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

Alfredo Erazo-Oliveras, Mónica Muñoz-Vega, Mohamed Mlih, Venkataramana Thiriveedi, Michael L. Salinas, Jaileen M. Rivera-Rodríguez, Eunjoo Kim, Rachel C. Wright, Xiaoli Wang, Kerstin K. Landrock, Jennifer S. Goldsby, Destiny A. Mullens, Jatin Roper, Jason Karpac and Robert S. Chapkin ()
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Alfredo Erazo-Oliveras: Texas A&M University
Mónica Muñoz-Vega: Texas A&M University
Mohamed Mlih: Texas A&M University, School of Medicine
Venkataramana Thiriveedi: Duke University School of Medicine
Michael L. Salinas: Texas A&M University
Jaileen M. Rivera-Rodríguez: Texas A&M University
Eunjoo Kim: University of Colorado Anschutz Medical Campus
Rachel C. Wright: Texas A&M University
Xiaoli Wang: Texas A&M University
Kerstin K. Landrock: Texas A&M University
Jennifer S. Goldsby: Texas A&M University
Destiny A. Mullens: Texas A&M University
Jatin Roper: Duke University School of Medicine
Jason Karpac: Texas A&M University, School of Medicine
Robert S. Chapkin: Texas A&M University

Nature Communications, 2023, vol. 14, issue 1, 1-28

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-39640-w

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