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古川 鋼一 Koichi Furukawa名古屋大学大学院医学系研究科機能分子制御学・教授・医学博士


専門分野

生化学 (糖鎖による癌と神経細胞のシグナル調節機構)

略歴

1975年 3月
名古屋大学医学部卒業
1975年 5月
名古屋市立東市民病院研修
1976年 4月
国立名古屋病院内科レジデント
1980年10月
名古屋大学医学部附属病院第一内科医員
1982年 5月
名古屋大学医学部附属病院分院内科医員
1984年 1月
ニューヨークスローンケッタリング癌研究所リサーチアソシエイト
1988年10月
長崎大学医学部腫瘍医学教室助手
1990年 4月
同上講師
1991年12月
同上助教授
1997年 3月
名古屋大学大学院医学系研究科生化学第二講座・教授
2000年 4月
名古屋大学大学院医学系研究科分子総合医学専攻生物化学講座・教授

研究課題名

糖鎖による癌と神経細胞のシグナル調節機構

これまでの成果と今後の展望

A. 研究目的
癌の発生と病態の進展、および神経変性の病態に関わる複合糖質糖鎖の作用機構を明らかにして、治療戦略構築の基盤とする。

B. 研究成果
悪性黒色腫に特異的に発現するガングリオシドGD3による悪性形質増強のメカニズムを解明するために、GD3欠損変異株と再発現を樹立して、GD3のp130Cas、paxillin、FAKに対するリン酸化の亢進作用を報告してきた。さらに、インテグリンを介する接着能が、GD3発現によるインテグリンの脂質ラフトへの移動によることが示された。また、Src family キナーゼの中のYesが恒常的に活性化することが示され、その細胞膜再構築系による実証に成功した。
これらの成果をふまえて、GD3と直接に相互作用する機能分子を同定するために、HRP標識抗GD3抗体を用いたEMARS(enzyme-mediated activation of radical resources)反応を試みた。その結果、神経repulsion分子として報告のあるneogenin が同定された。本分子はGD3陽性細胞にのみ発現して脂質ラフトに局在しており、GD3との直接的結合が証明された。よって、γセクレターゼによる切断産物が細胞核に移動して、悪性形質の発現に関わる遺伝子を活性化していることを示唆する結果が得られている。GD3の機能発現の具体的な証拠となる可能性が高い。
マウスLewis肺癌細胞を用いて高転移性亜株を樹立し、転移関連遺伝子・分子の同定を行った。高転移性亜株およびGM1合成酵素silencing細胞で著明に発現上昇する遺伝子、ppGalNAcT-13を同定した。本遺伝子はOグリカンの合成開始点に働くGalNAc転移酵素ファミリーの一つで、脳に高発現するとともに、trimeric Tn構造を合成することが知られている。実際、ppGalNAcT-13遺伝子の過剰発現細胞で増殖や浸潤能が亢進するとともに、trimeric Tnの発現が確認された。さらにそのキャリヤータンパク質を探索し、Syndecan-1を同定した。マウスに接種した癌細胞の転移実験では、Syndecan-1上のtrimeric Tn構造が癌転移を亢進させることが示された。現在、ヒトの癌腫における知見を検討中である。
ガングリオシドは脳神経系に豊富に発現し、その発生、分化、機能に関与すると考えられてきたが、実際にはその健常性の維持と再生能に深く関わることが、糖鎖合成系の酵素遺伝子ノックアウト(KO)により明らかになってきた。この数年間解析してきたGM2/GD2合成酵素とGD3合成酵素のダブル(D)KOマウスにより、ガングリオシドが補体系の調節、炎症の抑制により、脳神経系を制御していることが示された。ただ、C3欠損マウスとDKOマウスを交配したtriple KOマウスでは、ミクログリアの集積や炎症サイトカインの正常化が見られたにもかかわらず、アストロサイトの増生には変化が見られなかった。神経変性におけるグリア間の役割の差異につき検討中である。一方、DKOマウス脳で発現が亢進した遺伝子の中で、Wisp2/CCN5の発現と機能解析を行い、その発現細胞で神経突起の伸長とアポトーシス抵抗性が認められた。また、その機序として、Aktの活性化の亢進が認められた。これらの事実により、ガングリオシド欠損によって惹起された脳神経系のダメージに反応して、神経保護のために働く遺伝子が誘導されることが示唆された。

