WNK regulates Wnt signalling and ?-Catenin levels by interfering with the interaction between ?-Catenin and GID.

ABSTRACT: ?-Catenin is an important component of the Wnt signalling pathway. As dysregulation or mutation of this pathway causes many diseases, including cancer, the ?-Catenin level is carefully regulated by the destruction complex in the Wnt signalling pathway. However, the mechanisms underlying the regulation of ?-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 ?-Catenin and the Glucose-Induced degradation Deficient (GID) complex, which includes an E3 ubiquitin ligase targeting ?-Catenin, and that WNK regulates the ?-Catenin level. Furthermore, we show that WNK inhibitors induced ?-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 ?-Catenin and a therapeutic target of cancer.

SUBMITTER: Sato A 

PROVIDER: S-EPMC7665214 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature