Molecular mechanisms of Wnt pathway activation and inactivation.

Wnt signalling pathways are essential in embryonic development and have important functions in tissue regeneration and overall maintenance of tissue homeostasis throughout the lifespan of multicellular organisms. Furthermore, dysregulation of Wnt signalling is associated with many human diseases, most prominently cancer. Understanding how these pathways function at the molecular level is therefore of great importance. Dissecting molecular mechanisms governing the different steps in this pathway has proven difficult, to a large extent due to pathway complexity and absence of suitable research tools able to reduce such complexity. Recent advances 1 demonstrate that a reductionist approach would provide a well-controlled biochemical system to gain detailed functional insights to elucidate the molecular mechanisms governing pathway activation and termination. In this proposal I will address how: (i) the destruction complex is inactivated upon Wnt signalosome formation; (ii) the Wnt signal is transduced across the plasma membrane; (iii) the Wnt signal input at the plasma membrane is terminated. Answers to these questions will deepen our mechanistic understanding of the pathological activation of the Wnt/beta-catenin pathway at the plasma membrane, which contributes to various cancers 2. How the pathway is modulated in normal physiology is of great interest for stem cell therapy and regenerative medicine.