膜小胞輸送における新規カーゴ受容体Alcadeinの機能解析

• Project/Area Number: 18050001
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Hokkaido University
• Principal Investigator: 鈴木 利治 Hokkaido University, 大学院・薬学研究院, 教授 (80179233)
• Project Period (FY): 2006 – 2007
• Project Status: Completed (Fiscal Year 2007)
• Budget Amount: ¥6,600,000 (Direct Cost: ¥6,600,000); Fiscal Year 2007: ¥3,300,000 (Direct Cost: ¥3,300,000); Fiscal Year 2006: ¥3,300,000 (Direct Cost: ¥3,300,000)
• Keywords: 小胞輸送 / 軸索 / キネシン / 神経 / モーター分子 / JIP

Research Abstract

アルカデイン(Alc)は、申請者が見いだしたI型の膜タンパク質である。Alcの細胞質ドメインは、kinesin-1モーターの軽鎖(KLC)と結合する新規モチーフを含んでおり、kinsein-1のカーゴ受容体として機能していることを発表した(EMBO J.[2007]26,1475-1486)。解析が進展しているモーターファミリー分子KIFに比較して、カーゴ受容体の解析はほとんど進んでいない。Alcがkinesin-1のカーゴ受容体として、どのような特性を持ているのかを解析した。GFP-KLCをAlcと共に神経細胞に共発現させると、Alcはkinesin-1分子を組み立てGFP-KLCがが小胞輸送された。この活性は、おなじKLC結合タンパク質JIP1bでは観察できない。Kinesin-1モーターを機能的に組み立てる活性領域を同定する目的で、各種Alc細胞質ドメイン欠失変異体をGFP-KLCと共に共発現させ、Alc細胞質ドメインの機能領域を同定した。EGF受容体の細胞質ドメインをAlcの機能ドメインに入れ替えたキメラタンパク質は、kinesi-1をAlcと同様に組み立て効果的な小胞輸送活性を示す実験から、機能ドメイン最小単位の同定に成功した。現在、カーゴ受容体がモーター分子を活性化する詳細な分子機構に関する解析を進めている。

