Molecular mechanisms of phospholipid metabolism and cell morphology regulated by small G protein signaling

2009 Fiscal Year Final Research Report

• Project/Area Number: 17079008
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: University of Tsukuba
• Principal Investigator: KANAHO Yasunori University of Tsukuba, 大学院・人間総合科学研究科, 教授 (00214437)
• Co-Investigator(Kenkyū-buntansha): YOKOZEKI Takeaki 筑波大学, 大学院・人間総合科学研究科, 講師 (80373405)
• Co-Investigator(Renkei-kenkyūsha): FUNAKOSHI Yuji 筑波大学, 大学院・人間総合科学研究科, 助教 (30415286) ; HASEGAWA Hiroshi 筑波大学, 大学院・人間総合科学研究科, 教授 (88928814) ; SUGIMOTO Rika 筑波大学, 大学院・人間総合科学研究科, 研究員 (40455936)
• Project Period (FY): 2005 – 2009
• Keywords: 低分子量G蛋白質 / Arf6 / リン脂質キナーゼ / 神経細胞 / 腫瘍血管形成 / 肝臓 / スパイン / 神経突起

Research Abstract

In this study, mechanisms and physiological functions of the cellular signaling through the small G protein Arf6 have been investigated at the molecular, cellular and whole animal levels. It was found that (1) Arf6 regulates retraction of the spine in neurons through activation of the lipid kinase PIP5K・, (2) Arf6 plays critical roles in the development of the liver and tumor angiogenesis, indicating a possible target of Arf6 as the anti-cancer drug, and (3) Arf6 regulates neurite elongation and branching through the JNK-interacting protein.

Research Products

• [Journal Article] The scaffold protein JIP3 functions as a downstream effector of the small GTPase ARF6 to regulate neurite morphogenesis of cortical neurons (2010)
  • Author(s): Suzuki A., Arikawa C., Kuwahara Y., Itoh K., Watanabe M., Watanabe H., Suzuki T., Funakoshi Y., Hasegawa H., Kanaho Y.
  • Journal Title: FEBS Kett. (in press)
  • Peer Reviewed
• [Journal Article] Pertussis toxin up-regulates angiotensin type 1 receptors through Toll-like receptor 4-mediated Rac activation. (2010)
  • Author(s): Nishida M., Suda R., Nagamatsu Y., Tanabe S., Onohara N., Nakaya M., Kanaho Y., Shibata T., Uchida K., Sumimoto H., Sato Y., Kurose H.
  • Journal Title: J. Biol. Chem. 285 Pages: 15268-15277
  • Peer Reviewed
• [Journal Article] Phospholipase D signaling and its involvement in neurite outgrowth. (2009)
  • Author(s): Kanaho Y., Funakoshi Y., Hasegawa H.
  • Journal Title: Biochim. Biophys. Acta 1791 Pages: 898-904
  • Peer Reviewed
• [Journal Article] Sequential regulation of DOCK2 dynamics by two phospholipids during neutrophil chemotaxis. (2009)
  • Author(s): Nishikimi A., Fukuhara H., Su W., Hongu T., Takasuga S., Mihara H., Cao Q., Sanematsu F., Kanai M., Hasegawa H., Tanaka Y., Shibasaki M., Kanaho Y., Sasaki T., Frohman M.A., Fukui Y.
  • Journal Title: Science 324 Pages: 384-387
  • Peer Reviewed
• [Journal Article] RalA functions as an indispensable signal mediator for nutrient sensing system. (2008)
  • Author(s): Maehama T., Tanaka M., Nishina H., Murakami M., Kanaho Y., Hanada K.
  • Journal Title: J. Biol. Chem. 283 Pages: 35053-35059
  • Peer Reviewed
• [Journal Article] Loss of PIP5KI・demonstrates that PIP5KI isoform-specific PIP2 synthesis is required for IP3 formation. (2008)
  • Author(s): Wang Y., Chen X., Lian L., Tang T., Stalker TJ., Sasaki T., Kanaho Y., Brass LF., Choi J.K., Hartwig J.H., Abrams C.S.
