The roles of Wnt-associated deubiquitinases

点击翻译按钮获取中文摘要

The canonical Wnt signalling pathway promotes well-characterised transcriptional programmes regulated by beta-catenin, referred to as Wnt/beta-catenin signalling. We have recently discovered that Wnt signalling also promotes a rich post-translational programme by regulating the stability and activity of GSK3 target proteins other than beta-catenin, referred to as Wnt-mediated stabilisation of proteins (Wnt/STOP signalling). However, how Wnt/STOP contributes to the Wnt physiological functions remains mostly unexplored, and forms the basis of this proposal. I identified a group of deubiquitinases (DUBs) that contain conserved sites for the Wnt-associated kinase GSK3 and are stabilised by Wnt/STOP. Exploration of one of the Wnt/STOP targeted DUBs revealed that it is involved in a feedback loop to inhibit Wnt/beta-catenin signalling. Further epistasis and co-localisation experiments indicated that this DUB functions at the level of the beta-catenin destruction complex. Consistent with its roles as a novel negative regulator of Wnt/beta-catenin signalling, the DUB candidate is often mutated in Wnt-associated tumours. By investigating the roles of this DUB we aim to unravel an unexpected cross talk between the Wnt/STOP and the Wnt/beta-catenin cascades, which may have relevant implications in tissue renewal and oncogenesis. I therefore propose to i) elucidate the mechanisms of action of the candidate DUB within Wnt/beta-catenin and Wnt/STOP signalling, by biochemical and cell biological analyses; and ii) analyse its physiological roles using transgenic mice and organoids.