Research Products

• [Journal Article] Endoplasmic reticulum chaperones inhibit the production of amyloid-β peptides (2007)
  • Author(s): Hoshino, T., Nakaya, T., Araki, W., Suzuki, K., Suzuki, T. and Mizushima, T.
  • Journal Title: Biochemical Journal 402 Pages: 581-589
  • Peer Reviewed
• [Journal Article] The novel cargo receptor Alcadein induces vesicle association of kinesin-1 motor components and activates axonal transport (2007)
  • Author(s): Hoshino, T., Nakaya, T., Araki, W., Suzuki, K., Suzuki, T. and Mizushima, T.
  • Journal Title: The ENBO Journal 26 Pages: 1475-1486
  • Peer Reviewed
• [Journal Article] nvolvement of prostaglandine E2 in production of amyloid-β peptides both in vitro and in vivo. (2007)
  • Author(s): Hoshino, T., Nakaya, T., Homan, T., Tanaka, K., Sugimoto, Y., Araki, W., Narita, M., Narumiya, S., Suzuki, T. and Mizushima, T.
  • Journal Title: Journal of Biological Chemistry 282 Pages: 32676-32688
  • Peer Reviewed
• [Journal Article] Evidence against roles for phorbol binding protein Munc13-1, ADAM adaptor Eve-1, or vesicle trafficking phosphoprotein Munc 18 or NSF as phospho-state-sensitive modulators of phorbol/PKC-activated Alzheimer APP ectodomain shedding. (2007)
  • Author(s): Ikin, A., Causevic, M., Pedrini, S., Benson, L., Buxbaum, J. D., Suzuki, T., Lovestone, S., Higashiyama, S., Mustelin, T., Burgoyne, R. D. and Gandy S.
  • Journal Title: Mol. Neurodegen Pages: 2-23
  • Peer Reviewed
• [Journal Article] Role of APP phosphorylation in FE65-dependent gene transactivation mediated by AICD. (2006)
  • Author(s): Nakaya, T., Suzuki, T.
  • Journal Title: Genes to Cells 11 Pages: 633-645
• [Journal Article] Physiological mouse brain Aβ levels are not related to the phosphorylation atate of threonine-668 of Alzheimer's APP. (2006)
  • Author(s): Sano, Y., Nakaya, T., Pedrini, S., Takeda, S., Iijima-Ando, K., Iijima, K., Mathews, P.M., Itohara, S., Gandy, S., Suzuki.T.
  • Journal Title: Public Library of Science ONE 1
• [Journal Article] Enhanced amyloidogenic metabolism of APP in X11L-deficient mouse brain. (2006)
  • Author(s): Sano, Y., Takabatake-Syuzo, A., Nakaya, T., Tomita, S., Itohara, S., Suzuki, T.
  • Journal Title: Journal of Biological Chemistry 281 Pages: 37853-878560
• [Journal Article] Trafficking of Alzheimer's disease-related membrane proteins and its participation in disease pathogenesis.(Review) (2006)
  • Author(s): Suzuki, T., Araki, Y., Yamamoto, T., Nakaya, T.
  • Journal Title: Journal of Biochemistry 139 Pages: 949-955
• [Presentation] 細胞ストレス依存的なFE65の核内移行機構の解析 (2008)
  • Author(s): 中矢 正、河合智子、鈴木利治
  • Organizer: 第128回日本薬学会年会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2008-03-27
• [Presentation] アルカデインによるキネシンー1輸送小胞形成機構の解析 (2007)
  • Author(s): 河野高徳、荒木陽一、鈴木利治
  • Organizer: BMB2007(第30回日本分子生物学会年会、第80回日本生化学会大会 合同大会)
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2007-12-14
• [Presentation] 高浸透圧ストレスによるX11L多量体化の誘導 (2007)
  • Author(s): 佐久間めぐみ、田中絵美、多留偉功、鈴木利治
  • Organizer: BMB2007(第30回日本分子生物学会年会、第80回日本生化学会大会 合同大会)
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2007-12-14
• [Presentation] 新規軸索ガイド因子MDGA1マウス脳における発現と機能解析 (2007)
  • Author(s): 石川貴雄、岩下美里、松崎文雄、鈴木利治、山本融
  • Organizer: BMB2007(第30回日本分子生物学会年会、第80回日本生化学会大会 合同大会)
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2007-12-14
• [Presentation] Mechanism of kinesin-1 motor connection of APP via JIP1b (2007)
  • Author(s): 古郡慶子、内藤志保、荒木陽一、山本融、鈴木利治
  • Organizer: BMB2007(第30回日本分子生物学会年会、第80回日本生化学会大会 合同大会)
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2007-12-14
• [Presentation] Alcade in切断のメカニズム (2007)
  • Author(s): 羽田沙緒里、藤重沙弥香、荒木陽一、鈴木利治
  • Organizer: BMB2007(第30回日本分子生物学会年会、第80回日本生化学会大会 合同大会)
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2007-12-13
• [Presentation] Tolanslocation of FE65 into speckled nuclear matrix induces gamma-H2AX in cell suffered from hyper osmotic stress. (2007)
  • Author(s): 河合智子、中矢正、鈴木利治
  • Organizer: BMB2007(第30回日本分子生物学会年会、第80回日本生化学会大会 合同大会)
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2007-12-13
