Regulation of amyloid-beta clearance by the small GTPase Arf6 and the phospholipid kinase PIP5K

• Project/Area Number: 24770116
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Functional biochemistry
• Research Institution: University of Tsukuba
• Principal Investigator: FUNAKOSHI Yuji 筑波大学, 医学医療系, 助教 (30415286)
• Project Period (FY): 2012-04-01 – 2014-03-31
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2013: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000); Fiscal Year 2012: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: Arf6 / PIP5K / βアミロイド / 細胞内輸送 / Megalin / LRP1 / アミロイドβ / 膜輸送 / 低分子量G蛋白質Arf6 / リン脂質キナーゼPIP5K

Research Abstract

The plasma membrane receptors Megalin and LRP1, play a pivotal role in elimination of the Amyloid-beta peptide (Abeta), which is crucially involved in Alzheimer's disease, from the brain. In brain microvascular endothelial cells and choroid plexus epithelial cells, both receptors uptake Abeta from the brain fluid and transport them to the blood. In this research we find that the small GTPase Arf6 and the phospholipid kinase PIP5K bind to the cytoplasmic domains of Megalin and LRP1. We also demonstrate that knockdown of Arf6 causes accumulation of Megalin and LRP1 at intracellular endosomes and significant increase of the expression level of those proteins. These results indicate that Arf6 regulates transport of Megalin and LRP1 to lysosomes for degradation.

Research Products

• [Journal Article] Anti prolifetative protein Tob directly regulates c-myc proto-oncogene expression through cytoplasmic polyadenylation element-binding protein CPEB. (2013)
  • Author(s): Ogami, K., Hosoda, N., Funakoshi, N., Hoshino, S.
  • Journal Title: Oncogene Volume: - Issue: 1 Pages: 55-64
  • DOI: 10.1038/onc.2012.548
  • Peer Reviewed
• [Journal Article] Molecular mechanisms of N-formyl-methionyl-leucyl-phenylalanine-induce d superoxide generation and degranulation in mouse neutrophils : phospholipase D is dispensable (2013)
  • Author(s): Sato T., Hongu T., Sakamoto M., Funakoshi Y., Kanaho Y.
  • Journal Title: Mol. Cell. Biol. Volume: 33 Issue: 1 Pages: 136-145
  • DOI: 10.1128/mcb.00869-12
  • Peer Reviewed
• [Journal Article] Molecular mechanisms of fMLP-induced superoxide generation and degranulation in mouse neutrophils (2013)
  • Author(s): Kanaho Y., Sato T., Hongu T., Funakoshi Y.
  • Journal Title: Adv. Biol. Reg. Volume: 63 Issue: 1 Pages: 128-134
  • DOI: 10.1016/j.jbior.2012.09.001
  • Peer Reviewed
• [Journal Article] Antiproliferative protein Tob directly regulates c-myc proto-oncogene expression through cytoplasmic polyadenylation element-binding protein CPEB. (2013)
  • Author(s): Ogami K, Hosoda N, Funakoshi Y, Hoshino S.
  • Journal Title: Oncogene Volume: 未定
  • Peer Reviewed
• [Journal Article] Molecular mechanisms of N-formyl-methionyl-leucyl-phenylalanine-induced superoxide generation and degranulation in mouse neutrophils: phospholipase D is dispensable. (2013)
  • Author(s): Sato T, Hongu T, Sakamoto M, Funakoshi Y, Kanaho Y.
  • Journal Title: Molecular and Cellular Biology Volume: 33 Pages: 136-145
  • Peer Reviewed
• [Journal Article] Molecular mechanisms of fMLP-induced superoxide generation and degranulation in mouse neutrophils. (2013)
  • Author(s): Kanaho Y, Sato T, Hongu T, Funakoshi Y.
  • Journal Title: Advances in Biological Regulation Volume: 63 Pages: 128-134
• [Journal Article] Phosphatidylinositol 4-phosphate 5-kinase is indispensable for mouse spermatogenesis (2012)
  • Author(s): Hasegawa, H., Noguchi, J., Yamashita, M., Okada, R., Sugimoto, R., Furuya, M., Unoki, T., Funakoshi, Y., Baba, T., and Kanaho, Y.
  • Journal Title: Biol. Reprod Volume: 86 Issue: 5 Pages: 1-12
  • DOI: 10.1095/biolreprod.110.089896
  • Peer Reviewed
• [Journal Article] Phosphatidylinositol 4-phosphate 5-kinase is indispensable for mouse spermatogenesis. (2012)
  • Author(s): Hasegawa H, Noguchi J, Yamashita M, Okada R, Sugimoto R, Furuya M, Unoki T, Funakoshi Y, Baba T, Kanaho Y.
  • Journal Title: Biology of Reproduction Volume: 86 Pages: 1-12
  • Peer Reviewed
• [Presentation] Ubiquitin-specific prtotease TRE17/USP6 targets clathrin-independent cargo to recycling (2013)
  • Author(s): Yuji Funakoshi, Yasunori Kanaho, Julie G. Donaldson
  • Organizer: 第86回日本生化学会大会
  • Place of Presentation: 横浜
• [Presentation] リン脂質代謝酵素ホスホリパーゼD2は腫瘍形成を抑制する (2013)
  • Author(s): 本宮綱記、船越祐司、金保安則
  • Organizer: 第55回日本脂質生化学会
  • Place of Presentation: 宮城県松島町
• [Presentation] Ubiquitin-specific protease TRE17/USP6 targets clathrin-independent cargo to recycling (2013)
  • Author(s): Yuji Funakoshi, Yasunori Kanaho, Julie G. Donaldson
  • Organizer: 第86回日本生化学会大会
  • Place of Presentation: 横浜
• [Presentation] Ubiquitin-specific prtotease TRE17/USP6 targets clathrin-independent cargo to recycling (2012)
  • Author(s): Funakoshi Y, Kanaho Y, Donalson JD
  • Organizer: 2012 American Society for Cell Biology, Annual Meeting
  • Place of Presentation: サンフランシスコ、アメリカ合衆国
• [Presentation] Ubiquitin-specific protease TRE17/USP6 targets clathrin-independent cargo to recycling (2012)
  • Author(s): Funakoshi Y, Kanaho Y, Donaldson JG
  • Organizer: 2012 American Society for Cell Biology, Annual Meeting
  • Place of Presentation: サンフランシスコ、アメリカ合衆国
• [Remarks]
  • URL: http://www.md.tsukuba.ac.jp/basic-med/biochem/kanaholab/