title: Kdm2a/b Lysine Demethylases Regulate Canonical Wnt Signaling by Modulating the Stability of Nuclear β-Catenin.
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.
authors.affiliation: Model Animal Research Center of Nanjing University and MOE Key Laboratory of Model Animals for Disease Study, 12 Xuefu Road, Pukou High-Tech Zone, Nanjing 210061, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Lu
authors.affiliation: Model Animal Research Center of Nanjing University and MOE Key Laboratory of Model Animals for Disease Study, 12 Xuefu Road, Pukou High-Tech Zone, Nanjing 210061, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Model Animal Research Center of Nanjing University and MOE Key Laboratory of Model Animals for Disease Study, 12 Xuefu Road, Pukou High-Tech Zone, Nanjing 210061, China.
authors.forename: Zan
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Model Animal Research Center of Nanjing University and MOE Key Laboratory of Model Animals for Disease Study, 12 Xuefu Road, Pukou High-Tech Zone, Nanjing 210061, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Cao
authors.affiliation: Model Animal Research Center of Nanjing University and MOE Key Laboratory of Model Animals for Disease Study, 12 Xuefu Road, Pukou High-Tech Zone, Nanjing 210061, China.
authors.forename: Xuena
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Model Animal Research Center of Nanjing University and MOE Key Laboratory of Model Animals for Disease Study, 12 Xuefu Road, Pukou High-Tech Zone, Nanjing 210061, China.
authors.forename: Jianghuan
authors.initials: J
authors.lastname: Zou
authors.affiliation: Model Animal Research Center of Nanjing University and MOE Key Laboratory of Model Animals for Disease Study, 12 Xuefu Road, Pukou High-Tech Zone, Nanjing 210061, China. Electronic address: caoying@nju.edu.cn.
authors.forename: Ying
authors.initials: Y
authors.lastname: Cao
mesh_terms: D000818:Animals; D019521:Body Patterning / Q000235:genetics / Q000502:physiology; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D044783:F-Box Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D055785:Gene Knockdown Techniques; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D056466:Histone Demethylases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D008745:Methylation; D010766:Phosphorylation; D055550:Protein Stability; D059748:Proteolysis; D034741:RNA, Small Interfering / Q000235:genetics; D058125:Transcription Factor 7-Like 1 Protein / Q000235:genetics / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000502:physiology*; D029867:Xenopus Proteins / Q000235:genetics / Q000378:metabolism; D014982:Xenopus laevis / Q000196:embryology / Q000235:genetics / Q000378:metabolism; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
chemical_list: C495270:CTNNB1 protein, human; D044783:F-Box Proteins; D034741:RNA, Small Interfering; C544912:TCF7L1 protein, human; D058125:Transcription Factor 7-Like 1 Protein; D029867:Xenopus Proteins; D051176:beta Catenin; D056466:Histone Demethylases; D056484:Jumonji Domain-Containing Histone Demethylases; C534524:KDM2A protein, human; C581760:GSK3B protein, Xenopus; D038362:Glycogen Synthase Kinase 3