Tumorigenic mechanisms of Axin missense mutations

Abstract

The Wnt signaling pathway is of critical importance during both development and adult tissue homeostasis. Inappropriate activation of Wnt signaling is a major cause of cancer development in various tissues throughout the body. To keep Wnt signaling low in the off state, the effector protein β-catenin is continuously targeted for degradation by a specialized destruction complex. Mutations in core components of the Wnt signaling pathway are associated with various cancers. While APC and β-catenin mutations are relatively well studied, mutations in Axin remain poorly understood. Notably, the majority of Axin mutations comprise missense mutations. With the work presented in this thesis we aimed to understand how Axin missense mutations deregulate Wnt signaling and contribute to tumor development. Our work reveals that cancer mutations in Axin have a major impact on protein conformation. The results open up possibilities to develop targeted strategies to suppress Wnt pathway activation.