Analysis of Hippo-YAP signaling pathway that regulates cell tension in liver formation

• Project/Area Number: 17H03982
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Biological pharmacy
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: Nishina Hiroshi 東京医科歯科大学, 難治疾患研究所, 教授 (60212122)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥18,070,000 (Direct Cost: ¥13,900,000、Indirect Cost: ¥4,170,000); Fiscal Year 2019: ¥5,720,000 (Direct Cost: ¥4,400,000、Indirect Cost: ¥1,320,000); Fiscal Year 2018: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000); Fiscal Year 2017: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
• Keywords: 肝臓 / 細胞張力 / MDCK細胞 / YAP / サイズ / 品質管理 / Hippo-YAP / FRET / 張力 / シグナル伝達系 / Hippo / バイオセンサー / 細胞排除 / 肝細胞

Outline of Final Research Achievements

Organs including the liver are grown and maintained at an appropriate size through cell proliferation. Elucidation of the molecular mechanism that controls the size and quality of organs is an important issue both in Japan and abroad. From the isolation and analysis of medaka mutants, we showed that the transcriptional co-activator YAP plays an essential role in 3D organogenesis via cell tension, and that activated YAP-expressing canine kidney epithelial cells (MDCK) induces pressure on adjacent cells and extrusion of YAP-expressing cells to the apical surface. In this study, we found that 1) YAP-dependent elimination of impaired hepatocytes in mouse livers, and 2) an essential role of prostaglandin E2 in YAP-dependent MDCK elimination.

Academic Significance and Societal Importance of the Research Achievements

器官のサイズ制御と品質管理の分子機構の解明は、国内外を通じて重要で興味深い研究課題である。がん原遺伝子産物YAPが、細胞数の調節を介して器官サイズ制御に関与するという発見は多くの研究者に驚きをもって迎えられた。我々はYAPが細胞張力の調節を介して3D器官形成に関与することを見出した。また、異常細胞の排除の調節を介して器官の品質管理の制御にも関与することを示唆した。以上の研究成果は、器官のサイズと品質を制御する分子機構の一端を解明した学術的意義がある。また、再生医学の基盤研究として社会的意義がある。

