Deubiquitylase OTUD3 regulates PTEN stability and suppresses tumorigenesis.
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.
State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Collaborative Innovation Center for Cancer Medicine, Beijing 100850, China.|Institute of Cancer Stem Cell, Dalian Medical University, Liaoning Province 116044, China.
Lin
L
Yuan
Department of General Surgery, QiLu Hospital of Shandong University, Shandong Province 250012, China.
Yanrong
Y
Lv
State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Collaborative Innovation Center for Cancer Medicine, Beijing 100850, China.
Hongchang
H
Li
Department of General Surgery, QiLu Hospital of Shandong University, Shandong Province 250012, China.
Haidong
H
Gao
State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Collaborative Innovation Center for Cancer Medicine, Beijing 100850, China.
Shanshan
S
Song
State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Collaborative Innovation Center for Cancer Medicine, Beijing 100850, China.
Yuan
Y
Zhang
State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Collaborative Innovation Center for Cancer Medicine, Beijing 100850, China.
Guichun
G
Xing
State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Collaborative Innovation Center for Cancer Medicine, Beijing 100850, China.
Xiangzhen
X
Kong
Vascular Biology Research Institute, Guangdong Pharmaceutical University, Guangdong Province 510006, China.
Lijing
L
Wang
Department of Experimental Pathology, Beijing Institute of Radiation Medicine, Beijing 100850, China.
Yang
Y
Li
Institute of Basic Medical Sciences, China National Center of Biomedical Analysis, Beijing 100850, China.
Tao
T
Zhou
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.
Daming
D
Gao
School of Life Sciences, Sichuan University, Sichuan Province 610065, China.
Zhi-Xiong
ZX
Xiao
Institute of Systems Biomedicine, Center for Systems Biology and Medicine of Aging, Peking University Health Science Center, Beijing 100191, China.
Yuxin
Y
Yin
Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02115, USA.
Wenyi
W
Wei
State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Collaborative Innovation Center for Cancer Medicine, Beijing 100850, China.
Fuchu
F
He
State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Collaborative Innovation Center for Cancer Medicine, Beijing 100850, China.|Institute of Cancer Stem Cell, Dalian Medical University, Liaoning Province 116044, China.
Lingqiang
L
Zhang
D000818:Animals; D001943:Breast Neoplasms / Q000201:enzymology* / Q000473:pathology; D063646:Carcinogenesis / Q000378:metabolism*; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008822:Mice, Transgenic; D009154:Mutation; D009368:Neoplasm Transplantation; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D055550:Protein Stability; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D064570:Ubiquitin-Specific Proteases / Q000502:physiology*; D054875:Ubiquitination
D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; C000602831:OTUD3 protein, human; D064570:Ubiquitin-Specific Proteases