  • Journal Title: Proc. Natl. Acad. Sci. 105 Pages: 14064-16069
  • Peer Reviewed
• [Journal Article] Loss of PIP5KI・, unlike other PIP5KI isoforms, impairs the integrity of the membrane cytoskeleton in murine megakaryocytes. (2008)
  • Author(s): Wang Y., Litvinov RI., Chen X., Bach TL., Lian L., Petrich B.G., Monkley S.J., Kanaho Y., Critchley D.R., Sasaki T., Birnbaum M.J., Weisel J.W., Hartwig J., Abrams C.S.
  • Journal Title: J. Clin. Invest. 118 Pages: 812-819
  • Peer Reviewed
• [Journal Article] Role of activation of PIP5K・661 by AP-2 complex in synaptic vesicle endocytosis. (2007)
  • Author(s): Nakano-Kobayashi A., Yamazaki M., Unoki T., Hongu T., Murata C., Taguchi R., Katada T., Frohman M.A., Yokozeki T., Kanaho Y.
  • Journal Title: EMBO J. 26 Pages: 1105-1116
  • Peer Reviewed
• [Journal Article] Control of cell polarity and motility by the PtdIns(3, 4, 5)P(3) phosphatase SHIP1. (2007)
  • Author(s): Nishio M., Watanabe K., Sasaki J., Taya C., Takasuga S., Iizuka R., Balla T., Yamazaki M., Watanabe H., Itoh R., Kuroda S., Horie Y., Forster I., Mak T.S., Yonekawa H., Penninger J.M., Kanaho Y., Suzuki A., Sasaki T.
  • Journal Title: Nat. Cell Biol. 9 Pages: 36-44
  • Peer Reviewed
• [Journal Article] Critical role of PICT-1, a tumor suppressor candidate, in phosphatidylinositol 3, 4, 5-trisphosphate signals and tumorigenic transformation. (2006)
  • Author(s): Okahara F., Itoh K., Nakagawara A., Murakami M., Kanaho Y., Maehama T.
  • Journal Title: Mol. Biol. Cell 17 Pages: 4888-4895
  • Peer Reviewed
• [Journal Article] Crucial role of the small GTPase ARF6 in hepatic cord formation during liver development. (2006)
  • Author(s): Suzuki T., Kanai Y., Hara T., Sasaki J., Sasaki T., Kohara M., Maehama T., Taya C., Shitara H., Yonekawa H., Frohaman M.A., Yokozeki T., Kanaho Y.
  • Journal Title: Mol. Cell. Biol. 26 Pages: 6149-6156
  • Peer Reviewed
• [Journal Article] RhoA-mediated phospholipase D1 signaling is not required for the formation of stress fibers and focal adhesions. (2006)
  • Author(s): Su W., Chardin P., Yamazaki M., Kanaho Y., Du G.
  • Journal Title: Cell Signal. 18 Pages: 469-478
  • Peer Reviewed
• [Journal Article] The small GTPase ADP-ribosylation factor 6 negatively regulates dendritic spine formation. (2005)
  • Author(s): Miyazaki H., Yamazaki M., Watanabe H., Maehama T., Yokozeki T., Kanaho Y.
  • Journal Title: FEBS Lett. 579 Pages: 6834-6837
  • Peer Reviewed
• [Journal Article] Local change in phospholipid composition at the cleavage furrow is essential for completion of cytokinesis. (2005)
  • Author(s): Emoto K., Inadome H., Kanaho Y., Narumiya S., Umeda M.
  • Journal Title: J. Biol. Chem. 280 Pages: 37901-37907
  • Peer Reviewed
• [Journal Article] Regulation of anaphylactic responses by phosphatidylinositol phosphate kinase type I・. (2005)
  • Author(s): Sasaki J., Sasaki T., Yamazaki M., Matsuoka K., Taya C., Shitara H., Takasuga S., Nishio M., Mizuno K., Wada T., Miyazaki H., Watanabe H., Iizuka R., Kubo S., Murata S., Chiba T., Maehama T., Frohman M.A., Tanaka K., Penninger J.M., Yonekawa H., Suzuki A., Kanaho Y.
