Increasing β-catenin/Wnt3A activity levels drive mechanical strain-induced cell cycle progression through mitosis
Open accessAbstract
Mechanical force and Wnt signaling activate β-catenin-mediated transcription to promote proliferation and tissue expansion. However, it is unknown whether mechanical force and Wnt signaling act independently or synergize to activate β-catenin signaling and cell division. We show that mechanical strain induced Src-dependent phosphorylation of Y654 β-catenin and increased β-catenin-mediated transcription in mammalian MDCK epithelial cells. Under these conditions, cells accumulated in S/G2 (independent of DNA damage) but did not divide. Activating β-catenin through Casein Kinase I inhibition or Wnt3A addition increased β-catenin-mediated transcription and strain-induced accumulation of cells in S/G2. Significantly, only the combination of mechanical strain and Wnt/β-catenin activation triggered cells in S/G2 to divide. These results indicate that strain-induced Src phosphorylation of β-catenin and Wnt-dependent β-catenin stabilization synergize to increase β-catenin-mediated transcription to levels required for mitosis. Thus, local Wnt signaling may fine-tune the effects of global mechanical strain to restrict cell divisions during tissue development and homeostasis.
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A role for Wnt signaling during M phase has been suggested based on high Wnt/β-catenin signaling activity during cell division.
“A role for Wnt signaling during M phase has also been suggested based on high Wnt/β-catenin signaling activity during cell division, through an unknown mechanism (39, 40).”
From Wnt signaling regulates hepatocyte cell division by a transcriptional repressor cascade (2022) · cites this paper as [40]
The Discussion reports that higher Wnt3A/β-catenin activity drove mechanically strained cells from G2 into mitosis, supporting a suggested role in mitotic progression. It does not establish that signaling activity was high during M phase itself; the reported activity concerns progression into mitosis. (LLM, conf=0.83)
Experimental — accuracy not yet measuredHigh Wnt/βcatenin signaling activity during cell division suggests a link between Wnt signaling and mitosis.
“High Wnt/βcatenin signaling activity during cell division has suggested a link between Wnt signaling and mitosis through unknown mechanisms (Benham-Pyle et al. 2016;Niehrs and Acebron 2012).”
From Hepatocyte Cell Cycle Progression Depends on a Transcriptional Repressor Cascade Downstream of Wnt Signaling (2021) · cites this paper as Benham-Pyle et al. 2016
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Wnt Signaling through Inhibition of β-Catenin Degradation in an Intact Axin1 Complex
Li, V. S. W., Ng, S. S., Boersema, P. J., Low, T. Y., Karthaus, W. R., Gerlach, J. P., Mohammed, S., Heck, A. J. R., Maurice, M. M., Mahmoudi, T., et al. (2012) · Cell · doi:10.1016/j.cell.2012.05.002 · Cited by 889 · cited 3× · see citing works
“When Wnt ligand binds to Frizzled/LRP receptors, Axin is recruited to the plasma membrane and CKI/GSK3b are inactivated, resulting in inhibition of b-catenin ubiquitination and degradation (Li et al., 2012; Vinyoles et al., 2014).”
BackgroundA Specific Inhibitor of the Epidermal Growth Factor Receptor Tyrosine Kinase
Fry, D. W., Kraker, A. J., McMichael, A., Ambroso, L. A., Nelson, J. M., Leopold, W. R., Connors, R. W., & Bridges, A. J. (1994) · Science · doi:10.1126/science.8066447 · Cited by 806 · see citing works
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Wnt signaling regulates hepatocyte cell division by a transcriptional repressor cascade
Jin, Y., Anbarchian, T., Wu, P., Sarkar, A., Fish, M., Peng, W. C., & Nusse, R. (2022) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2203849119 · Cited by 26 · see citing works
“A role for Wnt signaling during M phase has also been suggested based on high Wnt/β-catenin signaling activity during cell division, through an unknown mechanism (39, 40).”
BackgroundRabben, H.-L., Andersen, G. T., Ianevski, A., Olsen, M. K., Kainov, D., Grønbech, J. E., Wang, T. C., Chen, D., & Zhao, C.-M. (2021) · Frontiers in Pharmacology · doi:10.3389/fphar.2021.625991 · Cited by 24 · see citing works
Jin, Y., Anbarchian, T., Wu, P., Sarkar, A., Fish, M., & Nusse, R. (2021) · doi:10.1101/2021.10.15.464616 · Cited by 2 · see citing works
- Authors
- Benham-Pyle, B. W., Sim, J. Y., Hart, K. C., Pruitt, B. L., & Nelson, W. J.
- Affiliations
- Stanford University (US)
- Stanford Cardiovascular Institute (US)
- Corresponding author
- Nelson, William James
- Venue
- eLife
- Publisher
- eLife Sciences Publications, Ltd
- Published
- 2016-10-26
- Volume
- 5
- ISSN
- 2050-084X (ISSN-L)
- PMC
- PMC5104517
- OpenAlex
- W2541569086
- Cited by
- 46
- References
- 2
- Citations by year
- 2026: 3 · 2025: 1 · 2024: 2 · 2023: 1 · 2022: 10 · 2021: 10 · 2020: 5 · 2019: 6 · 2018: 7 · 2017: 1
- FWCI
- 2.43
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- eLife (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- eScholarship (California Digital Library) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- Funders
- National Science Foundation (1136790, Graduate Student Fellowship, DGE-114747)
- National Institutes of Health (T32GM007276, 11R35GM118064-01)
- Stanford University (Bio-X Graduate Fellowship, Lieberman Graduate Fellowship)
- 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 › Cell Biology › Cellular Mechanics and Interactions
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hippo pathway signaling and YAP/TAZ
- Keywords
- β-catenin, Wnt3a, mechanical strain, cell cycle progression, mitosis, Src phosphorylation, casein kinase 1, β-catenin stabilization, Wnt/β-catenin signaling, mechanical forces, MDCK cells, tissue expansion
- MeSH terms
- Animals, Dogs, Mitosis, Phosphorylation, Protein Processing, Post-Translational, src-Family Kinases, beta Catenin, Mechanical Phenomena, Wnt Signaling Pathway, Wnt3A Protein, Madin Darby Canine Kidney Cells
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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.
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