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.
Copyright © 2015 Elsevier Inc. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Body Patterning / genetics
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Body Patterning / physiology
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Cell Line
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Cell Nucleus / metabolism
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F-Box Proteins / antagonists & inhibitors
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F-Box Proteins / genetics
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F-Box Proteins / metabolism*
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Gene Expression Regulation, Developmental
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Gene Knockdown Techniques
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Glycogen Synthase Kinase 3 / genetics
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Glycogen Synthase Kinase 3 / metabolism
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HEK293 Cells
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Histone Demethylases / genetics
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Histone Demethylases / metabolism
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Humans
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Jumonji Domain-Containing Histone Demethylases / antagonists & inhibitors
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Jumonji Domain-Containing Histone Demethylases / genetics
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Jumonji Domain-Containing Histone Demethylases / metabolism*
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Methylation
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Phosphorylation
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Protein Stability
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Proteolysis
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RNA, Small Interfering / genetics
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Transcription Factor 7-Like 1 Protein / genetics
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Transcription Factor 7-Like 1 Protein / metabolism
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Wnt Signaling Pathway / physiology*
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Xenopus Proteins / genetics
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Xenopus Proteins / metabolism
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Xenopus laevis / embryology
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Xenopus laevis / genetics
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Xenopus laevis / metabolism
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beta Catenin / genetics
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beta Catenin / metabolism*
Substances
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CTNNB1 protein, human
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F-Box Proteins
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RNA, Small Interfering
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TCF7L1 protein, human
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Transcription Factor 7-Like 1 Protein
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Xenopus Proteins
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beta Catenin
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Histone Demethylases
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Jumonji Domain-Containing Histone Demethylases
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KDM2A protein, human
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GSK3B protein, Xenopus
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Glycogen Synthase Kinase 3