Research Products

• [Journal Article] Prostaglandin E2 and its receptor EP2 trigger signaling that contributes to YAP-mediated cell competition. (2020)
  • Author(s): Ishihara E, Nagaoka Y, Okuno T, Kofuji S, Ishigami-Yuasa M, Kagechika H, Kamimura K, Terai S, Yokomizo T, Sugimoto Y, Fujita Y, Suzuki A, Nishina H.
  • Journal Title: Genes Cells. Volume: 25(3) Issue: 3 Pages: 197-214
  • DOI: 10.1111/gtc.12750
  • NAID: 120006873037
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The Hippo-YAP Pathway Regulates 3D Organ Formation and Homeostasis (2018)
  • Author(s): Ishihara Erika、Nishina Hiroshi
  • Journal Title: Cancers Volume: 10 Issue: 4 Pages: 122-122
  • DOI: 10.3390/cancers10040122
  • Peer Reviewed / Open Access
• [Journal Article] Erratum: YAP determines the cell fate of injured mouse hepatocytes in vivo (2017)
  • Author(s): Miyamura Norio、Hata Shoji、Itoh Tohru、Tanaka Minoru、Nishio Miki、Itoh Michiko、Ogawa Yoshihiro、Terai Shuji、Sakaida Isao、Suzuki Akira、Miyajima Atsushi、Nishina Hiroshi
  • Journal Title: Nature Communications Volume: 8 Issue: 1 Pages: 16017-16017
  • DOI: 10.1038/ncomms16146
  • Peer Reviewed / Open Access
• [Journal Article] Age-dependent motor dysfunction due to neuron-specific disruption of stress-activated protein kinase MKK7 (2017)
  • Author(s): Yamasaki T, Deki-Arima N, Kaneko A, Miyamura N, Iwatsuki M, Matsuoka M, Fujimori-Tonou N, Okamoto-Uchida Y, Hirayama J, Marth JD, Yamanashi Y, Kawasaki H, Yamanaka K, Penninger JM, Shibata S, Nishina H.
  • Journal Title: Sci. Rep. Volume: 7 Issue: 1 Pages: 7348-7348
  • DOI: 10.1038/s41598-017-07845-x
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Endosomal phosphatidylserine is critical for the YAP signalling pathway in proliferating cells (2017)
  • Author(s): Matsudaira, T., K. Mukai, T. Noguchi, J. Hasegawa, T. Hatta, S. Iemura, T. Natsume, N. Miyamura, H. Nishina, J. Nakayama, K. Semba, T. Tomita, S. Murata, H. Arai, and T. Taguchi
  • Journal Title: Nature Communications Volume: 8(1) Issue: 1 Pages: 651-651
  • DOI: 10.1038/s41467-017-01255-3
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] MOB1-YAP1/TAZ-NKX2.1 axis controls bronchioalveolar cell differentiation, adhesion and tumour formation. Oncogene (2017)
  • Author(s): Otsubo K, Goto H, Nishio M, Kawamura K, Yanagi S, Nishie W, Sasaki T, Maehama T, Nishina H, Mimori K, Nakano T, Shimizu H, Mak TW, Nakao K, Nakanishi Y, Suzuki A
  • Journal Title: Oncogene Volume: 印刷中 Issue: 29 Pages: 4201-4211
  • DOI: 10.1038/onc.2017.58
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Human Papillomavirus 16 E6 Upregulates APOBEC3B via the TEAD Transcription Factor. (2017)
  • Author(s): Mori S, Takeuchi T, Ishii Y, Yugawa T, Kiyono T, Nishina H, Kukimoto I.
  • Journal Title: Journal of Virology Volume: 91 Issue: 6
  • DOI: 10.1128/jvi.02413-16
  • Peer Reviewed / Open Access
• [Journal Article] Manganese and cobalt activate zebrafish ovarian cancer G-protein-coupled receptor 1 but not GPR4. (2017)
  • Author(s): J. Negishi, Y. Omori, M. Shindo, H. Takanashi, S. Musha, S. Nagayama, J. Hirayama, H. Nishina, T. Nakakura, C. Mogi, K. Sato, F. Okajima, Y. Mochimaru, H. Tomura
  • Journal Title: J. Recept. Signal Transduct. Res. Volume: - Issue: 4 Pages: 401-408
  • DOI: 10.1080/10799893.2017.1298130
  • Peer Reviewed / Open Access
• [Journal Article] Novel YAP1 Activator, Identified by Transcription-Based Functional Screen, Limits Multiple Myeloma Growth (2017)
  • Author(s): Maruyama Junichi、Inami Kazutoshi、Michishita Fumiyoshi、Jiang Xinliang、Iwasa Hiroaki、Nakagawa Kentaro、Ishigami-Yuasa Mari、Kagechika Hiroyuki、Miyamura Norio、Hirayama Jun、Nishina Hiroshi、Nogawa Daichi、Yamamoto Kouhei、Hata Yutaka
  • Journal Title: Molecular Cancer Research Volume: 16 Issue: 2 Pages: 197-211
  • DOI: 10.1158/1541-7786.mcr-17-0382
  • Peer Reviewed / Open Access
• [Journal Article] YAP is essential for 3D organogenesis withstanding gravity. (2017)
  • Author(s): Asaoka Y, Nishina H, Furutani-Seiki M.
  • Journal Title: Dev Growth Differ. Volume: 59 Issue: 1 Pages: 52-58
  • DOI: 10.1111/dgd.12338
  • Peer Reviewed / Open Access
• [Presentation] The Hippo-YAP Pathway Regulates liver size and homeostasis (2019)
  • Author(s): Hiroshi Nishina
  • Organizer: The Cold Spring Harber Asia conference on Liver, Biology, Diseases & Cancer
  • Int'l Joint Research / Invited
• [Presentation] 脊椎動物の3D器官形成と維持 (2019)
  • Author(s): 仁科 博史
  • Organizer: 国立医薬品食品衛生研究所
  • Invited
• [Presentation] 高次神経活動を制御するJNKシグナル (2019)
  • Author(s): 仁科博史
  • Organizer: 第92回日本生化学大会
  • Invited
• [Presentation] 脊椎動物の3D器官形成と維持 (2019)
  • Author(s): 仁科博史
  • Organizer: 脊椎動物の3D器官形成と維持
  • Invited
• [Presentation] 肝臓の形成と維持機構 (2019)
  • Author(s): 仁科博史
  • Organizer: 市原明先生追悼シンポジウム
  • Invited
• [Presentation] YAP acts as a stress sensor that induces elimination of injured hepatocytes (2018)
  • Author(s): Hiroshi Nishina
  • Organizer: FASEB Fundamental Biology and Pathophysiology of the Liver
  • Int'l Joint Research
• [Presentation] Active Yes-associated protein (YAP) induces mammalian cell extrusion in vitro and in vivo (2018)
  • Author(s): Hiroshi Nishina
  • Organizer: 9th Xiamen Winter Symposium, Xiamen,China
  • Int'l Joint Research / Invited
• [Presentation] 脊椎動物の3D器官構築と維持 (2018)
  • Author(s): 仁科博史
  • Organizer: 第29回加藤記念研究助成特別講演
  • Invited
• [Presentation] 異常肝細胞排除による品質管理機構の解明 (2018)
  • Author(s): 仁科博史
  • Organizer: 第25回肝細胞研究会
  • Invited
• [Presentation] The Hippo-YAP pathway regulates 3D liver formation and homeostasis (2018)
  • Author(s): Hiroshi Nishina
  • Organizer: 86th LGS seminar
  • Invited
• [Presentation] YAP determines the cell fate of injured mouse hepatocytes in vivo (2017)
  • Author(s): Hiroshi Nishina
  • Organizer: The 2017 Cold Spring Harboe Asia Conference
  • Int'l Joint Research / Invited
• [Book] 分子細胞生物学 第8版 (2019)
  • Author(s): H. Lodishほか、榎森 康文、堅田 利明、須藤 和夫、富田 泰輔、仁科 博史、山本 啓一
  • Total Pages: 1108
  • Publisher: 東京化学同人
  • ISBN: 9784807909766