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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
- Molecular cell 2019 v.73 no.1 pp. 7-21.e7
- carcinogenesis, gain-of-function mutation, humans, lysine, metastasis, neoplasms, sumoylation, transcription factors
- 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.