The TAK1–NLK–MAPK-related pathway antagonizes signalling between β-catenin and transcription factor TCF
Abstract
The Wnt signalling pathway regulates many developmental processes through a complex of beta-catenin and the T-cell factor/lymphoid enhancer factor (TCF/LEF) family of high-mobility-group transcription factors. Wnt stabilizes cytosolic beta-catenin, which then binds to TCF and activates gene transcription. This signalling cascade is conserved in vertebrates, Drosophila and Caenorhabditis elegans. In C. elegans, the proteins MOM-4 and LIT-1 regulate Wnt signalling to polarize responding cells during embryogenesis. MOM-4 and LIT-1 are homologous to TAK1 (a kinase activated by transforming growth factor-beta) mitogen-activated protein-kinase-kinase kinase (MAP3K) and MAP kinase (MAPK)-related NEMO-like kinase (NLK), respectively, in mammalian cells. These results raise the possibility that TAK1 and NLK are also involved in Wnt signalling in mammalian cells. Here we show that TAK1 activation stimulates NLK activity and downregulates transcriptional activation mediated by beta-catenin and TCF. Injection of NLK suppresses the induction of axis duplication by microinjected beta-catenin in Xenopus embryos. NLK phosphorylates TCF/LEF factors and inhibits the interaction of the beta-catenin-TCF complex with DNA. Thus, the TAK1-NLK-MAPK-like pathway negatively regulates the Wnt signalling pathway.
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The effect of mammalian NLK on Wnt signaling depends on cell type: suppressive in 293 and DLD-1, positive in SaOS-2, NB39-nu, and Nh12.
“Thus, the effect of mammalian NLK on Wnt signaling seems to depend on the cell type; NLK plays some suppressive role in Wnt signaling in 29317) and DLD-1 cell lines30) and a positive role in SaOS-2, NB39-nu and Nh12 cell lines (the present study).”
From Mammalian Nemo-like kinase enhances .BETA.-catenin-TCF transcription activity in human osteosarcoma and neuroblastoma cells (2007) · cites this paper as [17]
Flag-NLK suppresses pTOPFLASH reporter gene expression in 293 cells.
“In 293 cells, Flag-NLK suppressed reporter gene expression, a finding in agreement with previous reports.17), 34)”
From Mammalian Nemo-like kinase enhances .BETA.-catenin-TCF transcription activity in human osteosarcoma and neuroblastoma cells (2007) · cites this paper as [17]
NLK suppresses the transcriptional activity of the β-catenin-TCF complex through phosphorylation of TCF in human 293 cells.
“Ishitani et al. correspondingly reported that NLK could suppress the transcriptional activity of the β-catenin-TCF complex through phosphorylation of TCF in human 293 cells.17)”
From Mammalian Nemo-like kinase enhances .BETA.-catenin-TCF transcription activity in human osteosarcoma and neuroblastoma cells (2007) · cites this paper as [17]
DNA binding of LEF1 decreases with its phosphorylation at threonine 155 and serine 166 by overexpression of NLK.
“Ishitani et al. suggested that DNA binding of LEF1 decreased with its phosphorylation at threonine 155 and serine 166 by overexpression of NLK.17), 34)”
From Mammalian Nemo-like kinase enhances .BETA.-catenin-TCF transcription activity in human osteosarcoma and neuroblastoma cells (2007) · cites this paper as [17]
Active NLK phosphorylates LEF-1/TCF and prevents the β-catenin-TCF complex from binding to DNA, thereby inhibiting β-catenin-TCF transcriptional activation.
“Active NLK phosphorylates LEF-1/TCF and prevents the β-catenin-TCF complex from binding to DNA, thereby inhibiting the ability of β-catenin-TCF to activate transcription.”
TAK1 functions upstream of NLK and enhances NLK kinase activity.
“TAK1 functions upstream of NLK and enhances NLK kinase activity.”
The Wnt signaling pathway in mammalian cells is regulated by a MAPK-related pathway composed of TAK1 and NLK.
“Recent evidence indicates that the Wnt signaling pathway in mammalian cells is also regulated by a MAPK-related pathway composed of MAPK kinase kinase TAK1 and MAPK-related NLK (13).”
Ectopic expression of NLK blocks double-axis formation in Xenopus induced by overexpression of β-catenin but not by the downstream components siamois and twin.
“Consistent with this, ectopic expression of NLK blocks double-axis formation in Xenopus induced by overexpression of β-catenin but not by the downstream components siamois and twin (13).”
NLK interacts with the β-catenin-LEF-1/TCF complex.
“We have previously shown that NLK interacts with the β-catenin-LEF-1/TCF complex (13).”
NLK phosphorylates TCF-4 in vitro even in the absence of β-catenin transfection.
“As observed previously (13), NLK phosphorylated TCF-4 in vitro even in the absence of β-catenin transfection (Fig. 2, bottom panel, lane 4).”
NLK associates with TCF-4.
“We have previously shown that NLK associates with TCF-4 (13).”
The mobility shifts of LEF-1 and TCF-4 on SDS-PAGE are due to phosphorylation.
“These mobility shifts were shown to be due to phosphorylation (13).”
NLK phosphorylates TCF-4 and prevents the β-catenin-TCF-4 complex from binding DNA.
“We have previously shown that NLK phosphorylates TCF-4 and prevents the β-catenin-TCF-4 complex from binding DNA (13).”
NLK phosphorylation of TCF-4 prevents the β-catenin-TCF-4 complex from binding DNA.
