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Wnt‐induced deubiquitination FoxM1 ensures nucleus β‐catenin transactivation
Authors:Aihua Gong  Guanzhen Yu  Aidong Zhou  Kangyu Lin  Sicong Zhang  Nu Zhang  Cara J Gottardi  Suyun Huang
Institution:1. Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA;2. Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA;3. Program in Cancer Biology, The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, TX, USA
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.
Keywords:FoxM1  ICAT  ubiquitination  USP5  Wnt/β  ‐catenin signaling
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