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Cited by 27Wnt/β-catenin signaling in development and cancerLipid Membrane Structure and BehaviorCancer, Lipids, and Metabolism

Mutant APC reshapes Wnt signaling plasma membrane nanodomains by altering cholesterol levels via oncogenic β-catenin

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Erazo-Oliveras, Alfredo, Muñoz-Vega, Mónica, Mlih, Mohamed, Thiriveedi, Venkataramana, Salinas, Michael L., Rivera-Rodríguez, Jaileen M., Kim, Eunjoo, Wright, Rachel C. +7 more·2023·Nature Communications
DOI 10.1038/s41467-023-39640-wPMC PMC10356786
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Abstract

Although the role of the Wnt pathway in colon carcinogenesis has been described previously, it has been recently demonstrated that Wnt signaling originates from highly dynamic nano-assemblies at the plasma membrane. However, little is known regarding the role of oncogenic APC in reshaping Wnt nanodomains. This is noteworthy, because oncogenic APC does not act autonomously and requires activation of Wnt effectors upstream of APC to drive aberrant Wnt signaling. Here, we demonstrate the role of oncogenic APC in increasing plasma membrane free cholesterol and rigidity, thereby modulating Wnt signaling hubs. This results in an overactivation of Wnt signaling in the colon. Finally, using the Drosophila sterol auxotroph model, we demonstrate the unique ability of exogenous free cholesterol to disrupt plasma membrane homeostasis and drive Wnt signaling in a wildtype APC background. Collectively, these findings provide a link between oncogenic APC, loss of plasma membrane homeostasis and CRC development.

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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 [42]

    The Discussion reports that membrane free cholesterol interacts with Dvl and promotes its scaffolding function in Wnt signaling; the Results specifically measure Dvl1. The cited copy does not establish the sentence’s PI3K–Akt claim or identify Dvl2 as the protein studied. Its account of Dvl also describes cholesterol-dependent recruitment and interactions, rather than direct activation in isolation. (LLM, conf=0.84)

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Cited by

Sorted by citations

Authors
Erazo-Oliveras, A., Muñoz-Vega, M., Mlih, M., Thiriveedi, V., Salinas, M. L., Rivera-Rodríguez, J. M., Kim, E., Wright, R. C., Wang, X., Landrock, K. K., Goldsby, J. S., Mullens, D. A., Roper, J., Karpac, J., & Chapkin, R. S.
Affiliations
  • Texas A&M University (US)
  • Duke University (US)
  • University of Colorado Anschutz (US)
Corresponding author
Chapkin, Robert S.
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2023-07-19
Volume
14
Issue
1
Pages
4342-4342
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-023-39640-w
PMC
PMC10356786
OpenAlex
W4384819625
Cited by
27
References
4
Citations by year
2026: 12 · 2025: 11 · 2024: 4
FWCI
2.41
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Foundation for the National Institutes of Health (P30-ES029067)
  • U.S. Department of Health & Human Services | NIH | National Cancer Institute (RO1-CA244359, R35-CA197707)
  • National Academies of Sciences, Engineering, and Medicine (Ford Foundation 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 › Molecular Biology › Lipid Membrane Structure and Behavior
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
Keywords
APC mutation, Wnt signaling, plasma membrane nanodomains, free cholesterol, membrane rigidity, β-catenin, colon cancer, sterol auxotrophy, Drosophila, membrane homeostasis, oncogenic signaling
MeSH terms
Animals, Cell Membrane, Colon, Cytoskeletal Proteins, Drosophila, Drosophila Proteins, beta Catenin, Wnt Signaling Pathway, Carcinogenesis

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