Clarification of the reciprocal interactions between Amot and Lats in activation of the Hippo pathway

• Project/Area Number: 25440112
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Developmental biology
• Research Institution: Tokyo Medical and Dental University (2014-2015); Kumamoto University (2013)
• Principal Investigator: Hirate Yoshikazu 東京医科歯科大学, 実験動物センター, 講師 (70342839)
• Co-Investigator(Renkei-kenkyūsha): SASAKI HIROSHI 大阪大学, 大学院生命機能研究科, 教授 (10211939)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2014: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2013: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
• Keywords: 発生・分化 / シグナル伝達 / 細胞間コミュニケーション / Hippo経路 / 細胞極性 / 非対称分裂 / Angiomotin / Lats

Outline of Final Research Achievements

The Hippo signaling pathway regulates a number of cellular events, including the control of cell fates in preimplantation mouse embryos. The inner and outer cells of the embryo show high and low levels of Hippo signaling, respectively. This position-dependent Hippo signaling promotes the specification of distinct cell fates. The junction-associated scaffold protein Angiomotin (Amot) plays a key role in this mechanism. At the adherens junctions of the inner cells, Amot activates the Hippo pathway by recruiting and activating the protein kinase large tumor suppressor (Lats). In contrast, Amot at the apical membrane of the outer cells suppresses Hippo signaling by interacting with F-actin. The phosphorylation of Amot inhibits its interaction with F-actin and activates Hippo signaling. We propose that Amot acts as a molecular switch for the Hippo pathway and links F-actin with Lats activity.

Research Products

• [Journal Article] Par-aPKC-dependent and -independent mechanisms cooperatively control cell polarity, Hippo signaling, and cell positioning in 16-cell stage mouse embryos (2015)
  • Author(s): Hirate, Y., Hirahara, S., Inoue, K., Kiyonari, H., Niwa, H., and Sasaki, H.
  • Journal Title: Development, Growth and Differentiation Volume: 57 Issue: 8 Pages: 544-556
  • DOI: 10.1111/dgd.12235
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] The role of angiomotin phosphorylation in the Hippo pathway during preimplantation mouse development (2014)
  • Author(s): Hirate Y. and Sasaki H.
  • Journal Title: Tissue Barriers Volume: 2
  • Peer Reviewed
• [Journal Article] Polarity-dependent distribution of angiomotin localizes Hippo signaling in preimplantation embryos. (2013)
  • Author(s): Hirate Y, Hirahara S, Inoue K-i, Suzuki A, Alarcon VB, Akimoto K, Hirai T, Hara T, Adachi M, Chida K, Ohno S, Marikawa Y, Nakao K, Shimono A, Sasaki H
  • Journal Title: Curr. Biol. Volume: 23 Issue: 13 Pages: 1181-1194
  • DOI: 10.1016/j.cub.2013.05.014
  • Peer Reviewed / Open Access
• [Presentation] マウス着床前胚の細胞分化制御におけるHippo経路と細胞極性の役割 (2015)
  • Author(s): 平手 良和
  • Organizer: 第１０８回日本繁殖生物学会大会
  • Place of Presentation: 宮崎市民プラザ（宮崎県・宮崎市）
  • Year and Date: 2015-09-17
  • Int'l Joint Research / Invited
• [Presentation] マウス着床前胚の細胞分化はAngiomotinリン酸化によるHippo経路の活性化によって制御されている (2014)
  • Author(s): 平手良和、平原志乃、井上健一、鈴木厚、Vernadeth B. Alarcon、秋本和憲、平井孝明、千田和広、大野茂男、Yusuke Marikawa、中尾和貴、下野明彦、佐々木洋
  • Organizer: 第61回日本実験動物学会総会
  • Place of Presentation: 札幌コンベンションセンター
  • Year and Date: 2014-05-15 – 2014-05-17
• [Presentation] Phosphorylation of Angiomotin regulates the Hippo pathway in cell fate regulation of preimplantation mouse embryos (2014)
  • Author(s): 平手良和、平原志乃、井上健一、鈴木厚、Vernadeth B. Alarcon、秋本和憲、平井孝明、千田和広、大野茂男、Yusuke Marikawa、中尾和貴、下野明彦、佐々木洋
  • Organizer: 第61回日本実験動物学会総会
  • Place of Presentation: 札幌コンベンションセンター
• [Remarks] 熊本大学発生医学研究所分化制御分野
  • URL: http://www.imeg.kumamoto-u.ac.jp/divisions/cell_fate_control/index.html
• [Remarks] トピックス
  • URL: http://www.imeg.kumamoto-u.ac.jp/topics/sasaki130626.html