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OTUB2 Promotes Cancer Metastasis via Hippo-Independent Activation of YAP and TAZ.

Zhang, Zhengkui; Du, Jinjin; Wang, Shuai; Shao, Li; Jin, Ke; Li, Fang; Wei, Bajin; Ding, Wei; Fu, Peifen; van Dam, Hans; Wang, Aijun; Jin, Jin; Ding, Chen; Yang, Bing; Zheng, Min; Feng, Xin-Hua; Guan, Kun-Liang; Zhang, Long.
Mol Cell; 2018 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-30472188
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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