Functional annotation of the Hippo pathway somatic mutations in human cancers

Nat Commun. 2024 Nov 21;15(1):10106. doi: 10.1038/s41467-024-54480-y.

Han Han ^# ¹ ² ³, Zhen Huang ^# ⁴, Congsheng Xu ^# ⁵, Gayoung Seo ⁶, Jeongmin An ⁶, Bing Yang ⁶, Yuhan Liu ⁶, Tian Lan ⁶, Jiachen Yan ⁶, Shanshan Ren ⁵, Yue Xu ⁷ ⁸, Di Xiao ⁷ ⁸, Jonathan K Yan ⁶, Claire Ahn ⁶, Dmitry A Fishman ⁹, Zhipeng Meng ¹⁰, Kun-Liang Guan ¹¹, Ruxi Qi ¹², Ray Luo ¹³ ¹⁴ ¹⁵ ¹⁶, Wenqi Wang ¹⁷

Affiliations

1 Department of Pathophysiology, TaiKang Medical School (School of Basic Medical Sciences), Wuhan University, Wuhan, Hubei, China. hanhan@whu.edu.cn.
2 TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan, Hubei, China. hanhan@whu.edu.cn.
3 Department of Developmental and Cell Biology, University of California, Irvine, Irvine, CA, USA. hanhan@whu.edu.cn.
4 Chemical and Materials Physics Graduate Program, University of California, Irvine, Irvine, CA, USA.
5 Department of Chemistry and Shenzhen Grubbs Institute, Guangdong Provincial Key Laboratory of Catalysis, Southern University of Science and Technology, Shenzhen, Guangdong, China.
6 Department of Developmental and Cell Biology, University of California, Irvine, Irvine, CA, USA.
7 Department of Pathophysiology, TaiKang Medical School (School of Basic Medical Sciences), Wuhan University, Wuhan, Hubei, China.
8 TaiKang Center for Life and Medical Sciences, Wuhan University, Wuhan, Hubei, China.
9 Department of Chemistry, University of California, Irvine, Irvine, CA, USA.
10 Department of Molecular and Cellular Pharmacology and Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA.
11 School of Life Sciences, Westlake University, Hangzhou, Zhejiang, China.
12 Cryo-EM Center, Southern University of Science and Technology, Shenzhen, Guangdong, China. qirx@sustech.edu.cn.
13 Department of Molecular Biology and Biochemistry, University of California, Irvine, Irvine, CA, USA. rluo@uci.edu.
14 Department of Chemical and Biomolecular Engineering, University of California, Irvine, Irvine, CA, USA. rluo@uci.edu.
15 Department of Materials Science and Engineering, University of California, Irvine, Irvine, CA, USA. rluo@uci.edu.
16 Department of Biomedical Engineering, University of California, Irvine, Irvine, CA, USA. rluo@uci.edu.
17 Department of Developmental and Cell Biology, University of California, Irvine, Irvine, CA, USA. wenqiw6@uci.edu.
# Contributed equally.

PMID: 39572544 DOI: 10.1038/s41467-024-54480-y

Abstract

The Hippo pathway is commonly altered in Cancer initiation and progression; however, exactly how this pathway becomes dysregulated to promote human Cancer development remains unclear. Here we analyze the Hippo somatic mutations in the human Cancer genome and functionally annotate their roles in targeting the Hippo pathway. We identify a total of 85 loss-of-function (LOF) missense mutations for Hippo pathway genes and elucidate their underlying mechanisms. Interestingly, we reveal zinc-finger domain as an integral structure for MOB1 function, whose LOF mutations in head and neck Cancer promote tumor growth. Moreover, the schwannoma/meningioma-derived NF2 LOF mutations not only inhibit its tumor suppressive function in the Hippo pathway, but also gain an oncogenic role for NF2 by activating the VANGL-JNK pathway. Collectively, our study not only offers a rich somatic mutation resource for investigating the Hippo pathway in human cancers, but also provides a molecular basis for Hippo-based Cancer therapy.

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HY-13319

JNK-IN-8

99.67%, JNK Inhibitor

JNK

Cancer

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