  • Journal Title: J. Exp. Med. 201 Pages: 859-870
  • Peer Reviewed
• [Presentation] Involvement of small GTPase (2009)
  • Author(s): T. Hongu, Y. Funakoshi, H. Hasegawa, Y. Kanaho
  • Organizer: Arf6 in angiogenesis
  • Place of Presentation: 筑波
  • Year and Date: 20091118-20091119
• [Presentation] Regulation of morphology by the small GTPase Arf6 is mediated by the interaction with a novel down stream effector, JIP3. (2009)
  • Author(s): A. Suzuki, C. Arikawa, Y. Kuwahara, Y. Funakoshi, Y. Kanaho, H. Hasegawa
  • Organizer: International Symposium on Cellular Signaling ~principles and functions~
  • Place of Presentation: 筑波
  • Year and Date: 20091118-20081119
• [Presentation] 血管形成における低分子量GTP結合蛋白質ARF6の機能 (2009)
  • Author(s): 本宮綱記、船越祐司、長谷川潤、金保安則
  • Organizer: 第6回日本病理学会カンファレンス
  • Place of Presentation: 筑波
  • Year and Date: 20090731-20090801
• [Presentation] ホスファチジルイノシトール4-リン酸5-キナーゼ・、・は精子形成に不可欠である (2009)
  • Author(s): 長谷川潤、杉本里香、山下美鈴、野口純子、岡田理沙、鵜木隆光、船越祐司、馬場忠、金保安則
  • Organizer: 第6回日本病理学会カンファレンス
  • Place of Presentation: 筑波
  • Year and Date: 20090731-20090801
• [Presentation] ホスファチジルイノシトール4-リン酸5-キナーゼの精子形成への関与 (2009)
  • Author(s): 長谷川潤、杉本里香、山下美鈴、野口純子、岡田理沙、鵜木隆光、船越祐司、馬場忠、金保安則
  • Organizer: 第61回日本細胞生物学会大会
  • Place of Presentation: 名古屋
  • Year and Date: 20090605-20090606
• [Presentation] Isozyme specific activation of PIP5K by ARF6. (2009)
  • Author(s): T. Higuchi, T. Sato, H. Hasegawa, Y. Funakoshi, Y. Kanaho
  • Organizer: The 6th Japan-Korea Conference in Cellular Signaling for Young Scientists
  • Place of Presentation: 長崎
  • Year and Date: 2009-11-25
• [Presentation] The role of PIP5K in wound healing. (2009)
  • Author(s): R. Okada, H. Hasegawa, M. Furuya, Y. Funakoshi, Y. Kanaho
  • Organizer: The 6th Japan-Korea Conference in Cellular Signaling for Young Scientists
  • Place of Presentation: 長崎
  • Year and Date: 2009-11-25
• [Presentation] Novel activation mechanism of PIP5Kc by the small GTPase ARF6. (2009)
  • Author(s): Y. Funakoshi, T. Higuchi, T. Sato, H. Hasegawa, Y. Kanaho
  • Organizer: The 6th Japan-Korea Conference in -5 - Cellular Signaling for Young Scientists
  • Place of Presentation: 長崎
  • Year and Date: 2009-11-24
• [Presentation] Activation mechanism and physiological function of PIP5Kg in neurons. (2009)
  • Author(s): Y. Kanaho
  • Organizer: The 10th International Molecular Biology and Biotechnology Workshop.