“Thus, as observed previously (13), NLK phosphorylation of TCF-4 prevents the β-catenin-TCF-4 complex from binding DNA.”
NLK phosphorylation inhibits β-catenin-mediated transcription through LEF-1/TCF-binding sites in Wnt pathway-responsive promoters.
“and thereby inhibits β-catenin-mediated transcription through LEF-1/TCF-binding sites in Wnt pathway-responsive promoters.”
NLK phosphorylation does not disrupt the formation of a complex between LEF-1/TCF and β-catenin.
“This phosphorylation does not disrupt the formation of a complex between LEF-1/TCF and β-catenin”
In vivo, coinjection of NLK RNA into early Xenopus embryos results in the inhibition of double-axis formation by β-catenin.
“In vivo, coinjection of NLK RNA into early Xenopus embryos results in the inhibition of double-axis formation by β-catenin.”
NLK phosphorylation prevents DNA binding of the β-catenin-TCF-4 complex.
“yet it does prevent DNA binding of the β-catenin-TCF-4 complex”
NLK directly interacts with and phosphorylates TCF-4.
“Mechanistically, NLK directly interacts with and phosphorylates TCF-4.”
In both C. elegans and mammalian cells, the Nemo-like kinases LIT-1 and NLK, respectively, phosphorylate LEF-1/TCF.
“Furthermore, in both C. elegans and mammalian cells, the Nemo-like kinases LIT-1 and NLK, respectively, phosphorylate LEF-1/TCF.”
Phosphorylation inhibits LEF-1/TCF signaling by disruption of DNA binding.
“Phosphorylation inhibits LEF-1/TCF signaling by disruption of DNA binding (13)”
NLK can regulate the transcriptional activity of a β-catenin-LEF-1/TCF complex.
“We have previously demonstrated that NLK can regulate the transcriptional activity of a β-catenin-LEF-1/TCF complex (13).”
Phosphorylation of TCF4 by NLK prevents DNA binding of the β-catenin-TCF4 complex and limits β-catenin-mediated target gene transcription through TCF/LEF.
“This phosphorylation prevents DNA binding of the β-catenin-TCF4 complex and limits β-catenin-mediated target gene transcription through TCF/LEF [16,17].”
From Nemo-Like Kinase in Development and Diseases: Insights from Mouse Studies (2020) · cites this paper as [16]
NLK can regulate the transcriptional activity of the β-catenin-LEF/TCF complex by directly phosphorylating TCF4.
“Previous studies showed that NLK can regulate the transcriptional activity of the β-catenin-LEF/TCF complex by directly phosphorylating TCF4.”
From Nemo-Like Kinase in Development and Diseases: Insights from Mouse Studies (2020) · cites this paper as [16]
In vertebrates, NLK is considered to be a negative regulator of the Wnt signalling pathway.
“In vertebrates, NLK is considered to be a negative regulator of the Wnt signalling pathway.”
From Nemo-Like Kinase in Development and Diseases: Insights from Mouse Studies (2020) · cites this paper as [16]
NLK proteins function as important regulators of cell growth, patterning, and death by controlling diverse signaling pathways including Wnt and Notch pathways.
“Across species, NLK proteins function as important regulators of cell growth, patterning, and death by controlling diverse signaling pathways including Wnt and Notch pathways (Ishitani et al., 1999; Meneghini et al., 1999; Rocheleau et al., 1999; Verheyen et al., 2001; Rottinger et al., 2006).”
From Polyglutamine Disease Toxicity Is Regulated by Nemo-like Kinase in Spinocerebellar Ataxia Type 1 (2013) · cites this paper as Ishitani et al., 1999
CamKII activates TGFβ activated kinase (TAK1) and Nemo-like kinase (NLK) which can antagonize β-catenin/TCF signaling.
“CamK11 has also been shown to activate TGFβ activated kinase (TAK1) and Nemo-like kinase (NLK) which can antagonize β-catenin/TCF signaling.99”
From Wnt signal transduction pathways (2008) · cites this paper as [99]
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- Authors
- Ishitani, T., Ninomiya-Tsuji, J., Nagai, S.-I., Nishita, M., Meneghini, M., Barker, N., Waterman, M., Bowerman, B., Clevers, H., Shibuya, H., & Matsumoto, K.
- Affiliations
- Nagoya University (JP)
- National Institute for Basic Biology (JP)
- University of Oregon (US)
- University of California, Irvine (US)
- Corresponding author
- Matsumoto, Kunihiro
- ORCID
- Venue
- Nature
- Published
- 1999-06
- Volume
- 399
- Issue
- 6738
- Pages
- 798-802
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W1902879109
- Cited by
- 624
- References
- 28
- Citations by year
- 2026: 3 · 2025: 9 · 2024: 15 · 2023: 14 · 2022: 5 · 2021: 22 · 2020: 16 · 2019: 11 · 2018: 18 · 2017: 20 · 2016: 17 · 2015: 22 · 2014: 25 · 2013: 20 · 2012: 33
- FWCI
- 12.27
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- KNAW research portal (Royal Academy of Art and Sciences (KNAW)) (publishedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- KNAW Research Portal (The Royal Netherlands Academy of Arts and Sciences) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Signaling Pathways in Disease
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Keywords
- Wnt signaling, β-catenin, TCF/LEF transcription factors, TAK1, Nemo-like kinase, MAP3K, DNA binding inhibition, axis duplication
- MeSH terms
- MAP Kinase Kinase Kinase 7, Animals, Cytoskeletal Proteins, DNA, Humans, Mutation, Phosphorylation
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