Kdm2a/b Lysine Demethylases Regulate Canonical Wnt Signaling by Modulating the Stability of Nuclear β-Catenin

Dev Cell. 2015 Jun 22;33(6):660-74. doi: 10.1016/j.devcel.2015.04.006. Epub 2015 May 21.

Abstract

In the absence of Wnt activation, cytosolic β-catenin is degraded through GSK3/CK1-mediated phosphorylation at the N terminus. Here, we show that, upon Wnt activation, the stability of nuclear β-catenin is regulated via methylation/demethylation. The protein lysine demethylases Kdm2a and Kdm2b regulate the turnover of non-phosphorylated β-catenin specifically within the nucleus via direct interaction with the fourth and fifth armadillo repeats. The lysine residues within this region are required for the methylation of non-phosphorylated β-catenin, which is demethylated by Kdm2a/b and subsequently ubiquitylated. During Xenopus embryogenesis, kdm2a/b genes are transcribed during early embryogenesis and are required for the specification of the body axis. Kdm2a/b knockdown in Xenopus embryos leads to increases in non-phosphorylated and methylated β-catenin, concurrent with the upregulation of β-catenin target genes. This mechanism is required for controlling the output of the Wnt/β-catenin signaling pathway to maintain normal cellular functions.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Body Patterning / genetics
  • Body Patterning / physiology
  • Cell Line
  • Cell Nucleus / metabolism
  • F-Box Proteins / antagonists & inhibitors
  • F-Box Proteins / genetics
  • F-Box Proteins / metabolism*
  • Gene Expression Regulation, Developmental
  • Gene Knockdown Techniques
  • Glycogen Synthase Kinase 3 / genetics
  • Glycogen Synthase Kinase 3 / metabolism
  • HEK293 Cells
  • Histone Demethylases / genetics
  • Histone Demethylases / metabolism
  • Humans
  • Jumonji Domain-Containing Histone Demethylases / antagonists & inhibitors
  • Jumonji Domain-Containing Histone Demethylases / genetics
  • Jumonji Domain-Containing Histone Demethylases / metabolism*
  • Methylation
  • Phosphorylation
  • Protein Stability
  • Proteolysis
  • RNA, Small Interfering / genetics
  • Transcription Factor 7-Like 1 Protein / genetics
  • Transcription Factor 7-Like 1 Protein / metabolism
  • Wnt Signaling Pathway / physiology*
  • Xenopus Proteins / genetics
  • Xenopus Proteins / metabolism
  • Xenopus laevis / embryology
  • Xenopus laevis / genetics
  • Xenopus laevis / metabolism
  • beta Catenin / genetics
  • beta Catenin / metabolism*

Substances

  • CTNNB1 protein, human
  • F-Box Proteins
  • RNA, Small Interfering
  • TCF7L1 protein, human
  • Transcription Factor 7-Like 1 Protein
  • Xenopus Proteins
  • beta Catenin
  • Histone Demethylases
  • Jumonji Domain-Containing Histone Demethylases
  • KDM2A protein, human
  • GSK3B protein, Xenopus
  • Glycogen Synthase Kinase 3