The canonical Wnt/β-catenin signaling pathway regulates cell proliferation in development and adult tissue homeostasis. Dysregulated signaling contributes to human diseases, in particular cancer. Growing evidence suggests a role for clathrin and/or endocytosis in the regulation of this pathway, but conflicting results exist and demand a deeper mechanistic understanding. We investigated the consequences of clathrin depletion on Wnt/β-catenin signaling in cell lines and found a pronounced reduction in β-catenin protein levels, which affects the amount of nuclear β-catenin and β-catenin target gene expression. While we found no evidence that clathrin affects β-catenin levels via endocytosis or multivesicular endosome formation, an inhibition of protein transport through the biosynthetic pathway led to reduced levels of the Wnt co-receptor LRP6 and cell adhesion molecules of the cadherin family, thereby affecting steady-state levels of β-catenin. We conclude that clathrin impacts on Wnt/β-catenin signaling by controlling exocytosis of transmembrane proteins including cadherins and Wnt co-receptors that together control the membrane-bound and soluble pools of β-catenin.

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