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

Sixian Qi; Yuwen Zhu; Xincheng Liu; Pengyue Li; Yebin Wang; Yan Zeng; Aijuan Yu; Yu Wang; Zhao Sha; Zhenxing Zhong; Rui Zhu; Haixin Yuan; Dan Ye; Shenglin Huang; Chen Ling; Yanhui Xu; Dawang Zhou; Lei Zhang; Fa-Xing Yu

doi:10.1016/j.molcel.2022.03.027

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. Epub 2022 Apr 15.

Authors

Sixian Qi¹, Yuwen Zhu¹, Xincheng Liu¹, Pengyue Li², Yebin Wang¹, Yan Zeng¹, Aijuan Yu¹, Yu Wang¹, Zhao Sha¹, Zhenxing Zhong¹, Rui Zhu¹, Haixin Yuan³, Dan Ye³, Shenglin Huang³, Chen Ling⁴, Yanhui Xu³, Dawang Zhou⁵, Lei Zhang², Fa-Xing Yu⁶

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.

MeSH terms

Carcinogenesis
Hippo Signaling Pathway
Humans
Intracellular Signaling Peptides and Proteins / genetics
Intracellular Signaling Peptides and Proteins / metabolism
Phosphorylation
Protein Serine-Threonine Kinases* / genetics
Protein Serine-Threonine Kinases* / metabolism
Signal Transduction* / physiology
Tumor Suppressor Proteins / metabolism

Substances

Intracellular Signaling Peptides and Proteins
Tumor Suppressor Proteins
WWC1 protein, human
LATS1 protein, human
LATS2 protein, human
Protein Serine-Threonine Kinases