Molecular mechanisms for signals generated by the interaction between glycosphingolipids on the cell membrane and their ligands

• Project/Area Number: 24390078
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Pathological medical chemistry
• Research Institution: Chubu University (2015); Nagoya University (2012-2014)
• Principal Investigator: FURUKAWA Koichi 中部大学, 生命健康科学部, 教授 (80211530)
• Project Period (FY): 2012-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥18,720,000 (Direct Cost: ¥14,400,000、Indirect Cost: ¥4,320,000); Fiscal Year 2014: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2013: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000); Fiscal Year 2012: ¥7,930,000 (Direct Cost: ¥6,100,000、Indirect Cost: ¥1,830,000)
• Keywords: 糖脂質 / 細胞膜 / ミクロドメイン / シグナル / リガンド / 癌関連抗原 / スフィンゴ糖脂質 / 複合体 / 分子間相互作用 / ガングリオシド / ネオジェニン / EMARS法 / 複合糖質

Outline of Final Research Achievements

We have analyzed cell signaling generated by the interaction between glycosphingolipids expressed on cancer cells and neighboring membrane molecules expressed in the vicinity of them, and aimed to apply the results in the construction of cancer therapeutic strategies targeting membrane microdomain leading to obtain fundamental information by clarifying the implication of the signals in the regulation of cell phenotypes.
In order to do so, we used Enzyme-mediated activation of radical sources (EMARS)/mass spectrometry, to identify the interacting molecules with cancer-associated glycolipids. In melanomas, we identified neogenin as a GD3-associated molecule, in human gliomas, EphA2 as a GD2 associated molecule, and in small cell lung cancers, ESCT2 was identified as a GD2-associated molecule. Furthermore, PDGF receptor alpha was also identified as GD3-associated molecule in murine glioma cells. Then, individual molecular functions of these membrane molecules have been investigated.

Research Products

• [Journal Article] b-series gangliosides crucially regulate leptin secretion in adipose tissues. (2015)
  • Author(s): Ji S., Ohkawa Y., Tokizane K., Ohmi Y., Banno R., Furukawa K., Kiyama H. and Furukawa K.
  • Journal Title: Biochem Biophys Res Commun. Volume: 459 Issue: 2 Pages: 189-195
  • DOI: 10.1016/j.bbrc.2015.01.143
  • Peer Reviewed / Open Access
• [Journal Article] Impaired O-linked N-acetylglucosaminylation in the endoplasmic reticulum by mutated EGF domain-specific O-linked N-acetylglucosamine transferase found in Adams-Oliver syndrome (2015)
  • Author(s): M.Ogawa, S.Sawaguchi, T.Kawai, D.Nadano, T.Matsuda, H.Yagi, K.Kato, K.Furukawa, and T.Okajima
  • Journal Title: J. Biol. Chem. Volume: 290 Issue: 4 Pages: 2137-2149
  • DOI: 10.1074/jbc.m114.598821
  • Peer Reviewed / Open Access
• [Journal Article] Ganglioside GD3 Enhances Invasiveness of Gliomas by Forming a Complex with Platelet-derived Growth Factor Receptor α and Yes Kinase. (2015)
  • Author(s): Ohkawa Y, Momota H, Kato A, Hashimoto N, Tsuda Y, Kotani N, Honke K, Suzumura A, Furukawa K, Ohmi Y, Natsume A, Wakabayashi T, Furukawa K.
  • Journal Title: J Biol Chem. Volume: 290 Issue: 26 Pages: 16043-16058
  • DOI: 10.1074/jbc.m114.635755
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Deficiency in the Lipid Exporter ABCA1 Impairs Retrograde Sterol Movement and Disrupts Sterol Sensing at the Endoplasmic Reticulum (2015)
  • Author(s): Yamauchi Y, Iwamoto N, Rogers MA, Abe-Dohmae S, Fujimoto T, Chang CC, Ishigami M, Kishimoto T, Kobayashi T, Ueda K, Furukawa K, Chang TY, Yokoyama S.
  • Journal Title: J Biol Chem Volume: 290 Issue: 39 Pages: 23464-23477
  • DOI: 10.1074/jbc.m115.662668
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Akt-girdin signaling in cancer-associated fibroblasts contributes to tumor progression (2015)
  • Author(s): Yumiko Yamamura, Naoya Asai, Atsushi Enomoto, Takuya Kato, Shinji Mii, Yuji Kondo, Kaori Ushida, Kaoru Niimi, Nobuyuki Tsunoda, Masato Nagino, Shu Ichihara, Koichi Furukawa, Kengo Maeda, Toyoaki Murohara, Masahide Takahashi
  • Journal Title: Cancer Research Volume: 75 Issue: 5 Pages: 813-823
  • DOI: 10.1158/0008-5472.can-14-1317
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Glycosphingolipids in the regulation of the nervous system. (2014)
  • Author(s): Furukawa K, Ohmi Y, Ohkawa Y, Tajima O, Furukawa K
  • Journal Title: Adv Neurobiol. Volume: 9 Pages: 307-320
  • Peer Reviewed / Open Access
• [Journal Article] Ganglioside deficiellcy causes inflammation and neurodegeneration via the activation of complement system in the spinal cord. (2014)
  • Author(s): Yuhsuke Ohmi, Yuki Ohkawa, et al.
  • Journal Title: Journal of Neuroinflammation Volume: 61(印刷中) Issue: 1 Pages: 61-61
  • DOI: 10.1186/1742-2094-11-61
  • Peer Reviewed / Open Access
• [Journal Article] UVB-irradiated keratinocytes induce melanoma-associated ganglioside GD3 synthase gene in melanocytes via secretion of tumor necrosis factor α and interleukin 6. (2014)
  • Author(s): Miyata M.
  • Journal Title: Biochem Biophys Res Commun. Volume: 445 Issue: 2 Pages: 504-10
  • DOI: 10.1016/j.bbrc.2014.02.038
  • Peer Reviewed / Open Access
• [Journal Article] Gagnlioside GD3 induces convergence and synergism of adhesion and hepatocyte growth factor/Met signals in melanomas. (2014)
  • Author(s): Keiko Furukawa, Yuki Ohkawa, et al.
  • Journal Title: Cancer Science Volume: 105 Issue: 1 Pages: 52-63
  • DOI: 10.1111/cas.12310
  • Peer Reviewed
• [Journal Article] Trimeric Tn antigen on Syndecan-1 binds to integrins and enhances cancer metastasis via dynamic changes of membrane microdomains. (2013)
  • Author(s): Matsumoto Y, Zhang Q, Akita K, Nakada H, Hamamura K, Tsuchida A, Okajima T, Furukawa K, Urano T, Furukawa K
  • Journal Title: J. Biol. Chem. Volume: 288 Issue: 33 Pages: 24264-24276
  • DOI: 10.1074/jbc.m113.455006
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Binding of a sialic acid-recognizing lectin Siglec-9 modulates adhesion dynamics of cancer cells via calpain-mediated protein degradation. (2013)
  • Author(s): Sabit I.
  • Journal Title: J Biol Chem. Volume: 288 Issue: 49 Pages: 35417-27
  • DOI: 10.1074/jbc.m113.513192
  • Peer Reviewed
• [Journal Article] TLR4-MD-2 complex is negatively regulated by an endogenous ligand, globotetraosylceramide in vascular endothelial cells. (2013)
  • Author(s): Kondo, Y., Tokuda, N., Nishitani, C., Ohto, U., Akashi-TakKondo, Y., Tokuda, N., Nishitani, C., Ohto, U., Akashi-Takamura, S., Ito, Y., Uchikawa, M., Kuroki, Y., Miyake, K., Zhang, Q., Furukawa, K., Furukawa, K
  • Journal Title: Proc. Natl. Acad. Sci. USA Volume: 110 Issue: 12 Pages: 4714-4719
  • DOI: 10.1073/pnas.1218508110
  • Peer Reviewed
• [Journal Article] Enhancement of malignant properties of human osteosarcoma cells with disialyl gangliosides GD2/GD3. (2012)
  • Author(s): Shibuya, H., et al.
  • Journal Title: Cancer Science Volume: 103 Pages: 1656-1664
  • Peer Reviewed
• [Journal Article] Proteomic analysis of ganglioside-associated membrane molecules: Substantial basis for molecular clustering. (2012)
  • Author(s): Hashimoto, N., Hamamura, K., Kotani, N., Furukawa, K., Kaneko, K., Honke, K., Furukawa, K.
  • Journal Title: Proteomics Volume: 12 Issue: 21 Pages: 3154-3163
  • DOI: 10.1002/pmic.201200279
  • Peer Reviewed
• [Presentation] 糖脂質糖鎖によるシグナルの制御のメカニズム (2015)
  • Author(s): 古川鋼一、大川祐樹、大海雄介、橋本登、古川圭子
  • Organizer: 第38回日本分子生物学会年会 第88回日本生化学会大会 合同大会
  • Place of Presentation: 神戸ポートアイランド（神戸市）
  • Year and Date: 2015-12-04
  • Invited
• [Presentation] Functional analysis of GD2associated molecules identified by EMARS in lung cancer cells (2015)
  • Author(s): Nobutosi Esaki, Yuki Ohkawa, Yusuke Tuda,Kei Kaneko, Yusuke Ohmi, Noboru Hashimoto, Norihiro Kotani, Koichi Honke, Keiko Furukawa,.Koichi Furukawa
  • Organizer: 第38回日本分子生物学会年会 第88回日本生化学会大会 合同大会
  • Place of Presentation: 神戸ポートアイランド（神戸市）
  • Year and Date: 2015-12-02
• [Presentation] 癌関連連鎖との協同作用により癌形質を発現んする分子群の同定と作用機構 (2015)
  • Author(s): 古川鋼一,大川祐樹、橋本登、金子慶、小谷典弘、本家孝一、大海雄介、古川圭子
  • Organizer: 第74回日本癌学会学術総会
  • Place of Presentation: 名古屋国際会議場（名古屋市）
  • Year and Date: 2015-10-10
  • Int'l Joint Research / Invited
• [Presentation] ガングリオシドGD3の発現はグリオーマの発生・進展を促進する (2015)
  • Author(s): 大川祐樹、百田洋介、加藤 彰、橋本登、津田雄介、江崎寛季、古川圭子、大海雄介、夏目敦至、若林俊彦、古川鋼一
  • Organizer: 第74回日本癌学会学術総会
  • Place of Presentation: 名古屋国際会議場（名古屋市）
  • Year and Date: 2015-10-10
• [Presentation] ガングリオシドGD３とGD2はEphA2と関連することでヒトグリオブラストーマ細胞の悪性形質に寄与する (2015)
  • Author(s): 津田雄介, 大川祐樹、橋本登、岩沢太司、古谷典弘、本家孝一、岡島徹也、古川圭子、古川鋼一
  • Organizer: 第74回日本癌学会学術総会
  • Place of Presentation: 名古屋国際会議場（名古屋市）
  • Year and Date: 2015-10-10
• [Presentation] ヒトmelanoma細胞におけるNeogenin細胞内ドメイン（NelCD）標的遺伝子の同定 (2015)
  • Author(s): 金子 慶、大川祐樹、橋本 登、大海雄介、山内祥生、岡島徹也、小谷典弘、本家孝一、古川圭子、古川鋼一
  • Organizer: 第74回日本癌学会学術総会
  • Place of Presentation: 名古屋国際会議場（名古屋市）
  • Year and Date: 2015-10-08
• [Presentation] 肺癌におけるppGalNAc-T13mRNA の発現解析および臨床的意義の検討 (2014)
  • Author(s): 野木森健一、松本康之、石黒太志、横平香平、長谷川好規、古川鋼一
  • Organizer: 第73回日本癌学会学術総会
  • Place of Presentation: 横浜パシフィコ、神奈川県横浜市
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] UVB 照射ケラチノサイトは炎症性サイトカインを分泌してメラノサイトにおける癌関連GD3 合成酵素遺伝子の発現を誘導する (2014)
  • Author(s): 古川圭子、宮田麻衣子、田島織絵、神戸真理子、市原正智、祖父江沙矢加、古川鋼一
  • Organizer: 第73回日本癌学会学術総会
  • Place of Presentation: 横浜パシフィコ、神奈川横浜市
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] Binding of a sialic acid-recognizing lectin Siglec-9 modulates malignant properties of cancer cells via calpain-mediated degradation of focal adhesion kinase and related proteins. (2014)
  • Author(s): Koichi Furukawa, Ilhamjan Sabit, Noboru Hashimoto, Yasuyuki Matsumoto, Toshiyuki Yamaji, Keiko Furukawa
  • Organizer: SIALOGLYCO2014
  • Place of Presentation: Gold Coast, Australia
  • Year and Date: 2014-09-09 – 2014-09-10
  • Invited
• [Presentation] スフィンゴ糖脂質機能の統合的理解 (2014)
  • Author(s): 古川鋼一、橋本 登、大川祐樹、大海雄介、金子 慶、古川圭子
  • Organizer: 第33回日本糖質学会年会
  • Place of Presentation: 名古屋大学豊田講堂、愛知県名古屋市
  • Year and Date: 2014-08-10 – 2014-08-12
  • Invited
• [Presentation] Specificity and spatio-temporal dynamics of the interaction between glycosphingolipids and endogenous ligands. (2014)
  • Author(s): Koichi Furukawa, Yuji Kondo, Yasutomo Ito, Keiko Furukawa
  • Organizer: Glyco-T 2014, 9th International Symposium on Glycosyltransferases
  • Place of Presentation: Port, Portugal
  • Year and Date: 2014-06-18 – 2014-06-21
  • Invited
• [Presentation] Spatio-temporal dynamics of the interaction between glycosphingolipids and membrane molecules. (2014)
  • Author(s): Koichi Furukawa
  • Organizer: Gordon Research Conference, Glycolipid & and Sphingolipid Biology.
  • Place of Presentation: Ventura, CA,USA.
  • Invited
• [Presentation] 糖鎖による悪性形質の制御機構 (2013)
  • Author(s): 古川鋼一、松本康之、橋本 登、大川祐樹、大海雄介、古川圭子
  • Organizer: 第３２回日本糖質学会
  • Place of Presentation: 大阪国際センター（大阪市）
• [Presentation] 癌細胞の発症と進展に関わる糖鎖の作用機構 (2013)
  • Author(s): 古川鋼一、松本康之、橋本 登、大川祐樹、大海雄介、古川圭子
  • Organizer: 第３２回日本糖質学会
  • Place of Presentation: 大阪国際センター（大阪市）
• [Presentation] 複合糖質と糖鎖認識分子との相互作用の時空間的ダイナミクス (2013)
  • Author(s): 古川鋼一、近藤裕史、松本康之、古川圭子
  • Organizer: 第86回日本生化学会大会
  • Place of Presentation: パシフィコ横浜（横浜市）
• [Presentation] 糖鎖フィールド：糖鎖がシグナル伝達を制御する原理 (2013)
  • Author(s): 古川鋼一、近藤裕史、松本康之、古川圭子
  • Organizer: 第86回日本生化学会大会
  • Place of Presentation: パシフィコ横浜（横浜市）
• [Presentation] 糖鎖による癌細胞の悪性形質の制御機構 (2012)
  • Author(s): 古川鋼―, 他
  • Organizer: 第71回日本癌学会学術総会モーニングセミナー
  • Place of Presentation: 札幌(招待講演)
  • Year and Date: 2012-09-20
• [Presentation] Involvement of complex carbohydrates in the cancer phenotypes and therapeutic application. (2012)
  • Author(s): Koichi Furukawa., et al.
  • Organizer: GlycoT 2012 Hannover 8^<th> International Symposium on Glycosyltransferases
  • Place of Presentation: Hannover, Germany(招待講演)
  • Year and Date: 2012-06-06
• [Book] Regulatory Mechanisms for Malignant Properties of Cancer Cells with Disialyl and Monosialyl Gangliosides. In Glyco-signals in Cancer (2016)
  • Author(s): Koichi Furukawa, Yuki Ohkawa, Yasuyuki Matsumoto, Yuhsuke Ohmi, Noboru Hashimoto, Keiko Furukawa
  • Total Pages: 219
  • Publisher: Springer
• [Book] Roles of Glycosphingolipids in the Regulation of the Membrane Organization and Cell Signaling in Lipid Rafts. In Lipid/rafts (2016)
  • Author(s): Koichi Furukawa , Yuhsuke Ohmi, Yuki Ohkawa, Noboru Hashimoto, Yuji Kondo, Orie Tajima, Keiko Furukawa
  • Total Pages: 152
  • Publisher: Nova Science Publishers
• [Book] Sugar Chain (2015)
  • Author(s): Furukawa K, Matsumoto Y, Zhang Q, Furukawa K
  • Total Pages: 288
  • Publisher: Springer
• [Book] Lipid Rafts: Properties, controversies and roles in signal transduction. (2014)
  • Author(s): Koichi Furukawa, Yusuke Ohmi, Yuji Kondo, Yuki Ohkawa, Noboru Hashimoto, Orie Tajima, Keiko Furukawa
  • Total Pages: 268
  • Publisher: Nova Science Publishers
• [Book] Glycosphingolipids in the regulation of nervous systems. In Glycobiology of the Nervous System. (2014)
  • Author(s): Furukawa, K., Ohmi, Y., Ohkawa, Y., Tajima, O., Furukawa, K.
  • Total Pages: 584
  • Publisher: Springer, Publishing
• [Book] Glycoscience: Biology and Medicine (2014)
  • Author(s): Ogawa M, Furukawa K, Okajima T
  • Total Pages: 1568
  • Publisher: Springer
• [Book] Glycoscience: Biology and Medicine (2014)
  • Author(s): Koichi Furukawa, Yuhsuke Ohmi, Yuki Ohkawa, Noboru Hashimoto, Yoshio Yamauchi, Orie Tajima, Keiko Furukawa
  • Total Pages: 1568
  • Publisher: Springer
• [Book] The role of glycosphingolipids in lipid rafts: lessons from knockout mice. In Lipid Rafts: Properties, controversies and roles in signal transduction. Ed. by Dan Sillence (2014)
  • Author(s): Koichi Furukawa, Yusuke Ohmi, Yuji Kondo, Yuki Ohkawa, Noboru Hashimoto, Orie Tajima, Keiko Furukawa
  • Total Pages: 261
  • Publisher: Nova Science Publishers