Wnk Regulates Wnt Signalling And Beta-Catenin Levels By Interfering With The Interaction Between Beta-Catenin And Gid

beta -Catenin is an important component of the Wnt signalling pathway. As dysregulation or mutation of this pathway causes many diseases, including cancer, the beta -Catenin level is carefully regulated by the destruction complex in the Wnt signalling pathway. However, the mechanisms underlying the regulation of beta -Catenin ubiquitination and degradation remain unclear. Here, we find that WNK (With No Lysine [K]) kinase is a potential regulator of the Wnt signalling pathway. We show that WNK protects the interaction between beta -Catenin and the Glucose-Induced degradation Deficient (GID) complex, which includes an E3 ubiquitin ligase targeting beta -Catenin, and that WNK regulates the beta -Catenin level. Furthermore, we show that WNK inhibitors induced beta -Catenin degradation and that one of these inhibitors suppressed xenograft tumour development in mice. These results suggest that WNK is a previously unrecognized regulator of beta -Catenin and a therapeutic target of cancer. Sato et al. find that WNK (With No Lysine [K]) acts as a positive regulator of the Wnt signaling pathway by attenuating the interaction between beta -Catenin and the Glucose Induce degradation Deficient (GID) complex, and show that a WNK inhibitor also functions as a Wnt inhibitor, suppressing xenograft tumor development in mice. These findings suggest that WNK is a regulator of beta -Catenin and a potential therapeutic target