主要研究業績

  1. Sakaidani Y, Ichiyanagi N, Saito C, Nomura T, Ito M, Nishio Y, Nadano D, Matsuda T, Furukawa K, Okajima T: O-linked-N-acetylglucosamine modification of mammalian Notch receptors by an atypical O-GlcNAc transferase Eogt1. Biochem Biophys Res Commun, 419, 14-19 (2012)
  2. Matsumoto Y, Zhang Q, Akita K, Nakada H, Hamamura K, Tokuda N, Tsuchida A, Matsubara T, Hori T, Okajima T, Furukawa K, Urano T: pp-GalNAc-T13 induces high metastatic potential of murine Lewis lung cancer by generating trimeric Tn antigen. Biochem Biophys Res Commun, 419, 7-13 (2012)
  3. Nishiguchi KM, Yasuma TR, Tomida D, Nakamura M, Ishikawa K, Kikuchi M, Ohmi Y, Niwa T, Hamajima N, Furukawa K, Terasaki H: C9-R95X polymorphism in patients with neovascular age-related macular degeneration. Invest Ophthalmol Vis Sci, 53, 508-512 (2012)
  4. Kamasaki Y, Nakamura T, Yoshizaki K, Iwamoto T, Yamada A, Fukumoto E, Maruya Y, Iwabuchi K, Furukawa K, Fujiwara T, Fukumoto S: Glycosphingolipids regulate ameloblastin expression in dental epithelial cells. J Dent Res, 91, 78-83 (2012)
  5. Yuki N, Takahashi Y, Ihara T, Ito S, Nakajima T, Funakoshi K, Furukawa K, Kobayashi K, Odaka M: Lack of antibody response to Guillain-Barre syndrome-related gangliosides in mice and men after novel flu vaccination. J Neurol Neurosurg Psychiatry, 83, 116-117 (2012)
  6. Sakaidani Y, Nomura T, Matsuura A, Ito M, Suzuki E, Murakami K, Nadano D, Matsuda T, Furukawa K, Okajima T: O-linked-N-acetylglucosamine on extracellular protein domains mediates epithelial cell-matrix interactions. Nat Commun, 2, 583 (2011)
  7. Ohkawa Y, Ohmi Y, Tajima O, Yamauchi Y, Furukawa K: Wisp2/CCN5 up-regulated in the central nervous system of GM3-only mice facilitates neurite formation in Neuro2a cells via integrin-Akt signaling. Biochem Biophys Res Commun, 411, 483-489 (2011)
  8. Hayashi K, Ozaki N, Kawakita K, Itoh K, Mizumura K, Furukawa K, Yasui M, Hori K, Yi SQ, Yamaguchi T, Sugiura Y: Involvement of NGF in the rat model of persistent muscle pain associated with taut band. J Pain, 12, 1059-1068 (2011)
  9. Miyata M, Kambe M, Tajima O, Moriya S, Sawaki H, Hotta H, Kondo Y, Narimatsu H, Miyagi T, Furukawa K: Membrane sialidase NEU3 is highly expressed in human melanoma cells promoting cell growth with minimal changes in the composition of gangliosides. Cancer Sci, 102, 2139-2149 (2011)
  10. Ikarashi K, Fujiwara H, Yamazaki Y, Goto J, Kaneko K, Kato H, Fujii S, Sasaki H, Fukumoto S, Furukawa K, Waki H: Impaired hippocampal long-term potentiation and failure of learning in beta1,4-N-acetylgalactosaminyltransferase gene transgenic mice. Glycobiology, 21, 1373-1381 (2011)
  11. Yamauchi Y, Furukawa K, Hamamura K: Positive feedback loop between PI3K-Akt-mTORC1 signaling and the lipogenic pathway boosts Akt signaling: induction of the lipogenic pathway by a melanoma antigen. Cancer Res, 71, 4989-4997 (2011)
  12. Kondo Y, Tokuda N, Furukawa K, Ando R, Uchikawa M, Zhang Q, Xiaoyan F: Efficient generation of useful monoclonal antibodies reactive with globotriaosylceramide using knockout mice lacking Gb3/CD77 synthase. Glycoconj J, 28, 371-384 (2011)
  13. Hamamura K, Tsuji M, Hotta H, Nakashima H, Hashimoto N, Hattori H, Ueda M, Furukawa K, Furukawa K: Functional activation of Src family kinase Yes is essential for the enhanced malignant properties of human melanoma cells expressing ganglioside GD3. J Biol Chem, 286, 18526-18537 (2011)
