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首页> 外文期刊>The EMBO journal. >Wnt-induced deubiquitination FoxM1 ensures nucleus beta-catenin transactivation
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Wnt-induced deubiquitination FoxM1 ensures nucleus beta-catenin transactivation

机译：Wnt-induced deubiquitination FoxM1确保核β-连环蛋白transactivation

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摘要

A key step of Wnt signaling activation is the recruitment of beta-catenin to the Wnt target-gene promoter in the nucleus, but its mechanisms are largely unknown. Here, we identified FoxM1 as a novel target of Wnt signaling, which is essential for beta-catenin/TCF4 transactivation. GSK3 phosphorylates FoxM1 on serine 474 which induces FoxM1 ubiquitination mediated by FBXW7. Wnt signaling activation inhibits FoxM1 phosphorylation by GSK3-Axin complex and leads to interaction between FoxM1 and deubiquitinating enzyme USP5, thereby deubiquitination and stabilization of FoxM1. FoxM1 accumulation in the nucleus promotes recruitment of beta-catenin to Wnt target-gene promoter and activates the Wnt signaling pathway by protecting the beta-catenin/TCF4 complex from ICAT inhibition. Subsequently, the USP5-FoxM1 axis abolishes the inhibitory effect of ICAT and is required for Wnt-mediated tumor cell proliferation. Therefore, Wnt-induced deubiquitination of FoxM1 represents a novel and critical mechanism for controlling canonical Wnt signaling and cell proliferation.
机译：Wnt信号激活的关键一步招聘Wntβ-连环蛋白的目标基因启动子在细胞核中,但它的机制在很大程度上是未知的。确定FoxM1作为小说Wnt的目标信号,这是至关重要的β-连环蛋白/ TCF4 transactivation。在丝氨酸磷酸化FoxM1 474导致由FBXW7 FoxM1泛素化调节。信号激活抑制FoxM1磷酸化GSK3-Axin复杂而导致FoxM1和deubiquitinating之间的互动酶USP5,从而deubiquitination和FoxM1的稳定。核促进β-连环蛋白的招聘Wnt目标基因启动子和Wnt激活信号通路的保护从ICAT抑制β-连环蛋白/ TCF4复杂。随后,USP5-FoxM1轴也取消了抑制作用的ICAT和需要Wnt-mediated肿瘤细胞增殖。Wnt-induced deubiquitination FoxM1的代表小说和关键控制的机制规范Wnt信号和细胞增殖。

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