Clathrin regulates Wnt/β-catenin signaling by affecting Golgi to plasma membrane transport of transmembrane proteins.

The canonical Wnt/beta-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/beta-catenin signaling in cell lines and found a pronounced reduction in beta-catenin protein levels, which affects the amount of nuclear beta-catenin and beta-catenin target gene expression. Although we found no evidence that clathrin affects beta-catenin levels via endocytosis or multivesicular endosome formation, an inhibition of protein transport through the biosynthetic pathway led to reduced levels of a Wnt co-receptor, low-density lipoprotein receptor-related protein 6 (LRP6), and cell adhesion molecules of the cadherin family, thereby affecting steady-state levels of beta-catenin. We conclude that clathrin impacts on Wnt/beta-catenin signaling by controlling exocytosis of transmembrane proteins, including cadherins and Wnt co-receptors that together control the membrane-bound and soluble pools of beta-catenin.