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

Commun Biol. 2020 Nov 12;3(1):666. 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Humans
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism
  • Ubiquitin-Protein Ligase Complexes / metabolism
  • Ubiquitination / physiology
  • WNK Lysine-Deficient Protein Kinase 1* / genetics
  • WNK Lysine-Deficient Protein Kinase 1* / metabolism
  • Wnt Signaling Pathway / physiology*
  • beta Catenin / metabolism*

Substances

  • CTNNB1 protein, human
  • beta Catenin
  • Ubiquitin-Protein Ligase Complexes
  • Protein-Serine-Threonine Kinases
  • WNK Lysine-Deficient Protein Kinase 1
  • WNK1 protein, human
  • WNK4 protein, human