Molecular and functional studies of early embryonic phosphatidylinositol 3-kinase and its associating protein.

• Project/Area Number: 25850220
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Integrative animal science
• Research Institution: The University of Tokyo
• Principal Investigator: KAMEI HIROYASU 東京大学, 農学生命科学研究科, 特任研究員 (00610362)
• Project Period (FY): 2013-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2014: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000); Fiscal Year 2013: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: ホスファチジルイノシトール3キナーゼ / 胚性幹細胞 / ゼブラフィッシュ / PI3K結合分子

Outline of Final Research Achievements

Phosphatidylinositol 3-kinase catalytic beta (Pik3cb) plays crucial role in early embryonic survival and development; however, yet the detailed molecular mechanism regulating its embryonic action has been poorly understood. Here the embryonic Pik3cb and its associating proteins were studied in mouse embryonic stem cells (mESCs) and zebrafish embryo. The cDNA sequencing and subsequent biochemical analyses revealed that mESCs express a unique splicing variant of Pik3cb, which can interact with embryo specific associating protein (Pik3cbAP) only when growth factor signaling is activated. The embryonic cell specific Pik3cb-Pik3cbAP complex is seemingly important for activating the enzymatic function of Pik3cb. Furthermore, cDNAs encoding other potential Pik3cb associating molecules were cloned and their embryonic actions were tested in zebrafish embryo. These data will help to decipher the molecular mechanisms governing embryonic Pik3cb function and developmental competency.

Research Products

• [Journal Article] Nedd4-induced mono-ubiquitination of IRS-2 enhances IGF signaling and mitogenic activity. (2015)
  • Author(s): Toshiaki Fukushima, Hidehito Yoshihara, Haruka Furuta, Fumihiko Hakuno, Jing Luan, Cunming Duan, Yasushi Saeki, Keiji Tanaka, Shun-Ichiro Iemura, TohruNatsume, Kazuhiro Chida, Yusuke Nakatsu, Hideaki Kamata, Tomoichiro Asano, and Shin-Ichiro Takahashi
  • Journal Title: Nature communications Volume: 6 Issue: 1 Pages: 6780-6780
  • DOI: 10.1038/ncomms7780
  • NAID: 120006348510
  • Peer Reviewed / Open Access
• [Journal Article] In vivo loss of function study reveals the short stature homeobox-containing (shox) gene plays indispensable roles in early embryonic growth and bone formation in zebrafish. (2015)
  • Author(s): Sawada R., Kamei H., Hakuno F., Takahashi S., Shimizu T.
  • Journal Title: Dev. Dyn. Volume: 244 Issue: 2 Pages: 146-156
  • DOI: 10.1002/dvdy.24239
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Steroid hormones are novel nucleoside transport inhibitors by competition with nucleosides for their transporters. (2014)
  • Author(s): Kaneko M, Hakuno F, Kamei H, Yamanaka D, Chida K, Minami S, Coe RI, Takahashi S-I.
  • Journal Title: Bicohem Biophysic Res Commun. Volume: 443 Issue: 2 Pages: 505-510
  • DOI: 10.1016/j.bbrc.2013.11.132
  • Peer Reviewed
• [Journal Article] Pregnancy-associated plasma protein A (PAPP-A) modulates the early developmental rate in zebrafish independently of its proteolytic activity. (2013)
  • Author(s): Kjaer-Sorensen K, Engholm DH, Kamei H, Morch MG, Kristensen AO, Zhou J, Conover CA, Duan C, Oxvig C.
  • Journal Title: J. Biol. Chem. Volume: 288(14) Issue: 14 Pages: 9982-9992
  • DOI: 10.1074/jbc.m112.426304
  • Peer Reviewed
• [Journal Article] インスリン様活性と高齢化社会で克服すべき疾病 (2013)
  • Author(s): 高橋伸一郎，伯野史彦，亀井宏泰，Leonard Girnita，Ignacio Torres-Aleman，東 祐輔，福嶋俊明，柴野卓志，尾添淳文，山中大介
  • Journal Title: 化学と生物 Volume: 51(6) Pages: 389-399
  • NAID: 10031177626
• [Presentation] Early embryonic Irs1 signaling governs the neural crest cell survival that is indispensable for catch-up growth in zebrafish embryo induced by the changing environmental oxygen tension. (2015)
  • Author(s): Kamei H., Yoneyama Y., Sawada R., Duan C., Hakuno F., Shimizu T., Takahashi S.
  • Organizer: Gordon Research Conference "Insulin-Like Growth Factors In Physiology & Disease”
  • Place of Presentation: Ventura, CA, USA
  • Year and Date: 2015-03-08 – 2015-03-15
• [Presentation] PI 3-kinase-binding protein PI3KAP plays an important role in cell migration and is required for embryogenesis in zebrafish. (2015)
  • Author(s): Kawauchi H., Yamanaka D., Kamei H., Hakuno F., Minami S., Chida K., Takahashi S.
  • Organizer: Gordon Research Conference "Insulin-Like Growth Factors In Physiology & Disease”
  • Place of Presentation: Ventura, CA, USA
  • Year and Date: 2015-03-08 – 2015-03-15
• [Presentation] Insulin receptor substrate-1 promotes embryonic growth through IGF-IR signal-dependent and -independent mechanisms in response to developmental stages and environmental oxygen availability. (2014)
  • Author(s): Kamei H., Sawada R., Yoneyama Y., Hakuno F., Shimizu T., Takahashi S.
  • Organizer: The 7th International Congress of GRS and IGF Society in Singapore
  • Place of Presentation: Singapore
  • Year and Date: 2014-10-15 – 2014-10-18
• [Presentation] Roles of insulin receptor substrate-1 in catch-up growth: A lesson from tiny fish embryo. (2014)
  • Author(s): Kamei H.
  • Organizer: INTERNATIONAL SEMINAR “Evolution of Insulin-like Peptides and Their Function:Development, Growth, Metabolism and Ageing”
  • Place of Presentation: Tokyo, JAPAN
  • Year and Date: 2014-10-14
  • Invited
• [Presentation] 低酸素環境で成長が遅滞したゼブラフィッシュ胚が常酸素環境で追いつき成長を起こす機構の解明：インスリン受容体基質（IRS）-1の機能 (2014)
  • Author(s): 亀井宏泰・山口里恵・米山鷹介・伯野史彦・清水俊明・高橋伸一郎
  • Organizer: 日本内分泌学会学術総会
  • Place of Presentation: 福岡
  • Year and Date: 2014-04-24 – 2014-04-26
• [Presentation] ゼブラフィッシュの初期発生におけるphosphatidylinositol 3-kinase（PI3K）の新規結合タンパク質の役割 (2014)
  • Author(s): 川内啓希・山中大介・亀井宏泰・南史郎・伯野史彦・千田和広・高橋伸一郎
  • Organizer: 日本内分泌学会学術総会
  • Place of Presentation: 福岡
  • Year and Date: 2014-04-24 – 2014-04-26
• [Presentation] Early embryonic regulation of PI3K signaling:Identification and characterization of non-canonical PI3K interacting molecules, and their roles in embryogenesis. (2013)
  • Author(s): Kamei H.
  • Organizer: INTERNATIONAL OPEN WORKSHOP “Emerging Paradigms of Insulin-Like Activities in Physiology & Disease: From Pathophysiology to Targeted Therapy”
  • Place of Presentation: Karolinska Institute, Stockholm, Sweden
  • Invited
• [Remarks] 動物細胞制御学研究室のホームページ
  • URL: http://endo.ar.a.u-tokyo.ac.jp