The Pharmacology of WNT Signaling

WNT signaling was discovered almost four decades ago as a signaling pathway required for development, but at the same time its involvement in oncogenic transformation was established. Extensive research has revealed a large family of ligands, (co)receptors and endogenous inhibitors, as well as three main routes of signal transduction. Gradually, a picture has emerged of a pathway that is mainly active in local, paracrine control of its neighboring cells. WNT signaling was found to be active in every branch of the animal kingdom, and many of its members appear to be highly conserved in evolution. More recently, its critical role in the control of stem cell differentiation was identified. In this article, we will start by introducing the many WNT proteins and their posttranslational modification, required for their biological activity. We subsequently discuss the receptors and co-receptors involved in WNT signaling, as well as their endogenous antagonists. Next, the three main arms of the signal transduction are presented, together with their intracellular components. We finalize with a description of the contribution of WNT signaling to various pathologies and a listing of drugs that were developed over the years to intervene in WNT signaling at different levels of the pathways.