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Wnt‐induced deubiquitination FoxM1 ensures nucleus β‐catenin transactivation
Author(s) -
Chen Yaohui,
Li Yu,
Xue Jianfei,
Gong Aihua,
Yu Guanzhen,
Zhou Aidong,
Lin Kangyu,
Zhang Sicong,
Zhang Nu,
Gottardi Cara J,
Huang Suyun
Publication year - 2016
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.201592810
Subject(s) - neurosurgery , library science , medicine , surgery , computer science
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/ TCF 4 transactivation. GSK 3 phosphorylates FoxM1 on serine 474 which induces FoxM1 ubiquitination mediated by FBXW 7. Wnt signaling activation inhibits FoxM1 phosphorylation by GSK 3–Axin complex and leads to interaction between FoxM1 and deubiquitinating enzyme USP 5, 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/ TCF 4 complex from ICAT inhibition. Subsequently, the USP 5–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.