Wnt-induced deubiquitination FoxM1 ensures nucleus β-catenin transactivation.
A key step of Wnt signaling activation is the recruitment of β-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 β-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 β-catenin to Wnt target-gene promoter and activates the Wnt signaling pathway by protecting the β-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.
['Chen|Yaohui|Y|', 'Li|Yu|Y|', 'Xue|Jianfei|J|', 'Gong|Aihua|A|', 'Yu|Guanzhen|G|', 'Zhou|Aidong|A|', 'Lin|Kangyu|K|', 'Zhang|Sicong|S|', 'Zhang|Nu|N|', 'Gottardi|Cara J|CJ|', 'Huang|Suyun|S|']
D002460:Cell Line D010450:Endopeptidases D000072278:Forkhead Box Protein M1 D051858:Forkhead Transcription Factors D005786:Gene Expression Regulation D006801:Humans D015533:Transcriptional Activation D054875:Ubiquitination D051153:Wnt Proteins D060449:Wnt Signaling Pathway D051176:beta Catenin
FoxM1 ubiquitination USP5 ICAT Wnt/β‐catenin signaling