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

2013 Fiscal Year Final Research Report

• 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
• 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

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
  • 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, S., Minegishi, N., Tanabe, K., Watanabe, T., Funaki, T., Wong, W.F., Sakamoto, D., Higuchi, Y., Kiyonari, H., Asano, K., Iwakura, Y., Fukumoto, M., Osato, M., Sanada, M., Ogawa, S., Nakamura, T. and Satake, M.
  • Journal Title: J. Clin. Invest. Volume: 123 Pages: 1123-1137
  • DOI: 10.1172/JCI63711
  • Peer Reviewed
• [Journal Article] Localization of SMAP2 to the TGN and its function in the regulation of TGN protein transport (2011)
  • Author(s): Funaki, T., Kon, S., Ronn, R.E., Henmi, Y., Kobayashi, Y., Watanabe, T., Nakayama, K., Tanabe, K. and Satake, M.
  • Journal Title: Cell Struc. Func Volume: 36 Pages: 83-95
  • DOI: 10.1247/csf.10022
  • 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