2. Academic Validation
  3. OTUB2 Promotes Cancer Metastasis via Hippo-Independent Activation of YAP and TAZ

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

  • Mol Cell. 2019 Jan 3;73(1):7-21.e7. doi: 10.1016/j.molcel.2018.10.030.
Zhengkui Zhang 1,  Jinjin Du 2,  Shuai Wang 3,  Li Shao 4,  Ke Jin 2,  Fang Li 2,  Bajin Wei 5,  Wei Ding 5,  Peifen Fu 5,  Hans van Dam 6,  Aijun Wang 7,  Jin Jin 2,  Chen Ding 8,  Bing Yang 2,  Min Zheng 4,  Xin-Hua Feng 2,  Kun-Liang Guan 9,  Long Zhang 10
Affiliations

Affiliations

  • 1 MOE Laboratory of Biosystems Homeostasis and Protection and Innovation Center for Cell Signaling Network, Life Sciences Institute, Zhejiang University, Hangzhou 310058, China; Institutes of Biology and Medical Sciences, Soochow University, Suzhou 215006, China.
  • 2 MOE Laboratory of Biosystems Homeostasis and Protection and Innovation Center for Cell Signaling Network, Life Sciences Institute, Zhejiang University, Hangzhou 310058, China.
  • 3 Institutes of Biology and Medical Sciences, Soochow University, Suzhou 215006, China.
  • 4 State Key Laboratory for Diagnostic and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Disease, Hangzhou 310000, China.
  • 5 Breast Disease Center, First Affiliated Hospital of Medicine College of Zhejiang University, Hangzhou 310006, China.
  • 6 Department of Cell and Chemical Biology, Oncode Institute, Leiden University Medical Center, 2300 RC Leiden, the Netherlands.
  • 7 Department of Surgery, School of Medicine, UC Davis, Davis, CA 95817, USA.
  • 8 State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Institute of Biomedical Sciences, Fudan University, 200433 Shanghai, China.
  • 9 Department of Pharmacology and Moores Cancer Center, University of California, San Diego, La Jolla, CA 94158, USA.
  • 10 MOE Laboratory of Biosystems Homeostasis and Protection and Innovation Center for Cell Signaling Network, Life Sciences Institute, Zhejiang University, Hangzhou 310058, China. Electronic address: l_zhang@zju.edu.cn.
PMID: 30472188 DOI: 10.1016/j.molcel.2018.10.030
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.

Figures
Products