Mechanistic insights into Wnt–β-catenin pathway activation and signal transduction

Abstract

In multicellular organisms, Wnt proteins govern stem and progenitor cell renewal and differentiation to regulate embryonic development, adult tissue homeostasis and tissue regeneration. Defects in canonical Wnt signalling, which is transduced intracellularly by β-catenin, have been associated with developmental disorders, degenerative diseases and cancers. Although a simple model describing Wnt–β-catenin signalling is widely used to introduce this pathway and has largely remained unchanged over the past 30 years, in this Review we discuss recent studies that have provided important new insights into the mechanisms of Wnt production, receptor activation and intracellular signalling that advance our understanding of the molecular mechanisms that underlie this important cell–cell communication system. In addition, we review the recent development of molecules capable of activating the Wnt–β-catenin pathway with selectivity in vitro and in vivo that is enabling new lines of study to pave the way for the development of Wnt therapies for the treatment of human diseases. Wnt–β-catenin signalling regulates stem cell renewal, development and tissue homeostasis. In this Review, the authors examine recent findings concerning Wnt protein production, receptor activation and intracellular signalling, focusing on the regulation of the β-catenin destruction complex.