  • Place of Presentation: Taipei, Taiwan
  • Year and Date: 2009-11-13
• [Presentation] 血管形成における低分子量GTP結合蛋白質ARF6の関与 (2009)
  • Author(s): 本宮綱記、船越祐司、長谷川潤、金保安則
  • Organizer: 第82回日本生化学会大会
  • Place of Presentation: 神戸
  • Year and Date: 2009-10-24
• [Presentation] 低分子量G蛋白質Arf6による神経突起分枝制御機構 (2009)
  • Author(s): 鈴木篤史、有川千尋、桑原裕二、船越祐司、長谷川潤、金保安則
  • Organizer: 第82回日本生化学会大会
  • Place of Presentation: 神戸
  • Year and Date: 2009-10-24
• [Presentation] 低分子量G蛋白質ARF6による肝細胞遊走制御機構の解析 (2009)
  • Author(s): 周〓、船越祐司、長谷川潤、金保安則
  • Organizer: 第82回日本生化学会大会
  • Place of Presentation: 神戸
  • Year and Date: 2009-10-24
• [Presentation] ホスファチジルイノシトールホスファチジルイノシトール4-リン酸5-キナーゼは精子形成に不可欠である (2009)
  • Author(s): 長谷川潤、杉本里香、山下美鈴、野口純子、岡田理沙、鵜木隆光、船越祐司、馬場忠、金保安則
  • Organizer: 第82回日本生化学会大会
  • Place of Presentation: 神戸
  • Year and Date: 2009-10-24
• [Presentation] ARF6はPIP5Kをアイソザイム依存的に活性化する (2009)
  • Author(s): 金保安則、樋口珠美、渡辺宏子、小林裕一、佐藤隆信、長谷川潤、船越祐司
  • Organizer: 第82回日本生化学会大会
  • Place of Presentation: 神戸
  • Year and Date: 2009-10-23
• [Presentation] Regulation of PIP5K isozymes by ARF6. (2009)
  • Author(s): Y. Kanaho
  • Organizer: The 15th International Symposium on Regulation of Enzyme Activity and Synthesis
  • Place of Presentation: Bologna, Italy
  • Year and Date: 2009-09-28
• [Presentation] シグナル伝達足場タンパク質JIP3はArf6の下流因子として神経細胞の形態形成を制御する (2009)
  • Author(s): 鈴木篤史、桑原裕二、船越祐司、長谷川潤、金保安則
  • Organizer: 平成21年度特定領域「G蛋白質シグナル」研究班会議
  • Place of Presentation: 千葉
  • Year and Date: 2009-09-10
• [Presentation] 血管形成における低分子量GTP結合蛋白質ARF6の関与 (2009)
  • Author(s): 本宮綱記、長谷川潤、金保安則
  • Organizer: 第61回日本細胞生物学会大会
  • Place of Presentation: 名古屋
  • Year and Date: 2009-06-06
• [Presentation] リン脂質キナーゼPIP5K・661とAP-2複合体の結合はポストシナプス可塑性を制御する (2009)
  • Author(s): 鵜木隆光、松田信爾、船越祐司、長谷川潤、柚崎通介、金保安則
  • Organizer: 第61回日本細胞生物学会大会
  • Place of Presentation: 名古屋
  • Year and Date: 2009-06-06
• [Presentation] Physiological function of the small GTPase ARF6. (2008)
  • Author(s): Y. Kanaho, T. Hongu, Y. Funakoshi, H. Hasegawa
  • Organizer: 第31回日本分子生物学会年会・第81回日本生化学会大会 合同大会
  • Place of Presentation: 神戸
  • Year and Date: 2008-12-09
• [Presentation] 血管形成における低分子量G蛋白質ARF6の関与 (2008)
  • Author(s): 本宮綱記、長谷川潤、金保安則
  • Organizer: 第60回日本細胞生物学会大会
  • Place of Presentation: 横浜
  • Year and Date: 2008-07-01
• [Presentation] Activation mechanisms and physiological functions of the lipid kinase PIP5K. International Symposium of Organization for the Support and Development of Strategic Initiatives, University of Tsukuba. (2008)
  • Author(s): Y. Kanaho
  • Organizer: New Frontier for Lipid and Energy Metabolism
  • Place of Presentation: Tsukuba, Japan
  • Year and Date: 2008-02-18
• [Presentation] Novel activation mechanism and physiological function of PIP 5-kinase・661. (2007)
  • Author(s): Y. Kanaho
