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
  • 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: [email protected].
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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