  14. Furukawa K, Ohmi Y, Ohkawa Y, Tokuda N, Kondo Y, Tajima O, Furukawa K: Regulatory mechanisms of nervous systems with glycosphingolipids. Neurochem Res, in press (2011)
  15. Okajima, T., Furukawa, K., Sakaidani, Y.: O-GlcNAc modification of the extracellular domain of Notch receptors. Trends Glycosci Glycotechnol, in press (2011)
  16. Hamaguchi Y, Tatematsu Y, Furukawa K, Matsubara T, Nakayama S: Imipramine inhibition of TRPM-like plasmalemmal Mg transport in vascular smooth muscle cells. J Cell Mol Med, 15, 593-601 (2011)
  17. Shiozuka C, Taguchi A, Matsuda J, Noguchi Y, Kunieda T, Uciho K, Yoshioka H, Hamanaka R, Yano S, Yokoyama S, Mannen K, Kulkarni AB, Furukawa K, Ishii S: Increased globotriaosylceramide levels in a transgenic mouse expressing human α1,4-galactosyltransferase and a mouse model for treating Fabry disease. J Biochem, 149, 161-170 (2011)
  18. Ohmi Y, Tajima O, Ohkawa Y, Sugiura Y, Furukawa K, Furukawa K: Gangliosides are essential in the protection of inflammation and neurodegeneration via maintenance of lipid rafts : elucidation by a series of ganglioside-deficient mutant mice. J Neurochem, 116, 926-935 (2011)
  19. Ohkawa Y, Miyazaki S, Hamamura H, Ohmi Y, Yamauchi Y, Furukawa K, Furukawa K: Ganglioside GD3 enhances adhesion signals and augments malignant properties of melanoma cells by recruiting integrins to glycolipid-enriched microdomains. J Biol Chem, 285, 27213-27223 (2010)
  20. Dong Y, Ikeda K, Hamamura K, Zhang Q, Kondo Y, Matsumoto Y, Ohmi Y, Furukawa K, Taguchi R and Furukawa K: GM1/GD1b/GA1 synthase expression results in the reduced cancer phenotypes with modulation of composition and raft-localization of gangliosides in a melanoma cell line. Cancer Sci, 101, 2039-2047 (2010)
  21. Tajima O, Egashira N, Ohmi Y, Fukue Y, Mishima K, Iwasaki K, Fujiwara M, Sugiura Y, Furukawa K, Furukawa K: Dysfunction of muscarinic acetylcholine receptors as a substantial basis for progressive neurological deterioration in GM3-only mice. Behav Brain Res, 206, 101-108 (2010)
  22. Zitman FMP, Todorov R, Furukawa K, Furukawa K, Willison HJ, Plomp JJ: Total ganglioside ablation at mouse motor nerve terminals alters neurotransmitter release level. Synapse, 64, 335-338 (2010)
  23. McGonigal R, Rowan EG, Greenshields KN, Halstead SK, Humphreys PD, Rother RP, Furukawa K, Willison HJ: Anti-GD1a antibodies activate complement and calpain to injure distal motor nodes of Ranvier in mice. Brain, 133, 1944-1960 (2010)
  24. Sakaidani Y, Furukawa K, Okajima T: O-GlcNAc modification of the extracellular domain of Notch receptors. Methods Enzymol, 480, 355-373 (2010)
  25. Matsumoto Y, Kobata T, Odaka M, Furukawa K, Hirata K, Yuki N: BAFF aids generation of IgG anti-ganglioside antibodies in response to Campylobacter jejuni lipo-oligosaccharide. J Neuroimmunol, 218, 67-72 (2010)
  26. Inoko E, Nishiura Y, Tanaka H, Takahashi T, Furukawa K, Kitajima K, Sato C: Developmental stage-dependent expression of a trisialic acid unit on glycoproteins in mouse brain as revealed by mAb.A2B5. Glycobiology, 20, 916-928 (2010)
  27. Ohmi Y, Tajima O, Ohkawa Y, Mori A, Sugiura Y, Furukawa K, Furukawa K. Gangliosides play pivotal roles in the regulation of complement systems and in the maintenance of integrity in nerve tissues. Proc Natl Acad Sci USA, 106, 22405-22410 (2009)
  28. Tajima O, Egashira N, Ohmi Y, Fukue Y, Mishima M, Iwasaki K, Fujiwara M, Sugiura Y, Furukawa K, Furukawa K. Reduced motor and sensory functions and emotional response in GM3-only mice: emergence from early stage of life and exacerbation with aging. Behavioural Brain Research, 198, 74-82 (2009)
