Targeting Tankyrase to Fight WNT-dependent Tumours

Abstract

Aberrant WNT signalling activity is linked to various diseases due to the WNT dependency of fundamental processes during development and in adult tissue homeostasis. Mutations in components of the multi-protein β-catenin destruction complex promote excessive amounts of the main transcriptional activator β-catenin and are particularly common in colorectal cancer (CRC). The tankyrase enzymes were recently implicated as negative regulators of destruction complex activity by mediating degradation of the scaffolding protein AXIN. Indeed, tankyrase inhibitors (TNKSi) have emerged as promising therapeutics by restoring functional signal-limiting destruction complexes in CRCs. Furthermore, as TNKSi-induced destruction complexes (so-called degradasomes) can be visualized by microscopy, they have served as a valuable experimental model system to address unresolved aspects regarding the structure, function and composition of the β-catenin destruction complex. This MiniReview provides an overview of the current knowledge on the regulatory mechanisms and interactions that govern the β-catenin destruction complex activity. It further highlights the potential of TNKSi as anticancer drugs and as a novel research tool to dissect the WNT signalling pathway.