A Positive Role of Cadherin in Wnt/β-Catenin Signalling during Epithelial-Mesenchymal Transition

The Wnt/beta-catenin signalling pathway shares a key component, beta-catenin, with the cadherin-based adhesion system. The signalling function of beta-catenin is conferred by a soluble cytoplasmic pool that is unstable in the absence of a Wnt signal, whilst the adhesion function is based on a cadherin-bound, stable pool at the membrane. The cadherin complex is dynamic, allowing for cell-cell rearrangements such as epithelial-mesenchymal transition (EMT), where the complex turns over through internalisation. Potential interplay between the two pools remains poorly understood, but cadherins are generally considered negative regulators of Wnt signalling because they sequester cytoplasmic beta-catenin. Here we explore how cellular changes at EMT affect the signalling capacity of beta-catenin using two models of EMT: hepatocyte growth factor (HGF) treatment of MDCK cells, and gastrulation in embryonic development. We show that EMT not only provides a pool of signalling-competent beta-catenin following internalisation of cadherin, but also significantly facilitates activation of the Wnt pathway in response to both Wnt signals and exogenous beta-catenin. We further demonstrate that availability of beta-catenin in the cytoplasm does not necessarily correlate with Wnt/beta-catenin pathway activity, since blocking endocytosis or depleting endogenous cadherin abolishes pathway activation despite the presence of beta-catenin in the cytoplasm. Lastly we present data suggesting that cadherins are required for augmented activation of the Wnt/beta-catenin pathway in vivo. This suggests that cadherins play a crucial role in beta-catenin-dependent transcription.