Study on the mechanism of Girdin-mediated amino acid signaling and regulation of mTORC1 activity in cancer cells

• Project/Area Number: 15K21061
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Experimental pathology; Tumor biology
• Research Institution: Nagoya University
• Principal Investigator: Weng Liang 名古屋大学, 医学系研究科, 特任助教 (20729280)
• Project Period (FY): 2015-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2016: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2015: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: アミノ酸シグナル / mTORC1 / Girdin / Cell metabolism / mTOR

Outline of Final Research Achievements

Desensitization, which involves the downregulation of cell surface receptors, is a common negative regulatory process for cell signalings. Amino acid signaling mediated by the activation of mechanistic target of rapamycin complex 1 (mTORC1) is fundamental to cell growth and metabolism. However, how cells desensitize to amino acid signaling is unknown. Here, we show that interaction between 4F2 heavy chain (4F2hc), a subunit of multiple amino acid transporters, and the multifunctional hub protein Girdin downregulates mTORC1 activity. 4F2hc interacts with Girdin in mitogen-activated protein kinase- and amino acid signaling-dependent manners to translocate to the lysosome. The resultant decrease in cell-surface 4F2hc leads to lowered cytoplasmic glutamine content, which desensitizes cells to amino acid signaling. These findings uncovered the mechanism underlying desensitization of amino acid signaling, which may play a role in tightly regulated cell growth and metabolism.

Research Products

• [Journal Article] Identification of Meflin as a Potential Marker for Mesenchymal Stromal Cells (2016)
  • Author(s): Maeda K, Enomoto A, Hara A, Asai N, Kobayashi T, Horinouchi A, Maruyama S, Ishikawa Y, Nishiyama T, Kiyoi H, Kato T, Ando K, Weng L, Mii S, Asai M, Mizutani Y, Watanabe O, Hirooka Y, Goto H, Takahashi M
  • Journal Title: Sci Rep Volume: 6 Issue: 1 Pages: 22288-22288
  • DOI: 10.1038/srep22288
  • Peer Reviewed / Open Access
• [Journal Article] Potential involvement of kinesin-1 in the regulation of subcellular localization of Girdin (2015)
  • Author(s): Aya Muramatsu, Atsushi Enomoto, Takuya Kato, Liang Weng, Keisuke Kuroda, Naoya Asai, Masato Asai, Shinji Mii, Masahide Takahashia
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 463 Issue: 4 Pages: 999-1005
  • DOI: 10.1016/j.bbrc.2015.06.049
  • Peer Reviewed / Open Access
• [Journal Article] Girdin/GIV regulates transendothelial permeability by controlling VE-cadherin trafficking through the small GTPase, R-Ras. (2015)
  • Author(s): Ichimiya H, Maeda K, Enomoto A, Weng L, Takahashi M, Murohara T.
  • Journal Title: Biochem Biophys Res Commun. Volume: 461 Issue: 2 Pages: 260-267
  • DOI: 10.1016/j.bbrc.2015.04.012
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] 脳腫瘍幹細胞におけるmTORC1活性制御とその分子機構の解析 (2016)
  • Author(s): 榎本篤、翁良、韓一梵、浅井直也、三井伸二、高橋雅英
  • Organizer: 第62回日本病理学会秋期特別総会
  • Place of Presentation: 金沢市文化ホール（石川県金沢市）