Unravelling the molecular mechanisms of the canonical Wnt signalling pathway

Abstract

The Canonical Wnt signaling pathway (Wnt/beta-catenin pathway) is required during embryonic development and maintenance of adult-renewing tissue homeostasis. Deregulation of this pathway is found associated with cancer and other diseases. The main goal of this thesis is to discern the regulation mechanisms of canonical Wnt signaling and thereby identify potential drug targets. We found that, neither the dissembled of Axin1, APC or GSK3 from the destruction complex nor inactivation of GSK3 and CKI alpha leads to inactivation of dedicated complex. But dissociation of beta-catenin E3-ubiquitin ligase, beta-Trcp from the complex leads to the saturation of limited Axin1-scaffolded destruction complex by phophorylated beta-catenin. We had also identified several potential Axin binding partners and phosphorylation sites of Axin, APC and WTX, which will guide us to further understanding of the dissociation mechanisms. In additionally, we also found Axin1 bound GSK3 is protected from PKB phosphorylation thereby PI3K/PKB signaling is not able to modulate canonical Wnt signaling through GSK3 inactivation. We also identified MAP3K1 as a positive regulator on canonical Wnt signaling through its E3 ubiquitin ligase function. Lastly, we found a novel potential drug target, Tnik which specifically phosphorylates Tcf4 through recruitment of beta-catenin.