WNK regulates Wnt signalling and \u03b2-Catenin levels by interfering with the interaction between \u03b2-Catenin and GID

Atsushi Sato,Toshiyasu Goto,Hiroyuki Kagechika,Hiroshi Shibuya,Masahiro Shimizu,Nobuyuki Tanaka,Hiroyuki Masuno

doi:10.1038/s42003-020-01386-2

Abstract

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

Highlights

Β-Catenin is an important component of the Wnt signalling pathway
In the absence of Wnt, the destruction complex formed by Axin[1], Adenomatous Polyposis Coli (APC) and Glycogen Synthase Kinase 3β (GSK3β) phosphorylates the N-terminus of β-Catenin, which is in turn recognized and ubiquitinated by βTrCP E3 ubiquitin ligases[6,7]
We found that WNK1 and WNK4 induce the expression of Lhx[8] and are important for neural specification through GSK3β26,27

Summary

Introduction

Β-Catenin is an important component of the Wnt signalling pathway. As dysregulation or mutation of this pathway causes many diseases, including cancer, the β-Catenin level is carefully regulated by the destruction complex in the Wnt signalling pathway. We show that WNK inhibitors induced β-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 β-Catenin and a therapeutic target of cancer. The Wnt signalling pathway is activated by the binding of Wnt ligand to a receptor complex[8,9], which leads to Dishevelled (DVL) recruitment, where DVL polymerizes with Axin and the remaining components of the destruction complex This polymerization inactivates the destruction complex, inducing β-Catenin accumulation in the cytoplasm. We showed that the WNK inhibitor functions as a Wnt inhibitor, suppressing xenograft tumour development in mice These findings suggest that WNK is a regulator of β-Catenin and might be a therapeutic cancer target

Methods

Results

Conclusion