OTUB2 Promotes Cancer Metastasis via Hippo-Independent Activation of YAP and TAZ
OTUB2 Promotes Cancer Metastasis via Hippo-Independent Activation of YAP and TAZ
复制标题
OTUB2 通过 Hippo 独立激活 YAP 和 TAZ 促进癌症转移
DOI：
10.1016/j.molcel.2018.10.030
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发表时间：
2019-01-03
期刊：
影响因子：
16
通讯作者：
Zhang, Long
中科院分区：
文献类型：
--
作者：
Zhang, Zhengkui;Du, Jinjin;Zhang, Long
转录调节因子雅普和TAZ在发育、生理和肿瘤发生中起重要作用，并且受Hippo通路负控制。目前还不清楚为什么雅普/ TAZ蛋白在Hippo途径仍然活跃的人类恶性肿瘤中频繁活化。在这里，通过功能获得性癌症转移筛选，我们发现OTUB 2作为癌症干性和转移促进因子，其去泛素化并激活雅普/TAZ。我们发现OTUB 2在赖氨酸233上被聚SUMO化，并且这种SUMO化使其能够结合雅普/TAZ。我们还在雅普和TAZ中鉴定了一个未知的SUMO相互作用基序（SIM），这是它们与SUMO化OTUB 2结合所必需的。重要的是，EGF和致癌KRAS诱导OTUB 2聚SUMO化，从而激活雅普/TAZ。我们的研究结果确立了OTUB 2作为雅普/TAZ的重要调节剂，并揭示了致癌KRAS诱导雅普/TAZ活性的新机制。
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.