• [Presentation] Role of phosphorylation of APP at Thr668. (2007)
  • Author(s): Matushima, T., Sano, Y., Nakaya, T., Itohara, S., Suzuki, T.
  • Organizer: American Society for Neuroscience annual meeting, Neuroscience 2007
  • Place of Presentation: San Diego Convention Center
  • Year and Date: 2007-11-07
• [Presentation] Mechanism of regulated intramembrane proteolysis of Alcadein and its possible role in cell (2007)
  • Author(s): Urano, S, Fujishige, S., Nakaya, T., Yamamoto, T., Suzuki, T.
  • Organizer: American Society for Neuroscience annual meeting, Neuroscience 2007
  • Place of Presentation: San Diego Convention Center
  • Year and Date: 2007-11-07
• [Presentation] Effect of X11-and/or X11L-deficiency on APP metabolism in vivo. (2007)
  • Author(s): Saito, Y., Sano, Y., Nakaya, T., Itohara, S., Suzuk, T.
  • Organizer: Society for Neuroscience USA
  • Place of Presentation: San Diego Convention Center
  • Year and Date: 2007-11-07
• [Presentation] Mechanism of a tripartite complex formation composed of APP, X11L and Alcadein. (2007)
  • Author(s): Akiyama, M., Sakuma, M., Araki, Y., Fujishige, S., Nakaya, T. and Suzuki, T.
  • Organizer: American Society for Neuroscience annual meeting, Neuroscience 2007
  • Place of Presentation: San Diego Convention Center
  • Year and Date: 2007-11-07
• [Presentation] Nuclear accumulation of FE65 under osmotic stress. (2007)
  • Author(s): Kawai, T., Nakaya, T. and Suzuk, T.
  • Organizer: American Society for Neuroscience annual meeting, Neuroscience 2007
  • Place of Presentation: San Diego Convention Center
  • Year and Date: 2007-11-07
• [Presentation] Axonal paths of chick embryonic spinal commissural neurons after crossing the midline. (2007)
  • Author(s): Arakawa, T., Iwashita, M., Matsuzaki, T., Suzuki, T. and Yamamoto, T.
  • Organizer: American Society for Neuroscience annual meeting, Neuroscience 2007
  • Place of Presentation: San Diego Convention Center
  • Year and Date: 2007-11-06
• [Presentation] Participation of Alcadein α and its proteolytic product in the axonal transport of APP and the generation of Aβ. (2007)
  • Author(s): Kawano, T., Araki, Y. and Suzuki, T.
  • Organizer: Silver Congress of the International Psychogeriatric Association
  • Place of Presentation: 大阪国際会議場
  • Year and Date: 2007-10-16
• [Presentation] Suppression of APP metabolism by DHHC family proteins. (2007)
  • Author(s): Mizumaru, C., Kihara, A. and Suzuki, T.
  • Organizer: Silver Congress of the International Psychogeriatric Association
  • Place of Presentation: 大阪国際会議場
  • Year and Date: 2007-10-15
• [Presentation] Translocation of FE65 into nuclear matrix speckles induces γH2AX in cells and APP metabolic fragment AICD suppresses this process.(招待講演) (2007)
  • Author(s): Toshiharu Suzuki
  • Organizer: 1st Dependence Receptor Meeting and 10th Neuroblastoma Research Meeting
  • Place of Presentation: 国立がんセンター研究所
  • Year and Date: 2007-10-06
• [Presentation] Alcade inのプロテオリシスと機能発現 (2007)
  • Author(s): 羽田沙緒里、藤重沙弥香、浦野里美、荒木陽一、鈴木利治
  • Organizer: 第12回 病態と治療におけるプロテアーゼとインヒビター学会
  • Place of Presentation: 千里ライフサイエンスセンター
  • Year and Date: 2007-08-03
• [Presentation] Transport of APP and Alcadein by kinesin-1 (2007)
  • Author(s): Suzuki, T., Araki, Y., Kawano, T., Akiyama, M., Arakawa, T., Urano, S., Kawai, T., Matsushima, T., Nakaya, T., Yamamoto, T. and Kinjo, M.
  • Organizer: Experimental Biology 2007
  • Place of Presentation: Washington, DC, USA
  • Year and Date: 2007-04-28
• [Book] 特集「Alzheimer病 -基礎・臨床研究の最新動向-」(企画 岩坪威) (2007)
  • Author(s): 中矢 正、鈴木利治
  • Total Pages: 5
  • Publisher: 医学のあゆみ
• [Book] バイオとナノの融合II(北海道大学COE研究成果編集委員会 編)第10章 (2007)
  • Author(s): 中矢 正、荒木陽一、佐久間めぐみ、水丸智絵、鈴木利治、金城政孝、高橋保夫
  • Total Pages: 14
  • Publisher: 北海道大学出版会
• [Book] アルカデイン(Alcadein)研究の進歩 (2007)
  • Author(s): 羽田沙緒里、佐久間めぐみ、鈴木利治
  • Total Pages: 10
  • Publisher: Dementia Japan 21
• [Book] Cognition and Dementia vo7(1) (2007)
  • Author(s): 中矢 正、鈴木利治
  • Total Pages: 6
  • Publisher: メディカルレビュー社