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• W4324309676 abstract "Article15 March 2023 Source DataTransparent process Two Hippo signaling modules orchestrate liver size and tumorigenesis Sixian Qi Sixian Qi Institute of Pediatrics, Children's Hospital of Fudan University, Shanghai, China 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 Contribution: Formal analysis, ​Investigation, Methodology, Writing - review & editing Search for more papers by this author Zhenxing Zhong Zhenxing Zhong orcid.org/0000-0001-5283-1066 Institute of Pediatrics, Children's Hospital of Fudan University, Shanghai, China 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 Contribution: Formal analysis, ​Investigation, Methodology, Writing - review & editing Search for more papers by this author Yuwen Zhu Yuwen Zhu orcid.org/0000-0003-2059-075X Institute of Pediatrics, Children's Hospital of Fudan University, Shanghai, China 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 Contribution: Formal analysis, ​Investigation, Methodology Search for more papers by this author Yebin Wang Yebin Wang Institute of Pediatrics, Children's Hospital of Fudan University, Shanghai, China 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 Contribution: Formal analysis Search for more papers by this author Mingyue Ma Mingyue Ma Institute of Pediatrics, Children's Hospital of Fudan University, Shanghai, China 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 Contribution: ​Investigation Search for more papers by this author Yu Wang Yu Wang orcid.org/0000-0003-1070-2818 Institute of Pediatrics, Children's Hospital of Fudan University, Shanghai, China 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 Contribution: ​Investigation Search for more papers by this author Xincheng Liu Xincheng Liu orcid.org/0000-0002-2950-729X Institute of Pediatrics, Children's Hospital of Fudan University, Shanghai, China 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 Contribution: ​Investigation Search for more papers by this author Ruxin Jin Ruxin Jin Institute of Pediatrics, Children's Hospital of Fudan University, Shanghai, China 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 Contribution: ​Investigation Search for more papers by this author Zhihan Jiao Zhihan Jiao orcid.org/0000-0001-6018-1577 Institute of Pediatrics, Children's Hospital of Fudan University, Shanghai, China 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 Contribution: ​Investigation Search for more papers by this author Rui Zhu Rui Zhu Institute of Pediatrics, Children's Hospital of Fudan University, Shanghai, China 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 Contribution: ​Investigation Search for more papers by this author Zhao Sha Zhao Sha Institute of Pediatrics, Children's Hospital of Fudan University, Shanghai, China 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 Contribution: ​Investigation, Project administration Search for more papers by this author Kyvan Dang Kyvan Dang Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA, USA Contribution: Resources Search for more papers by this author Ying Liu Ying Liu Department of Pathology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, China Contribution: Formal analysis Search for more papers by this author Dae-Sik Lim Dae-Sik Lim orcid.org/0000-0003-2356-7555 Department of Biological Sciences, National Creative Research Initiatives Center, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea Contribution: Resources Search for more papers by this author Junhao Mao Junhao Mao Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA, USA Contribution: Resources Search for more papers by this author Lei Zhang Lei Zhang orcid.org/0000-0003-2566-6493 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 Sheng Yushou Center of Cell Biology and Immunology, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China School of Life Science and Technology, ShanghaiTech University, Shanghai, China Contribution: Resources, Formal analysis Search for more papers by this author Fa-Xing Yu Corresponding Author Fa-Xing Yu [email protected] orcid.org/0000-0003-4834-9335 Institute of Pediatrics, Children's Hospital of Fudan University, Shanghai, China 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 Contribution: Conceptualization, Resources, Formal analysis, Supervision, Funding acquisition, ​Investigation, Methodology, Writing - original draft, Project administration, Writing - review & editing Search for more papers by this author Sixian Qi Sixian Qi Institute of Pediatrics, Children's Hospital of Fudan University, Shanghai, China 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 Contribution: Formal analysis, ​Investigation, Methodology, Writing - review & editing Search for more papers by this author Zhenxing Zhong Zhenxing Zhong orcid.org/0000-0001-5283-1066 Institute of Pediatrics, Children's Hospital of Fudan University, Shanghai, China 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 Contribution: Formal analysis, ​Investigation, Methodology, Writing - review & editing Search for more papers by this author Yuwen Zhu Yuwen Zhu orcid.org/0000-0003-2059-075X Institute of Pediatrics, Children's Hospital of Fudan University, Shanghai, China 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 Contribution: Formal analysis, ​Investigation, Methodology Search for more papers by this author Yebin Wang Yebin Wang Institute of Pediatrics, Children's Hospital of Fudan University, Shanghai, China 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 Contribution: Formal analysis Search for more papers by this author Mingyue Ma Mingyue Ma Institute of Pediatrics, Children's Hospital of Fudan University, Shanghai, China 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 Contribution: ​Investigation Search for more papers by this author Yu Wang Yu Wang orcid.org/0000-0003-1070-2818 Institute of Pediatrics, Children's Hospital of Fudan University, Shanghai, China 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 Contribution: ​Investigation Search for more papers by this author Xincheng Liu Xincheng Liu orcid.org/0000-0002-2950-729X Institute of Pediatrics, Children's Hospital of Fudan University, Shanghai, China 