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

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

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.

Journal Article

JOURNAL
Communications Biology

TITLE
WNK regulates Wnt signalling and β-Catenin levels by interfering with the interaction between β-Catenin and GID

DOI
https://doi.org/10.1038/s42003-020-01386-2

Correspondence to

Hiroshi Shibuya, Ph.D., Professor

Department of Molecular Cell Biology,
Medical Research Institute (MRI),
Tokyo Medical and Dental University (TMDU),
E-mail:shibuya.mcb(at)mri.tmd.ac.jp


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