Identification of factors involved in the amino acid signaling to mTOR in lysosome and clarification of its functional significance

• Project/Area Number: 16K19018
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: General pharmacology
• Research Institution: Osaka University
• Principal Investigator: Okuda Suguru 大阪大学, 医学系研究科, 助教 (50511846)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: アミノ酸 / トランスポーター / mTOR / 細胞増殖 / 情報伝達 / 機能解析 / 蛋白質 / シグナル伝達

Outline of Final Research Achievements

To understand the mechanism of cell growth and proliferation induced by amino acids, we sought factors involved in the process, and analyzed an amino acid transporter localizing cell membrane to take amino acids into cells. We successfully determined in which tissue one of the uncharacterized transporters exist, and identified candidates that interacts with the amino acid transporter and may affect its function.

Academic Significance and Societal Importance of the Research Achievements

アミノ酸輸送体のなかにはその機能が病気に関連するものが多数存在する。例えば、がんにおいては一部のアミノ酸輸送体が正常な細胞より多く存在するため、アミノ酸の取り込みが速く、細胞の成長・増殖も早い。本研究の成果はアミノ酸による細胞成長・増殖の仕組みを解明するために重要な知見であり、将来的には本研究の成果が新たな薬の開発に繋がることが期待される。

Research Products

• [Journal Article] Boron delivery for boron neutron capture therapy targeting a cancer-upregulated oligopeptide transporter (2019)
  • Author(s): Miyabe Junji、Ohgaki Ryuichi、Saito Keijiro、Wei Ling、Quan Lili、Jin Chunhuan、Liu Xingming、Okuda Suguru、Nagamori Shushi、Ohki Hiroshi、Yoshino Kazuo、Inohara Hidenori、Kanai Yoshikatsu
  • Journal Title: Journal of Pharmacological Sciences Volume: 139 Issue: 3 Pages: 215-222
  • DOI: 10.1016/j.jphs.2019.01.012
  • Peer Reviewed / Open Access
• [Journal Article] Ratiometric fluorescence imaging of cell surface pH by poly(ethylene glycol)-phospholipid conjugated with fluorescein isothiocyanate (2017)
  • Author(s): Ryuichi Ohgaki, Yuji Teramura, Daichi Hayashi, Suguru Okuda, Shushi Nagamori, Madoka Taka and Yoshikatsu Kanai
  • Journal Title: Sci Res Volume: 7 Issue: 1 Pages: 17484-17484
  • DOI: 10.1038/s41598-017-17459-y
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Structure-activity relationship of a novel series of inhibitors for cancer type transporter L-type amino acid transporter 1 (LAT1). (2017)
  • Author(s): Kongpracha P, Nagamori S, Wiriyasermkul P, Tanaka Y, Kaneda K, Okuda S, Ohgaki R, Kanai Y.
  • Journal Title: J Pharmacol Sci. Volume: 133 Issue: 2 Pages: 96-102
  • DOI: 10.1016/j.jphs.2017.01.006
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Essential roles of L-type amino acid transporter 1 in syncytiotrophoblast development by presenting fusogenic 4F2hc. (2017)
  • Author(s): Ohgaki R, Ohmori T, Hara S, Nakagomi S, Kanai-Azuma M, Kaneda-Nakashima K, Okuda S, Nagamori S, Kanai Y.
  • Journal Title: Mol Cell Biol. Volume: 印刷中 Issue: 11
  • DOI: 10.1128/mcb.00427-16
  • Peer Reviewed / Open Access
• [Presentation] Essential roles of amino acid transporter LAT1 in cell fusion for the development of placental syncytiotrophoblast (2019)
  • Author(s): Ryuichi Ohgaki, Takahiro Ohmori, Saori Hara, Saya Nakagomi, Masami Kanai, Kazuko Kaneda-Nakashima, Suguru Okuda, Shushi Nagamori, Yoshikatsu Kanai
  • Organizer: The 1st OIST-OU Joint Symposium - Cell Biology and Immunology-
• [Presentation] Critical moieties of aromatic amino acids for the interaction with organic anion transporter OAT1: Implications for reducing the renal background in tumor imaging. (2019)
  • Author(s): Chunhuan Jin, Ling Wei, Ryuichi Ohgaki, Hideyuki Tominaga, Suguru Okuda, Shushi Nagamori, Yoshikatsu Kanai
  • Organizer: 第92回 日本薬理学会年会
• [Presentation] アミノ酸トランスポーター阻害薬の併用による大腸癌細胞株に対する増殖抑制効果 (2019)
  • Author(s): へ ビーフィ、西窪 航、大垣 隆一 、岡西 広樹、奥田 傑、金井 好克
  • Organizer: 第92回 日本薬理学会年会
• [Presentation] メラノーマ同種同所移植マウスモデルにおけるLAT1阻害薬の抗腫瘍効果の検討 (2019)
  • Author(s): 石 梓童、大垣 隆一、兼田 加珠子、奥田 傑、永森 收志、遠藤 仁、金井 好克
  • Organizer: 第92回 日本薬理学会年会
• [Presentation] アミノ酸アベイラビリティが細胞内遊離アミノ酸濃度に与える影響 (2019)
  • Author(s): 西窪 航，大垣 隆一，岡西 広樹，奥田 傑，金井 好克
  • Organizer: 第92回 日本薬理学会年会
• [Presentation] Identification of substrate recognition by leucine-specific binding protein (2019)
  • Author(s): Yu Ma, Pattama Wiriyasermkul, Suguru Okuda, Ryuichi Ohgaki, Shushi Nagamori, Yoshikatsu Kanai
