Implication of deregulated vesicles' traffic in the occurence of acute leukemia

• Project/Area Number: 23501256
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Carcinogenesis
• Research Institution: Tohoku University
• Principal Investigator: SATAKE Masanobu 東北大学, 加齢医学研究所, 教授 (50178688)
• Project Period (FY): 2011 – 2013
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2013: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2012: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2011: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 小胞輸送 / ArfGAP / 骨髄異形成症候群 / 急性骨髄性白血病 / 遺伝子ターゲティング / 骨髄異形性症候群

Research Abstract

The formation of clathrin-coated vesicles is essential for intracellular membrane trafficking and is triggered by the ARF GTPases. We previously identified SMAP1 as an ARF GTPase-activating protein.We targeted Smap1 in mice and Smap1-deficent erythroblasts exhibited enhanced transferrin endocytosis. In addition, Smap1 deficiency impaired the sorting of internalized c-Kit from multivesicular bodies to lysosomes, resulting in accumulation of c-KIT that was accompanied by enhanced activation of ERK and increased cell growth. Interestingly, aged Smap1-deficient mice developed anemia associated with morphologically dysplastic cells of erythroid-myeloid lineage, which are abnormalities similar to myelodysplastic syndrome (MDS) in humans. Furthermore, some Smap1-deficient mice developed acute myeloid leukemia (AML) of various subtypes. Collectively, the deregulation of clathrin-dependent membrane trafficking is likely involved in the development of MDS and subsequent AML.

Research Products

• [Journal Article] Altered trafficking of mutated growth factor receptors and their associated molecules : implication for human cancers (2014)
  • Author(s): Kon, S., Kobayashi, N. and Satake, M.
  • Journal Title: Cellular Logistics Volume: 4 Issue: 1 Pages: e28461-e28461
  • DOI: 10.4161/cl.28461
  • Peer Reviewed
• [Journal Article] The Arf GAP SMAP2 is necessary for organized vesicle budding from the trans-Golgi-network and subsequent acrosome formation in spermiogenesis (2013)
  • Author(s): Funaki, T., Kon, S., Tanabe, K., Natsume, W., Sato, S., Shimizu, T., Yoshida, N., Wong, W.F., Ogura, A., Ogawa, T., Inoue, K., Ogonuki, N., Miki, H., Mochida, K., Endoh, K., Yomogida, K., Fukumoto, M., Horai, R., Iwakura, Y., Ito, C., Toshimori, K., Watanabe, T. and Satake, M.
  • Journal Title: Mol. Biol. Cell Volume: 24 Pages: 2633-2644
  • URL: http://mbc.E13-05-0234v124/17/2633
  • Peer Reviewed
• [Journal Article] Smap1 deficiency perturbs receptor trafficking and predisposes mice to myelodysplasia. (2013)
  • Author(s): Kon et al.
  • Journal Title: J. Clin. Invest. Volume: 123 Issue: 3 Pages: 1123-1137
  • DOI: 10.1172/jci63711
  • Peer Reviewed
• [Journal Article] The Arf GAP SMAP2 is necessary for organized vesicle budding from the trans-Golgi network and subsequent acrosome formation in spermiogenesis. (2013)
  • Author(s): Funaki T, Kon S, Tanabe K, Natsume W, Sato S, Shimizu T, Yoshida N, Wong WF, Ogura A, Ogawa T, Inoue K, Ogonuki N, Miki H, Mochida K, Endoh K, Yomogida K, Fukumoto M, Horai R, Iwakura Y, Ito C, Toshimori K, Watanabe T, Satake M.
  • Journal Title: Mol. Biol. Cell Volume: 24 Issue: 17 Pages: 2633-44
  • DOI: 10.1091/mbc.e13-05-0234
  • Peer Reviewed
• [Journal Article] Localization of SMAP2 to the TGN and its Function in the Regulation of TGN Protein Transport (2011)
  • Author(s): Tomo Funaki, Shunsuke Kon, Roger E Ronn, Yuji Henmi, Yuka Kobayashi, Toshio Watanabe, Keiko Nakayama, Kenji Tanabe, Masanobu Satake
  • Journal Title: Cell Structure and Function Volume: 36 Issue: 1 Pages: 83-95
  • DOI: 10.1247/csf.10022
  • NAID: 130004137566
  • ISSN: 0386-7196, 1347-3700
  • Peer Reviewed
• [Journal Article] Putative terminator and/or effector functions of Arf GAPs in the trafficking of clathrin-coated vesicles. (2011)
  • Author(s): Kon S, Funaki T, Satake M.
  • Journal Title: Cellular Logistics Volume: 1 Issue: 3 Pages: 86-89
  • DOI: 10.4161/cl.1.3.16192
  • Peer Reviewed
• [Presentation] SMAP1 欠損による細胞内小胞輸送の異常と骨髄異型性症候群 (2012)
  • Author(s): 昆俊亮、他15名
  • Organizer: 第35回日本分子生物学会
  • Place of Presentation: 福岡市
  • Year and Date: 2012-12-12
• [Presentation] クラスリン小胞形成因子SMAP1の欠損は細胞内小胞輸送の異常をきたし,骨髄異型性症候群を誘引する (2012)
  • Author(s): 昆俊亮, 峯岸直子, 田邊賢司, 渡邊利雄, 船木智, 坂元大輔, 樋口雄大, 清成寛, 浅野克敏, 福本学, 真田昌, 小川誠司, 中村卓郎, 佐竹正延
  • Organizer: 日本分子生物学会
  • Place of Presentation: 福岡国際会議場