WNK regulates Wnt signalling and ?-Catenin levels by interfering with the interaction between ?-Catenin and GID.
?-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.
Mesh Terms:
Animals, Cell Line, Tumor, Humans, Male, Mice, Mice, Inbred BALB C, Protein Serine-Threonine Kinases, Ubiquitin-Protein Ligase Complexes, Ubiquitination, WNK Lysine-Deficient Protein Kinase 1, Wnt Signaling Pathway, beta Catenin
Animals, Cell Line, Tumor, Humans, Male, Mice, Mice, Inbred BALB C, Protein Serine-Threonine Kinases, Ubiquitin-Protein Ligase Complexes, Ubiquitination, WNK Lysine-Deficient Protein Kinase 1, Wnt Signaling Pathway, beta Catenin
Commun Biol
Date: Nov. 12, 2020
PubMed ID: 33184430
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