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

Wnt proteins control diverse biological processes through β-catenin-dependent canonical signaling and β-catenin-independent non-canonical signaling. The mechanisms by which these signaling 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 signaling over non-canonical signaling 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 signaling complex. Collectively, our results suggest a new regulatory role of cholesterol in Wnt signaling and a potential link between cellular cholesterol levels and the balance between canonical and non-canonical Wnt signaling activities.