Kdm2a/b Lysine Demethylases Regulate Canonical Wnt Signaling by Modulating the Stability of Nuclear β-Catenin
Kdm2a/b Lysine Demethylases Regulate Canonical Wnt Signaling by Modulating the Stability of Nuclear β-Catenin
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DOI：
10.1016/j.devcel.2015.04.006
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发表时间：
2015-06-22
影响因子：
11.8
通讯作者：
Cao, Ying
中科院分区：
文献类型：
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作者：
Lu, Lei;Gao, Yan;Cao, Ying
在没有Wnt激活的情况下，胞质β-连环蛋白通过GSK 3/CK 1介导的N端磷酸化降解。在这里，我们表明，Wnt激活后，核β-连环蛋白的稳定性是通过甲基化/去甲基化调节。蛋白质赖氨酸脱甲基酶Kdm 2a和Kdm 2b通过与第四和第五犰狳重复序列的直接相互作用特异性地在细胞核内调节非磷酸化β-连环蛋白的周转。该区域内的赖氨酸残基是非磷酸化β-连环蛋白甲基化所必需的，其被Kdm 2a/B去甲基化并随后被泛素化。在非洲爪蟾胚胎发生过程中，kdm 2a/B基因在早期胚胎发生过程中转录，并需要为身体轴的规格。在非洲爪蟾胚胎中Kdm 2a/B敲低导致非磷酸化和甲基化β-连环蛋白的增加，同时β-连环蛋白靶基因的上调。这种机制是控制Wnt/β-连环蛋白信号通路的输出以维持正常细胞功能所必需的。
In the absence of Wnt activation, cytosolic beta-catenin is degraded through GSK3/CK1-mediated phosphorylation at the N terminus. Here, we show that, upon Wnt activation, the stability of nuclear beta-catenin is regulated via methylation/demethylation. The protein lysine demethylases Kdm2a and Kdm2b regulate the turnover of non-phosphorylated beta-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 beta-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 beta-catenin, concurrent with the upregulation of beta-catenin target genes. This mechanism is required for controlling the output of the Wnt/beta-catenin signaling pathway to maintain normal cellular functions.