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 Contribution: ​Investigation Search for more papers by this author Ruxin Jin Ruxin Jin Institute of Pediatrics, Children's Hospital of Fudan University, Shanghai, China 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 Contribution: ​Investigation Search for more papers by this author Zhihan Jiao Zhihan Jiao orcid.org/0000-0001-6018-1577 Institute of Pediatrics, Children's Hospital of Fudan University, Shanghai, China 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 Contribution: ​Investigation Search for more papers by this author Rui Zhu Rui Zhu Institute of Pediatrics, Children's Hospital of Fudan University, Shanghai, China 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 Contribution: ​Investigation Search for more papers by this author Zhao Sha Zhao Sha Institute of Pediatrics, Children's Hospital of Fudan University, Shanghai, China 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 Contribution: ​Investigation, Project administration Search for more papers by this author Kyvan Dang Kyvan Dang Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA, USA Contribution: Resources Search for more papers by this author Ying Liu Ying Liu Department of Pathology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, China Contribution: Formal analysis Search for more papers by this author Dae-Sik Lim Dae-Sik Lim orcid.org/0000-0003-2356-7555 Department of Biological Sciences, National Creative Research Initiatives Center, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea Contribution: Resources Search for more papers by this author Junhao Mao Junhao Mao Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA, USA Contribution: Resources Search for more papers by this author Lei Zhang Lei Zhang orcid.org/0000-0003-2566-6493 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 Sheng Yushou Center of Cell Biology and Immunology, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China School of Life Science and Technology, ShanghaiTech University, Shanghai, China Contribution: Resources, Formal analysis Search for more papers by this author Fa-Xing Yu Corresponding Author Fa-Xing Yu [email protected] orcid.org/0000-0003-4834-9335 Institute of Pediatrics, Children's Hospital of Fudan University, Shanghai, China 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 Contribution: Conceptualization, Resources, Formal analysis, Supervision, Funding acquisition, ​Investigation, Methodology, Writing - original draft, Project administration, Writing - review & editing Search for more papers by this author Author Information Sixian Qi1,2,†, Zhenxing Zhong1,2,†, Yuwen Zhu1,2,†, Yebin Wang1,2,†, Mingyue Ma1,2, Yu Wang1,2, Xincheng Liu1,2, Ruxin Jin1,2, Zhihan Jiao1,2, Rui Zhu1,2, Zhao Sha1,2, Kyvan Dang3, Ying Liu4, Dae-Sik Lim5, Junhao Mao3, Lei Zhang6,7,8 and Fa-Xing Yu *,1,2 1Institute of Pediatrics, Children's Hospital of Fudan University, Shanghai, China 2The 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 3Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA, USA 4Department of Pathology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, China 5Department of Biological Sciences, National Creative Research Initiatives Center, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea 6State Key Laboratory of Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China 7Sheng Yushou Center of Cell Biology and Immunology, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China 8School of Life Science and Technology, ShanghaiTech University, Shanghai, China † These authors contributed equally to this work *Corresponding author. Tel: +86 21 54237834; E-mail: [email protected] The EMBO Journal (2023)42:e112126https://doi.org/10.15252/embj.2022112126 See also: H Han & W Wang (June 2023) Full textView the full text of the articlePDFDownload PDF of article text and main figures.PDF PLUSDownload PDF of article text, main figures, expanded view figures and appendix. Peer ReviewDownload a summary of the editorial decision process including editorial decision letters, reviewer comments and author responses to feedback. ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions Figures & Info 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. Synopsis The Hippo pathway inhibits YAP/TAZ transcriptional co-activators to regulate organ size and tumorigenesis. This study shows that upstream kinases and associated adaptor proteins of the Hippo pathway form two signaling modules that differentially regulate YAP/TAZ activity and its function in the liver. The HPO1 module is formed by MST1/2 kinases and the adaptor proteins SAV1 and WWC1-3, while the HPO2 module includes MAP4K1-7 and the adaptor protein NF2. Simultaneous deletion of HPO1 and HPO2 components leads to full activation of YAP/TAZ in a manner comparable with LATS1/2 deficiency. Liver-specific inactivation of either HPO1 or HPO2 module results in partial YAP/TAZ activation, bile duct hyperplasia, and hepatocellular carcinoma. Inactivation of both HPO1 and HPO2 modules in the liver results in intrahepatic cholangiocarcinoma and early lethality. HPO1 is the major organ size regulator, and its inactivation causes rapid hepatomegaly. Previous ArticleNext Article Read MoreAbout the coverClose modalView large imageVolume 42,Issue 11,01 June 2023This cover highlights the article Single cell analysis of lymphatic endothelial cell fate specification and differentiation during zebrafish development by Lin Grimm, Elizabeth Mason, Ben Hogan and colleagues. A combination of single cell analysis and functional genomics reveals the timing of lymphatic differentiation in zebrafish and a role of the master fate regulator Prox1 in this process. The cover shows stages of craniofacial vascular development in zebrafish at 3, 5, 7 and 14 days post-fertilisation. (Scientific image by Ryan Brown, Peter MacCallum Cancer Centre, Melbourne, Australia) Volume 42Issue 111 June 2023In this issue ReferencesRelatedDetailsLoading ..." @default.
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• W4324309676 title "Two Hippo signaling modules orchestrate liver size and tumorigenesis" @default.
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