title: Wnt-induced deubiquitination FoxM1 ensures nucleus β-catenin transactivation.
abstract: 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.
authors.affiliation: Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Yaohui
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA Cell Engineering Research Center and Department of Cell Biology, Fourth Military Medical University, Xi'an, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Jianfei
authors.initials: J
authors.lastname: Xue
authors.affiliation: Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Aihua
authors.initials: A
authors.lastname: Gong
authors.affiliation: Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Guanzhen
authors.initials: G
authors.lastname: Yu
authors.affiliation: Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Aidong
authors.initials: A
authors.lastname: Zhou
authors.affiliation: Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Kangyu
authors.initials: K
authors.lastname: Lin
authors.affiliation: Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Sicong
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Nu
authors.initials: N
authors.lastname: Zhang
authors.affiliation: Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: Cara J
authors.initials: CJ
authors.lastname: Gottardi
authors.affiliation: Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA Program in Cancer Biology, The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX, USA suhuang@mdanderson.org.
authors.forename: Suyun
authors.initials: S
authors.lastname: Huang
mesh_terms: D002460:Cell Line; D010450:Endopeptidases / Q000378:metabolism; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D015533:Transcriptional Activation; D054875:Ubiquitination; D051153:Wnt Proteins / Q000378:metabolism*; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000378:metabolism*
chemical_list: C495270:CTNNB1 protein, human; C107585:FOXM1 protein, human; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; D051153:Wnt Proteins; D051176:beta Catenin; D010450:Endopeptidases; C091939:ubiquitin isopeptidase
keywords: FoxM1; ICAT; USP5; Wnt/β‐catenin signaling; ubiquitination