]Takaesu G Surabhi RM Park K-J Ninomiya-Tsuji J Matsumoto K Gaynor RB TAK1 is critical for IκB kinase-mediated activation of the NF-κB pathway J. Mol. Biol 2003 326 105 115 12547194
- [20]Wang C Deng L Hong M Akkaraju GR Inoue J-i Chen ZJ TAK1 is a ubiquitin-dependent kinase of MKK and IKK Nature 2001 412 346 351 11460167
- [21]Brott BK Pinsky BA Erikson RL Nlk is a murine protein kinase related to Erk/MAP kinases and localized in the nucleus Proc. Natl. Acad. Sci 1998 95 963 968 9448268 PMC18639
- [22]Rago C Vogelstein B Bunz F Genetic knockouts and knockins in human somatic cells Nat. Protoc 2007 2 2734 2746 18007609
- [23]Zhang X Guo C Chen Y Shulha HP Schnetz MP LaFramboise T Bartels CF Markowitz S Weng Z Scacheri PC Epitope tagging of endogenous proteins for genome-wide ChIP-chip studies Nat. Methods 2008 5 163 165 18176569 PMC2435063
- [24]Yasuda J Yokoo H Yamada T Kitabayashi I Sekiya T Ichikawa H Nemo-like kinase suppresses a wide range of transcription factors, including nuclear factor-kappaB Cancer Sci 2004 95 52 57 14720327 PMC11158368
- [25]Ishitani S Inaba K Matsumoto K Ishitani T Homodimerization of nemo-like kinase is essential for activation and nuclear localization Mol. Biol. Cell 2011 22 266 277 21118996 PMC3020921
- [26]Vasileva A Linden RM Jessberger R Homologous recombination is required for AAV-mediated gene targeting Nucleic Acids Res 2006 34 3345 3360 16822856 PMC1488886
- [27]Chen Z Hagler J Palombella VJ Melandri F Scherer D Ballard D Maniatis T Signal-induced site-specific phosphorylation targets I kappa B alpha to the ubiquitin-proteasome pathway Gene Dev 1995 9 1586 1597 7628694
- [29]Yamada M Ohkawara B Ichimura N Hyodo-Miura J Urushiyama S Shirakabe K Shibuya H Negative regulation of Wnt signalling by HMG2L1, a novel NLK-binding protein Genes Cells 2003 8 677 684 12875653
- [30]Scherer DC Brockman JA Chen Z Maniatis T Ballard DW Signal-induced degradation of I kappa B alpha requires site-specific ubiquitination Proc. Natl. Acad. Sci 1995 92 11259 11263 7479976 PMC40611
- [31]Delhase M Hayakawa M Chen Y Karin M Positive and negative regulation of IκB kinase activity through IKKβ subunit phosphorylation Science 1999 284 309 313 10195894
Cited by
Sorted by citations
Selective suppression of the α isoform of p38 MAPK rescues late-stage tau pathology
Maphis, N., Jiang, S., Xu, G., Kokiko-Cochran, O. N., Roy, S. M., Van Eldik, L. J., Watterson, D. M., Lamb, B. T., & Bhaskar, K. (2016) · Alzheimer's Research & Therapy · doi:10.1186/s13195-016-0221-y · Cited by 144 · see citing works
Nemo-Like Kinase in Development and Diseases: Insights from Mouse Studies
Daams, R., & Massoumi, R. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21239203 · Cited by 21 · see citing works
“NLK has the ability to inhibit NFκB signalling via IKK-complex and inhibition of p65 translocation [25].”
BackgroundTejwani, L., Jung, Y., Kokubu, H., Sowmithra, S., Ni, L., Lee, C., Sanders, B., Lee, P. J., Xiang, Y., Luttik, K., et al. (2023) · Journal of Clinical Investigation · doi:10.1172/jci138207 · Cited by 17 · see citing works
“…are involved in central nervous system disorders (9) as well as indirectly to affect inflammation through altered NF-κ B transcriptional activity (10), the physiological role of Nlk and the general effects of its modulation in the adult nervous system have not yet been comprehensively examined.”
- Authors
- Li, S.-Z., Zhang, H.-H., Liang, J.-B., Song, Y., Jin, B.-X., Xing, N.-N., Fan, G.-C., Du, R.-L., & Zhang, X.-D.
- Affiliations
- Wuhan University (CN)
- University of Cincinnati (US)
- Corresponding author
- Du, Run-Lei
- Venue
- Biochimica et Biophysica Acta (BBA) - Molecular Cell Research
- Publisher
- Elsevier BV
- Published
- 2014-07
- Volume
- 1843
- Issue
- 7
- Pages
- 1365-1372
- ISSN
- 0167-4889 (ISSN-L)
- PMC
- PMC4655877
- OpenAlex
- W1979414462
- Cited by
- 35
- References
- 1
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 2 · 2023: 2 · 2022: 5 · 2021: 4 · 2020: 2 · 2019: 3 · 2018: 2 · 2017: 1 · 2016: 5 · 2015: 2 · 2014: 1
- FWCI
- 0.96
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Biochimica et Biophysica Acta (BBA) - Molecular Cell Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Basic Research Program of China (2011CB944404)
- National Natural Science Foundation of China (81270306, 30971499)
- Trans-Century Training Program Foundation for the Talents by the State Education Commission (NCET-10-0655)
- Fundamental Research Funds for the Central Universities (204275771)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Signaling Pathways in Disease
- Health Sciences › Medicine › Complementary and alternative medicine › Natural Compounds in Disease Treatment
- Keywords
- Nemo-like kinase, NF-κB signaling, TAK1, IKKβ, TNF-α, negative regulation of NF-κB, IκBα degradation, protein-protein interaction, kinase phosphorylation
- MeSH terms
- MAP Kinase Kinase Kinase 7, Cell Nucleus, Gene Expression Regulation, Humans, Phosphorylation, Protein Binding, Tumor Necrosis Factor-alpha, Signal Transduction, NF-kappa B, Protein Serine-Threonine Kinases, MAP Kinase Kinase Kinases, RNA, Small Interfering, HCT116 Cells, Intracellular Signaling Peptides and Proteins, I-kappa B Kinase, HEK293 Cells, Proteolysis
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