  • Organizer: 第92回 日本薬理学会年会
• [Presentation] PEPT1-targeted boron delivery for boron neutron capture therapy using BPA-containing dipeptide (2019)
  • Author(s): Junji Miyabe, Ryuichi Ohgaki, Keijiro Saito, Ling Wei, Lili Quan, Chunhuan Jin, Xingming Liu, Suguru Okuda, Shushi Nagamori, Hiroshi Ohki, Kazuo Yoshino, Hidenori Inohara, Yoshikatsu Kanai
  • Organizer: 第92回 日本薬理学会年会
• [Presentation] Suppression of tumor angiogenesis by inhibition of LAT1 in stromal endothelial cells (2019)
  • Author(s): Lili Quan, Ryuichi Ohgaki, Suguru Okuda, Shushi Nagamori, Hitoshi Endou, Yoshikatsu Kanai
  • Organizer: 第92回 日本薬理学会年会
• [Presentation] ペプチドトランスポーターを標的としたホウ素中性子捕捉療法に用いる新規ペプチド型ホウ素化合物の検討 (2018)
  • Author(s): 宮部淳二、大垣隆一、齋藤桂似郎、Wei Ling、奥田傑、永森收志、大木寛、 吉野和夫、猪原秀典、金井好克
  • Organizer: 第133回 日本薬理学会近畿部会
• [Presentation] L-type amino acid transporter 1 (LAT1) in endothelial cells of tumor vessels contributes to tumor angiogenesis (2018)
  • Author(s): Chunhuan Jin, Ling Wei, Ryuichi Ohgaki, Hideyuki Tominaga, Suguru Okuda, Shushi Nagamori, Yoshikatsu Kanai
  • Organizer: WCP2018 KYOTO 18th World congress of basic and clinical pharmacology
  • Int'l Joint Research
• [Presentation] Combination of amino acids necessary and sufficient for the optimal activation of mTORC1 (2018)
  • Author(s): Ryuichi Ohgaki, Chunhuan Jin, Suguru Okuda, Shushi Nagamori, Yoshikatsu Kanai
  • Organizer: WCP2018 KYOTO 18th World congress of basic and clinical pharmacology
  • Int'l Joint Research
• [Presentation] BPA-dipeptides, novel boron delivery agents for boron neutron capture therapy, are transported by oligopeptide transporter (2018)
  • Author(s): Junji Miyabe, Ryuichi Ohgaki, Keijiro Saito, Ling Wei, Suguru Okuda, Shushi Nagamori, Hiroshi Ohki, Kazuo Yoshino, Hidenori Inohara, Yoshikatsu Kanai
  • Organizer: WCP2018 KYOTO 18th World congress of basic and clinical pharmacology
  • Int'l Joint Research
• [Presentation] L-type amino acid transporter 1 (LAT1) in endothelial cells of tumor vessels contributes to tumor angiogenesis (2018)
  • Author(s): Lili Quan, Ryuichi Ohgaki, Suguru Okuda, Shushi Nagamori, Yoshikatsu Kanai
  • Organizer: WCP2018 KYOTO 18th World congress of basic and clinical pharmacology
  • Int'l Joint Research
• [Presentation] Effect of five amino acids stimulation on mTORC1 signaling pathway in HEK293T cells (2018)
  • Author(s): Xuhao Huang, Chunhuan Jin, Ryuichi Ohgaki, Suguru Okuda, Yoshikatsu Kanai
  • Organizer: Campus Asia Program Faculty meeting, Symopsium and Workshop
• [Presentation] アミノ酸トランスポーターLAT1によるロイシン誘導体の認識とmTORC1シグナル活性化の関係 (2017)
  • Author(s): Suguru Okuda, Pattama Wiriyasermkul, Ryuichi Ohgaki, Shushi Nagamori, Yoshikatsu Kanai
  • Organizer: 第９０回 日本薬理学会
  • Place of Presentation: 長崎
  • Year and Date: 2017-03-15
• [Presentation] Phosphoproteomics reveals the cellular processes affected by leucine transported through LAT1 (2017)
  • Author(s): Pornparn Kongpracha, Pattama Wiriyasermkul,, Suguru Okuda, Ryuichi Ohgaki, Shushi Nagamori, Yoshikatsu Kanai
  • Organizer: 日本プロテオーム学会2017年大会 JHUPO 第15回大会
• [Presentation] A C-terminus mutation of SLC7A9 amino acid transporter retains substrate binding but diminishes the transport activity (2017)
  • Author(s): Nagamori S, Kawamoto Y, Wiriyasermkul P, Nakagomi S, Okuda S, Ohgaki R, Kanai Y
  • Organizer: Gordon Research Conference: Mechanisms of Membrane Transport
  • Int'l Joint Research
• [Presentation] Structure-activity relationship of novel inhibitors for cancer type amino acid transporter LAT1 (2017)
  • Author(s): Pornparn Kongpracha, Pattama Wiriyasermkul,Kazuko Kaneda-Nakashima, Suguru Okuda, Ryuichi Ohgaki, Shushi Nagamori, Yoshikatsu Kanai
  • Organizer: 第131回 日本薬理学会近畿部会
• [Presentation] Non-competitive LAT1 inhibitors suppress mTORC1 signaling similary to competitive LAT1 inhibitors (2017)
  • Author(s): Pornparn Kongpracha, Suguru Okuda, Ryuichi Ohgaki, Yoshikatsu Kanai, Shushi Nagamori
  • Organizer: 第132回 日本薬理学会近畿部会
• [Presentation] LAT1による認識とmTORC1シグナル活性化に必要なロイシンの構造部位の同定 (2016)
  • Author(s): 奥田 傑、Pattama Wiriyasermkul、大垣 隆一、永森 收志、金井 好克
  • Organizer: 第130回 日本薬理学会近畿部会
  • Place of Presentation: 京都