NLK-mediated phosphorylation of HDAC1 negatively regulates Wnt signaling
Open accessAbstract
The Wnt signaling pathway is essential in regulating various cellular processes. Different mechanisms of inhibition for Wnt signaling have been proposed. Besides β-catenin degradation through the proteasome, nemo-like kinase (NLK) is another molecule that is known to negatively regulate Wnt signaling. However, the mechanism by which NLK mediates the inhibition of Wnt signaling was not known. In the present study, we used primary embryonic fibroblast cells isolated from NLK-deficient mice and showed that these cells proliferate faster and have a shorter cell cycle than wild-type cells. In NLK-knockout cells, we observed sustained interaction between Lef1 and β-catenin, leading to elevated luciferase reporter of β-catenin/Lef1–mediated transcriptional activation. The mechanism for the reduced β-catenin/Lef1 promoter activation was explained by phosphorylation of HDAC1 at serine 421 via NLK. The phosphorylation of HDAC1 was achieved only in the presence of wild-type NLK because a catalytically inactive mutant of NLK was unable to phosphorylate HDAC1 and reduced the luciferase reporter of β-catenin/Lef1–mediated transcriptional activation. This result suggests that NLK and HDAC1 together negatively regulate Wnt signaling, which is vital in preventing aberrant proliferation of nontransformed primary fibroblast cells.
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Inhibition of class I HDACs is associated with activation of Wnt/β-catenin signaling.
“It has been demonstrated that inhibition of class I HDACs is associated with activation of Wnt/β-catenin signaling [42–47].”
From CI-994 is a dual modulator of class I HDACs and Wnt/β-catenin signaling for the treatment of Alzheimer's disease (2026) · cites this paper as [44]
The Results section reports that active HDAC1 represses a Wnt/β-catenin-responsive Tcf/Lef reporter, while a catalytically inactive HDAC1 mutant does not. The Discussion identifies HDAC1 as a class I HDAC. The paper therefore supports a role for HDAC1 activity in limiting this signaling, but does not demonstrate that inhibition of class I HDACs as a group activates it. (LLM, conf=0.84)
Experimental — accuracy not yet measuredA growing body of evidence shows that inhibition of class I HDACs results in activation of Wnt/β-catenin signaling.
“A growing body of evidence shows that inhibition of class I HDACs results in activation of Wnt/β-catenin signaling.”
From CI-994 is a dual modulator of class I HDACs and Wnt/β-catenin signaling for the treatment of Alzheimer's disease (2026) · cites this paper as [44]
The Results section (Figure 6) reports that active HDAC1 represses Tcf/Lef reporter activity in MEF cells, while a deacetylase-inactive HDAC1 mutant does not. The Discussion identifies HDAC1 as a class I HDAC. These findings support a role for HDAC1 activity in limiting Wnt signaling, but the paper does not show that inhibition of class I HDACs generally activates Wnt/β-catenin signaling. (LLM, conf=0.85)
Experimental — accuracy not yet measuredActivation of NLK can directly phosphorylate HDAC1, which in turn binds to LEF1 followed by repressed transcriptional activation of Wnt-target genes, including those supporting cell proliferation.
“It was shown that activation of NLK can directly phosphorylate HDAC1, which in turn binds to LEF1 followed by repressed transcriptional activation of Wnt-target genes, including those supporting cell proliferation [37].”
From Nemo-Like Kinase in Development and Diseases: Insights from Mouse Studies (2020) · cites this paper as [37]
Endogenous Wnt inhibitory protein NLK negatively regulates Wnt/β-catenin signaling via mediating HDAC1 phosphorylation.
“Fourthly, endogenous Wnt inhibitory protein NLK negatively regulates Wnt/β-catenin signaling via mediating HDAC1 phosphorylation [44].”
From CI-994 is a dual modulator of class I HDACs and Wnt/β-catenin signaling for the treatment of Alzheimer's disease (2026) · cites this paper as [44]
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Cites
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“Previously it was shown that Lef1 phosphorylation by NLK prevents the binding of Lef1 to the promoter/DNA (Ishitani et al., 2003).”
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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
“It was shown that activation of NLK can directly phosphorylate HDAC1, which in turn binds to LEF1 followed by repressed transcriptional activation of Wnt-target genes, including those supporting cell proliferation [37].”
BackgroundSelf-citationLu, W., Kawatani, K., Ren, Y., Nambara, T., Jia, L., Jeevaratnam, S., Lee, E., Martinez, P. R., Izhar, T., Wang, N., et al. (2026) · Alzheimer's Research & Therapy · doi:10.1186/s13195-026-01982-0 · Cited by 4 · see citing works
- Authors
- Masoumi, K. C., Daams, R., Sime, W., Siino, V., Ke, H., Levander, F., & Massoumi, R.
- Affiliations
- Lund University (SE)
- Corresponding author
- Massoumi, Ramin
- ORCID
- Venue
- Molecular Biology of the Cell
- Published
- 2017-01-15
- Volume
- 28
- Issue
- 2
- Pages
- 346-355
- ISSN
- 1059-1524 (ISSN-L)
- 1939-4586
- PMC
- PMC5231902
- OpenAlex
- W2558144809
- Cited by
- 35
- References
- 3
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 5 · 2023: 2 · 2022: 4 · 2021: 2 · 2020: 4 · 2019: 8 · 2018: 2 · 2017: 1
- FWCI
- 1.91
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- cc-by-nc-sa
- Locations
- Molecular Biology of the Cell (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- Lund University Publications (Lund University) (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 › Hedgehog Signaling Pathway Studies
- Keywords
- Nemo-like kinase, HDAC1, Wnt signaling, β-catenin, LEF1, protein phosphorylation, transcriptional repression, cell proliferation, cell cycle, embryonic fibroblasts
- MeSH terms
- Animals, Cell Cycle, Fibroblasts, Phosphorylation, Transcription Factors, Signal Transduction, Transcriptional Activation, Trans-Activators, Protein Serine-Threonine Kinases, Mice, Knockout, Mitogen-Activated Protein Kinases, MAP Kinase Kinase Kinases, Wnt Proteins, beta Catenin, Lymphoid Enhancer-Binding Factor 1, Histone Deacetylase 1, Wnt Signaling Pathway, Primary Cell Culture
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