a positive role of cadherin in wntβ-catenin signalling during epithelial-mesenchymal transition积极作用的钙粘着蛋白在epithelial-mesenchymal wntβ-catenin信号过渡.pdfVIP

A Positive Role of Cadherin in Wnt/b-Catenin Signalling during Epithelial-Mesenchymal Transition 1 1 2,3 1 ¤ Sara Howard , Tom Deroo , Yasuyuki Fujita , Nobue Itasaki * 1 MRC National Institute for Medical Research, London, United Kingdom, 2 MRC Laboratory for Molecular Cell Biology and Cell Biology Unit, Department of Cell and Developmental Biology, University College London, London, United Kingdom, 3 Division of Molecular Oncology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Hokkaido, Japan Abstract The Wnt/b-catenin signalling pathway shares a key component, b-catenin, with the cadherin-based adhesion system. The signalling function of b-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 b-catenin. Here we explore how cellular changes at EMT affect the signalling capacity of b-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 b-catenin following internalisation of cadherin, but also significantly facilitates activation of the Wnt pathway in response to both Wnt signals and exogenous b- catenin. We further demonstrate that availability of b-catenin in the cytoplasm does not ne