机构：[1]State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Collaborative Innovation Center for Cancer Medicine, Beijing 100850, China.[2]Institute of Cancer Stem Cell, Dalian Medical University, Liaoning Province 116044, China.[3]Department of General Surgery, QiLu Hospital of Shandong University, Shandong Province 250012, China.[4]Vascular Biology Research Institute, Guangdong Pharmaceutical University, Guangdong Province 510006, China.[5]Department of Experimental Pathology, Beijing Institute of Radiation Medicine, Beijing 100850, China.[6]Institute of Basic Medical Sciences, China National Center of Biomedical Analysis, Beijing 100850, China.[7]Key Laboratory of Systems Biology, Innovation Center for Cell Signaling Network, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.[8]School of Life Sciences, Sichuan University, Sichuan Province 610065, China.[9]Institute of Systems Biomedicine, Center for Systems Biology and Medicine of Aging, Peking University Health Science Center, Beijing 100191, China.[10]Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02115, USA.
PTEN is one of the most frequently mutated tumour suppressors and reduction in PTEN protein stability also plays a role in tumorigenesis. Although several ubiquitin ligases for PTEN have been identified, the deubiquitylase for de-polyubiquitylation and stabilization of PTEN is less defined. Here, we report OTUD3 as a deubiquitylase of PTEN. OTUD3 interacts with, de-polyubiquitylates and stabilizes PTEN. Depletion of OTUD3 leads to the activation of Akt signalling, induction of cellular transformation and cancer metastasis. OTUD3 transgenic mice exhibit higher levels of the PTEN protein and are less prone to tumorigenesis. Reduction of OTUD3 expression, concomitant with decreased PTEN abundance, correlates with human breast cancer progression. Furthermore, we identified loss-of-function OTUD3 mutations in human cancers, which either abolish OTUD3 catalytic activity or attenuate the interaction with PTEN. These findings demonstrate that OTUD3 is an essential regulator of PTEN and that the OTUD3-PTEN signalling axis plays a critical role in tumour suppression.
基金：
This work was supported
by Chinese National Basic Research Programs (2012CB910702, 2011CB910602,
2012CB910304), the Program of International S&T Cooperation (2014DFB30020),
Chinese National Natural Science Foundation Projects (31330021, 31125010,
81221004) and Beijing Natural Science Foundation Project (5142020).
语种：
外文
PubmedID：
中科院(CAS)分区：
出版当年[2015]版：
大类|1 区生物
小类|1 区细胞生物学
最新[2023]版：
大类|1 区生物学
小类|1 区细胞生物学
第一作者：
第一作者机构：[1]State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Collaborative Innovation Center for Cancer Medicine, Beijing 100850, China.[2]Institute of Cancer Stem Cell, Dalian Medical University, Liaoning Province 116044, China.
共同第一作者：
通讯作者：
通讯机构：[1]State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Collaborative Innovation Center for Cancer Medicine, Beijing 100850, China.[2]Institute of Cancer Stem Cell, Dalian Medical University, Liaoning Province 116044, China.
生物