Cholesterol selectively activates canonical Wnt signalling over non-canonical Wnt signalling
Open accessAbstract
Wnt proteins control diverse biological processes through β-catenin-dependent canonical signalling and β-catenin-independent non-canonical signalling. The mechanisms by which these signalling pathways are differentially triggered and controlled are not fully understood. Dishevelled (Dvl) is a scaffold protein that serves as the branch point of these pathways. Here, we show that cholesterol selectively activates canonical Wnt signalling over non-canonical signalling under physiological conditions by specifically facilitating the membrane recruitment of the PDZ domain of Dvl and its interaction with other proteins. Single-molecule imaging analysis shows that cholesterol is enriched around the Wnt-activated Frizzled and low-density lipoprotein receptor-related protein 5/6 receptors and plays an essential role for Dvl-mediated formation and maintenance of the canonical Wnt signalling complex. Collectively, our results suggest a new regulatory role of cholesterol in Wnt signalling and a potential link between cellular cholesterol levels and the balance between canonical and non-canonical Wnt signalling activities.
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Altering membrane cholesterol might affect lipid raft formation and subsequent PI3K signaling, or membrane-bound cholesterol can directly activate certain downstream signaling proteins such as Akt or Dvl2 (Wnt signaling).
“Enrichment in the PI3K-Akt and Wnt signaling pathways was of interest given reports that altering membrane cholesterol might affect lipid raft formation and subsequent PI3K signaling (42–44), or that membrane-bound cholesterol can directly activate certain downstream signaling proteins such as Akt or Dvl2 (Wnt signaling).”
From Cholesterol efflux protein, ABCA1, supports anticancer functions of myeloid immune cells (2026) · cites this paper as [43]
The Results section ('Dvl PDZ domain specifically binds cholesterol') reports that Dvl2 binds cholesterol-containing membranes, and the Discussion says this binding promotes Dvl2’s role in canonical Wnt signaling. The paper does not establish direct activation of Akt or a lipid-raft-mediated PI3K effect; its Discussion says Dvl’s cholesterol-dependent activity need not involve lipid-raft formation. The supplied copy gives no page numbers for these passages. (LLM, conf=0.86)
Experimental — accuracy not yet measuredCertain PZD-domain containing proteins such as Dvl2 can be directly activated by cholesterol within the inner leaflet of the plasma membrane.
“Recent reports suggest that certain PZD-domain containing proteins such as Dvl2 can be directly activated by cholesterol within the inner leaflet of the plasma membrane (43, 44, 82–84).”
From Cholesterol efflux protein, ABCA1, supports anticancer functions of myeloid immune cells (2026) · cites this paper as [43]
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- Authors
- Sheng, R., Kim, H., Lee, H., Xin, Y., Chen, Y., Tian, W., Cui, Y., Choi, J.-C., Doh, J., Han, J.-K., & Cho, W.
- Affiliations
- University of Illinois Chicago (US)
- Pohang University of Science and Technology (KR)
- Corresponding author
- Han, Jin-Kwan
- Cho, Wonhwa
- Venue
- Nature Communications
- Published
- 2014-07-15
- Volume
- 5
- Issue
- 1
- Pages
- 4393-4393
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC4100210
- OpenAlex
- W2057871099
- Cited by
- 157
- References
- 70
- Citations by year
- 2026: 6 · 2025: 19 · 2024: 20 · 2023: 31 · 2022: 19 · 2021: 22 · 2020: 9 · 2019: 7 · 2018: 9 · 2017: 3 · 2016: 9 · 2015: 3
- FWCI
- 2.05
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Nature Communications (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Open Access System for Information Sharing (Pohang University of Science and Technology) (submittedVersion)
- Seoul National University Open Repository (Seoul National University) (submittedVersion)
- Funders
- National Research Foundation
- National Research Foundation of Korea (R31-2008-000-10105-0)
- National Institutes of Health
- National Institute of General Medical Sciences (GM 68849, GM110128, R01GM068849, R01GM110128)
- 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 › Hedgehog Signaling Pathway Studies
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Keywords
- cholesterol, Wnt signaling, Wnt/β-catenin signaling, non-canonical Wnt signaling, Dishevelled, PDZ domain, membrane recruitment, Frizzled receptors, LRP5/6, β-catenin, single-molecule imaging, plasma membrane cholesterol
- MeSH terms
- Dishevelled Proteins, Animals, Cholesterol, HeLa Cells, Humans, Phosphoproteins, Protein Binding, Xenopus, Blotting, Western, Signal Transduction, In Situ Hybridization, Xenopus Proteins, Adaptor Proteins, Signal Transducing, Wnt Proteins, Wnt Signaling Pathway
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