2. Academic Validation
  3. WWC proteins mediate LATS1/2 activation by Hippo kinases and imply a tumor suppression strategy

WWC proteins mediate LATS1/2 activation by Hippo kinases and imply a tumor suppression strategy

  • Mol Cell. 2022 May 19;82(10):1850-1864.e7. doi: 10.1016/j.molcel.2022.03.027.
Sixian Qi 1,  Yuwen Zhu 1,  Xincheng Liu 1,  Pengyue Li 2,  Yebin Wang 1,  Yan Zeng 1,  Aijuan Yu 1,  Yu Wang 1,  Zhao Sha 1,  Zhenxing Zhong 1,  Rui Zhu 1,  Haixin Yuan 3,  Dan Ye 3,  Shenglin Huang 3,  Chen Ling 4,  Yanhui Xu 3,  Dawang Zhou 5,  Lei Zhang 2,  Fa-Xing Yu 6
Affiliations

Affiliations

  • 1 Institute of Pediatrics, Children's Hospital of Fudan University, and Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China.
  • 2 State Key Laboratory of Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China.
  • 3 Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China.
  • 4 State Key Laboratory of Genetic Engineering and Engineering Research Center of Gene Technology (Ministry of Education), School of Life Sciences, Zhongshan Hospital, Fudan University, Shanghai 200438, China.
  • 5 School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China.
  • 6 Institute of Pediatrics, Children's Hospital of Fudan University, and Shanghai Key Laboratory of Medical Epigenetics, International Co-laboratory of Medical Epigenetics and Metabolism, Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China. Electronic address: fxyu@fudan.edu.cn.
PMID: 35429439 DOI: 10.1016/j.molcel.2022.03.027
Abstract

YAP and TAZ (YAP/TAZ), two major effectors of the Hippo signaling pathway, are frequently activated in human cancers. The activity of YAP/TAZ is strictly repressed upon phosphorylation by LATS1/2 tumor suppressors. However, it is unclear how LATS1/2 are precisely regulated by upstream factors such as Hippo kinases MST1/2. Here, we show that WWC proteins (WWC1/2/3) directly interact with LATS1/2 and SAV1, and SAV1, in turn, brings in MST1/2 to phosphorylate and activate LATS1/2. Hence, WWC1/2/3 play an organizer role in a signaling module that mediates LATS1/2 activation by MST1/2. Moreover, we have defined a minimum protein interaction interface on WWC1/2/3 that is sufficient to activate LATS1/2 in a robust and specific manner. The corresponding minigene, dubbed as SuperHippo, can effectively suppress tumorigenesis in multiple tumor models. Our study has uncovered a molecular mechanism underlying LATS1/2 regulation and provides a strategy for treating diverse malignancies related to Hippo pathway dysregulation.

Keywords

Hippo; KIBRA; LATS1; LATS2; MST1; MST2; TAZ; WWC1; YAP; cancer.

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