Cholesterol selectively activates canonical Wnt signalling over non-canonical Wnt signalling

Ren Sheng, Hyunjoon Kim, Hyeyoon Lee, Yao Xin, Yong Chen, Wen Tian, Yang Cui, Jong-Cheol Choi, Junsang Doh, Jin-Kwan Han () and Wonhwa Cho ()
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Ren Sheng: University of Illinois at Chicago
Hyunjoon Kim: Divisions of Molecular and Life Sciences
Hyeyoon Lee: Divisions of Molecular and Life Sciences
Yao Xin: University of Illinois at Chicago
Yong Chen: University of Illinois at Chicago
Wen Tian: University of Illinois at Chicago
Yang Cui: University of Illinois at Chicago
Jong-Cheol Choi: Pohang University of Science and Technology
Junsang Doh: Pohang University of Science and Technology
Jin-Kwan Han: Divisions of Molecular and Life Sciences
Wonhwa Cho: University of Illinois at Chicago

Nature Communications, 2014, vol. 5, issue 1, 1-13

Abstract: Abstract 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.

Date: 2014
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DOI: 10.1038/ncomms5393

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