期刊
MOLECULAR CELL
卷 73, 期 1, 页码 7-+出版社
CELL PRESS
DOI: 10.1016/j.molcel.2018.10.030
关键词
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资金
- Ministry of Science and Technology of China [2016YFA0502500]
- Chinese National Natural Science Funds [31471315, 31671457, 31741086, 91753139, 31870902, 31500678, 31870839]
- Zhejiang Outstanding Youth Fund [LR14C070001]
- Jiangsu Outstanding Youth Fund [BK20180043]
- Major Social Development Projects of the Zhejiang S&T Major Projects [2015C03045]
- NIH, United States [CA196878, DE15964, GM51586]
The transcriptional regulators YAP and TAZ play important roles in development, physiology, and tumorigenesis and are negatively controlled by the Hippo pathway. It is yet unknown why the YAP/ TAZ proteins are frequently activated in human malignancies in which the Hippo pathway is still active. Here, by a gain-of-function cancer metastasis screen, we discovered OTUB2 as a cancer stemness and metastasis-promoting factor that deubiquitinates and activates YAP/TAZ. We found OTUB2 to be poly-SUMOylated on lysine 233, and this SUMOylation enables it to bind YAP/TAZ. We also identified a yet-unknown SUMO-interacting motif (SIM) in YAP and TAZ required for their association with SUMOylated OTUB2. Importantly, EGF and oncogenic KRAS induce OTUB2 poly-SUMOylation and thereby activate YAP/TAZ. Our results establish OTUB2 as an essential modulator of YAP/TAZ and also reveal a novel mechanism via which YAP/TAZ activity is induced by oncogenic KRAS.
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