  • Organizer: 48th International Symposium on Regulation of Enzyme Activity and Synthesis in Normal and Neoplastic Tissues
  • Place of Presentation: Bologna, Italy (Invited)
  • Year and Date: 20070924-20070925
• [Presentation] Roe of small GTPase ARF6 in embryonic angiogenesis (2007)
  • Author(s): T. Hongu, T. Suzuki, T. Yokozeki, Y. Kanaho
  • Organizer: 2007 International Symposium on "G-protein Signaling"
  • Place of Presentation: 東京
  • Year and Date: 2007-07-28
• [Presentation] The scaffold protein JLP as a novel -6 - partner protein of the small GTPase ARF6. (2007)
  • Author(s): C. Arikawa, T. Yokozeki, Y. Kanaho
  • Organizer: 2007 International Symposium on "G-protein Signaling"
  • Place of Presentation: 東京
  • Year and Date: 2007-07-28
• [Presentation] Regulation membrane dynamics by the small GTPase ARF6. (2007)
  • Author(s): Y. Kanaho
  • Organizer: 2007 International Symposium on "G-protein Signaling"
  • Place of Presentation: 東京(Invited)
  • Year and Date: 2007-07-28
• [Presentation] Role of small GTPase in Embryonic angiogenesis. (2007)
  • Author(s): T. Hongu, T. Suzuki, T. Yokozeki, Y. Kanaho
  • Organizer: The 5th Korea-Japan Conference on Cellular Signaling for Young Scientists
  • Place of Presentation: Gyeongju, Republic of Korea
  • Year and Date: 2007-07-09
• [Presentation] Gタンパク質による細胞形態の制御 (2007)
  • Author(s): 金保安則
  • Organizer: 日本薬学会127年会(シンポジウム)
  • Place of Presentation: 富山
  • Year and Date: 2007-03-29
• [Presentation] Physiological function of the small G protein ARF6 in hepatic cord formation and liver development. (2006)
  • Author(s): T. Suzuki, Y. Kanai, T. Hara, J. Sasaki, T. Sasaki, M. Kohara, T. Maehama, T. Yokozeki, Y. Kanaho
  • Organizer: The 20th IUBMB Congress and 11th FAOBMB Congress
  • Place of Presentation: 京都
  • Year and Date: 2006-06-21
• [Presentation] ARF6による樹状突起スパイン形成の制御機構 (2006)
  • Author(s): 金保安則
  • Organizer: 特定領域研究「細胞情報ネットワークを統合するg蛋白質シグナル研究の新展開」
  • Place of Presentation: 茨城県稲敷郡
  • Year and Date: 2006-02-10
• [Presentation] ARF6 is required for hepatic cord formation and liver development. (2005)
  • Author(s): T. Suzuki, Y. Kanai, T. Hara, J. Sasaki, T. Sasaki, M. Kohara, T. Yokozeki, T. Maehama, Y. Kanaho
  • Organizer: 第78回日本生化学会大会
  • Place of Presentation: 神戸
  • Year and Date: 20051019-20051022
• [Remarks]
  • URL: http://www.md.tsukuba.ac.jp/basic-med/biochem/kanaholab/index.html
• [Patent(Industrial Property Rights)] Arf6遺伝子機能喪失動物及びその利用方法 (2010)
  • Inventor(s): 金保安則
  • Industrial Property Rights Holder: 筑波大学
  • Industrial Property Number: 特許・特願2010-050431
  • Filing Date: 2010-03-08
  • Acquisition Date: 2010-03-08
• [Patent(Industrial Property Rights)] GTP結合型ARF6タンパク質の測定方法及びその用途 (2010)
  • Inventor(s): 金保安則
  • Industrial Property Rights Holder: 筑波大学
  • Industrial Property Number: 特許・特願2010-063109
  • Filing Date: 2010-03-18
  • Acquisition Date: 2010-03-18