Two Hippo signaling modules orchestrate liver size and tumorigenesis

  • EMBO J. 2023 Mar 15;e112126. doi: 10.15252/embj.2022112126.
Sixian Qi  #  1  2 ,  Zhenxing Zhong  #  1  2 ,  Yuwen Zhu  #  1  2 ,  Yebin Wang  #  1  2 ,  Mingyue Ma  1  2 ,  Yu Wang  1  2 ,  Xincheng Liu  1  2 ,  Ruxin Jin  1  2 ,  Zhihan Jiao  1  2 ,  Rui Zhu  1  2 ,  Zhao Sha  1  2 ,  Kyvan Dang  3 ,  Ying Liu  4 ,  Dae-Sik Lim  5 ,  Junhao Mao  3 ,  Lei Zhang  6  7  8 ,  Fa-Xing Yu  1  2
Affiliations
  • 1. Institute of Pediatrics, Children's Hospital of Fudan University, Shanghai, China.
  • 2. The Shanghai Key Laboratory of Medical Epigenetics, The International Co-laboratory of Medical Epigenetics and Metabolism, The State Key Laboratory of Genetic Engineering, Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China.
  • 3. Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA, USA.
  • 4. Department of Pathology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, China.
  • 5. Department of Biological Sciences, National Creative Research Initiatives Center, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea.
  • 6. State Key Laboratory of Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.
  • 7. Sheng Yushou Center of Cell Biology and Immunology, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China.
  • 8. School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
  • # Contributed equally.
PMID: 36919851 DOI: 10.15252/embj.2022112126
Abstract

The Hippo pathway is a central regulator of organ size and tumorigenesis and is commonly depicted as a kinase cascade, with an increasing number of regulatory and adaptor proteins linked to its regulation over recent years. Here, we propose that two Hippo signaling modules, MST1/2-SAV1-WWC1-3 (HPO1) and MAP4K1-7-NF2 (HPO2), together regulate the activity of LATS1/2 kinases and YAP/TAZ transcriptional co-activators. In mouse livers, the genetic inactivation of either HPO1 or HPO2 module results in partial activation of YAP/TAZ, bile duct hyperplasia, and hepatocellular carcinoma (HCC). On the contrary, inactivation of both HPO1 and HPO2 modules results in full activation of YAP/TAZ, rapid development of intrahepatic cholangiocarcinoma (iCCA), and early lethality. Interestingly, HPO1 has a predominant role in regulating organ size. HPO1 inactivation causes a homogenous YAP/TAZ activation and cell proliferation across the whole liver, resulting in a proportional and rapid increase in liver size. Thus, this study has reconstructed the order of the Hippo signaling network and suggests that LATS1/2 and YAP/TAZ activities are finetuned by HPO1 and HPO2 modules to cause different cell fates, organ size changes, and tumorigenesis trajectories.

Keywords
Hippo; NF2; YAP; liver cancer; organ size.
Products