Nemo-like kinase suppresses Notch signalling by interfering with formation of the Notch active transcriptional complex
Open accessAbstract
The Notch signalling pathway has a crucial function in determining cell fates in multiple tissues within metazoan organisms. On binding to ligands, the Notch receptor is cleaved proteolytically and releases its intracellular domain (NotchICD). The NotchICD enters the nucleus and acts cooperatively with other factors to stimulate the transcription of target genes. High levels of Notch-mediated transcriptional activation require the formation of a ternary complex consisting of NotchICD, CSL (CBF-1, suppressor of hairless, LAG-1) and a Mastermind family member. However, it is still not clear how the formation of the ternary complex is regulated. Here we show that Nemo-like kinase (NLK) negatively regulates Notch-dependent transcriptional activation by decreasing the formation of this ternary complex. Using a biochemical screen, we identified Notch as a new substrate of NLK. NLK-phosphorylated Notch1ICD is impaired in its ability to form a transcriptionally active ternary complex. Furthermore, knockdown of NLK leads to hyperactivation of Notch signalling and consequently decreases neurogenesis in zebrafish. Our results both define a new function for NLK and reveal a previously unidentified mode of regulation in the Notch signalling pathway.
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NLK is a negative regulator of Notch-dependent transcriptional activation by phosphorylating NotchICD and thereby decreasing formation of the ternary complex.
“NLK is a negative regulator of Notch-dependent transcriptional activation by phosphorylating NotchICD and thereby decreasing the formation of this ternary complex [26].”
From Nemo-Like Kinase in Development and Diseases: Insights from Mouse Studies (2020) · cites this paper as [26]
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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
Self-citationRotation of photoreceptor clusters in the developing drosophila eye requires the nemo gene
Choi, K.-W., & Benzer, S. (1994) · Cell · doi:10.1016/0092-8674(94)90579-7 · Cited by 339 · see citing works
Variable Control of Ets-1 DNA Binding by Multiple Phosphates in an Unstructured Region
Pufall, M. A., Lee, G. M., Nelson, M. L., Kang, H.-S., Velyvis, A., Kay, L. E., McIntosh, L. P., & Graves, B. J. (2005) · Science · doi:10.1126/science.1111915 · Cited by 246 · see citing works
Ishitani, T., Ninomiya-Tsuji, J., & Matsumoto, K. (2003) · Molecular and Cellular Biology · doi:10.1128/mcb.23.4.1379-1389.2003 · Cited by 212 · see citing works
Self-citationTakke, C., Dornseifer, P., Weizsäcker, E. V., & Campos-Ortega, J. A. (1999) · Development · doi:10.1242/dev.126.9.1811 · Cited by 192 · see citing works
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Research works printed but not linked: 3
- Oyama, T., Harigaya, K., Muradil, A., Hozumi, K., Habu, S., Oguro, H., Iwama, A., Matsuno, K., Sakamoto, R., Sato, M., Yoshida, N., & Kitagawa, M. Mastermind-1 is required for Notch signal-dependent steps in lymphocyte development in vivo. Proc. Natl. Acad. Sci. U. S. A. 104, 9764-9769 (2007).
- Kojima, H., Sasaki, T., Ishitani, T., Iemura, S., Zhao, H., et al. STAT3 regulates Nemo-like kinase by mediating its interaction with IL-6-stimulated TGF-activated kinase 1 for STAT3 Ser-727 phosphorylation. Proc. Natl. Acad. Sci. U. S. A. 102, 4524- 4529 (2005).
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Fine-tuning of the intracellular canonical Notch signaling pathway
Borggrefe, T., & Liefke, R. (2012) · Cell Cycle · doi:10.4161/cc.11.2.18995 · Cited by 102 · 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 is a negative regulator of Notch-dependent transcriptional activation by phosphorylating NotchICD and thereby decreasing the formation of this ternary complex [26].”
BackgroundNemo-like kinase disrupts nuclear import and drives TDP43 mislocalization in ALS
Bekier, M. E., Pinarbasi, E., Krishnan, G., Mesojedec, J. J., Hurley, M., Harikumar Sheela, H., Collins, C. A., Ghaffari, L., de Majo, M., Ullian, E. M., et al. (2025) · Journal of Clinical Investigation · doi:10.1172/jci188138 · Cited by 2 · see citing works
“FLAG-NLK-WT and FLAG-NLK-KN were a gift from Tohru Ishitani Ishitani (Unit on Nervous Development Systems, Nagoya, Japan) (77).”
- Authors
- Ishitani, T., Hirao, T., Suzuki, M., Isoda, M., Ishitani, S., Harigaya, K., Kitagawa, M., Matsumoto, K., & Itoh, M.
- Affiliations
- Kyushu University (JP)
- Chiba University (JP)
- Nagoya University Institute for Advanced Research (JP)
- Corresponding author
- Ishitani, Tohru
- Itoh, Motoyuki
- Venue
- Nature Cell Biology
- Published
- 2010-01-31
- Volume
- 12
- Issue
- 3
- Pages
- 278-285
- ISSN
- 1465-7392 (ISSN-L)
- 1476-4679
- OpenAlex
- W2018588361
- Cited by
- 131
- References
- 5
- Citations by year
- 2026: 4 · 2025: 5 · 2024: 3 · 2023: 3 · 2022: 8 · 2021: 5 · 2020: 7 · 2019: 4 · 2018: 7 · 2017: 10 · 2016: 5 · 2015: 10 · 2014: 9 · 2013: 13 · 2012: 21
- FWCI
- 6.52
- Type
- journal article
- Language
- en
- Open access
- green
- hdl.handle.net
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Cell Biology (publishedVersion)
- PubMed (publishedVersion)
- Institutional Repositories DataBase (IRDB) (submittedVersion)
- Kyushu University Institutional Repository (QIR) (Kyushu University) (submittedVersion, other-oa)
- Funders
- Ministry of Education, Culture, Sports, Science and Technology
- Astellas Pharma
- Astellas Foundation for Research on Metabolic Disorders
- Japan Society for the Promotion of Science (21247031, 19687013)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- Nemo-like kinase, Notch signaling, Notch1 intracellular domain, CSL transcription factor, protein phosphorylation, transcriptional activation, neurogenesis, zebrafish
- MeSH terms
- ELAV-Like Protein 3, Transcription Factor HES-1, Animals, DNA, Embryo, Nonmammalian, Gene Expression Regulation, Humans, Models, Biological, Nerve Tissue Proteins, Nuclear Proteins, Phosphorylation, Protein Binding, Transcription Factors, Transfection, Xenopus, Zebrafish, Signal Transduction, Oligonucleotides, Antisense, Protein Serine-Threonine Kinases, Homeodomain Proteins, Amino Acid Substitution, Mitogen-Activated Protein Kinases, Zebrafish Proteins, RNA, Small Interfering, Cell Line, Tumor, Intracellular Signaling Peptides and Proteins, Mice, Basic Helix-Loop-Helix Transcription Factors, Basic Helix-Loop-Helix Proteins, Immunoglobulin J Recombination Signal Sequence-Binding Protein, Receptors, Notch, Receptor, Notch1, ELAV Proteins, Protein Interaction Domains and Motifs, Neurogenesis
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