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. 2019 Jan 3;73(1):7-21.e7.
doi: 10.1016/j.molcel.2018.10.030. Epub 2018 Nov 21.

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

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

Zhengkui Zhang et al. Mol Cell. .
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Abstract

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.

Keywords: OTUB2; SUMOylation; YAP/TAZ; deubiquitination; metastasis.

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