  29. Ban R, Matsuzaki H, Akashi T, Sakashita G, Taniguchi H, Park SY, Tanaka H, Furukawa K, Urano T. Mitotic regulation of the stability of microtubule plus-end tracking protein EB3 by ubiquitin ligase SIAH-1 and Aurora mitotic kinases. J Biol Chem, 284, 28367-28381 (2009)
  30. Kondo Y, Tokuda N, Fan X, Yamashita T, Honke K, Takematsu H, Togayachi A, Ohta M, Kotzusumi Y, Narimatsu H, Tajima O, Furukawa K, Furukawa K. Glycosphingolipids are not pivotal receptors for Subtilase cytotoxin in vivo: Sensitivity analysis with glycosylation-defective mutant mice. Biochem Biophys Res Commun, 378, 179-181 (2009)
  31. Greenshields KN, Halstead SK, Zitman FM, Rinaldi S, Brennan KM, O'Leary C, Chamberlain LH, Easton A, Roxburgh J, Pediani J, Furukawa K, Furukawa K, Goodyear CS, Plomp JJ, Willison HJ. The neuropathic potential of anti-GM1 autoantibodies is regulated by the local glycolipid environment in mice. J Clin Invest, 119, 595-610 (2009)
  32. Hamamura K, Tsuji M, Nakashima H, Miyazaki S, Urano T, Yamamoto N, Ueda M, Furukawa K, Furukawa K. Focal adhesion kinase as well as p130Cas and paxillin is crucially involved in the enhanced malignant properties under expression of ganglioside GD3 in melanoma cells. Biochim Biophys Acta, 1780, 513-519 (2008)
  33. Furukawa K, Aixinjueluo W, Kasama T, Ohkawa Y, Yoshihara M, Ohmi Y, Tajima O, Suzumura A, Kittaka D, Furukawa K. Disruption of GM2/GD2 synthase gene resulted in neo-expression of 9-O-acetyl GD3 irrespective of Tis21. J Neurochem, 105, 1057-1066 (2008)
  34. Kittaka D, Itoh M, Ohmi Y, Kondo Y, Fukumoto S, Urano T, Tajima O, Furukawa K, Furukawa K. Impaired hypoglossal nerve regeneration in complex ganglioside-lacking mutant mice: down-regulation of neurotrophic factors and receptors as possible mechanisms. Glycobiology, 18, 509-516 (2008)
  35. Miyamoto K, Takada K, Furukawa K, Furukawa K, Kusunoki S. Roles of complex gangliosides in the development of experimental autoimmune encephalomyelitis. Glycobiology, 18, 408-413 (2008)
  36. Ohkawa Y, Miyazaki S, Miyata M, Hamamura K, Furukawa K, Furukawa K. Essential roles of integrin-mediated signaling for the enhancement of malignant properties of melanomas based on the expression of GD3. Biochem Biophys Res Commun, 373, 14-19 (2008)
  37. Fujii Y, Ozaki N, Taguchi T, Mizumura K, Furukawa K, Sugiura Y. TRP channels and ASICs mediate mechanical hyperalgesia in models if infmammatory muscle pain and delayed onset muscle soreness. Pain, 140, 292-304 (2008)
  38. Matsuura A, Ito M, Sakaidani Y, Kondo T, Murakami K, Furukawa K, Nadano D, Matsuda, T Okajima T. O-linked N-acetylglucosamine is present on the extracellular domain of notch receptors. J Biol Chem, 283, 35486-35495 (2008)
  39. Furukawa K et al. Molecules in the signaling pathway activated by gangliosides can be targets of therapeutics for malignant melanomas. Proteomics 8: 3312-3316 (2008)
  40. Kondo Y et al. Gene silencing in cancer by histone H3 lysine 27 tri-methylation independent of promoter DNA methylation. Nat. Genet. 40: 741-750 (2008)
  41. Matsumoto Y et al. Guillain-Barre syndrome-associated IgG response to gangliosides are generated independently of CD1 function in mice. J. Immunol. 180: 39-43 (2008)
  42. Yamauchi Y et al. Plasma membrane rafts complete cholesterol synthesis by participating in retrograde movement of precursor sterols. J. Biol. Chem. 282: 34994-35004 (2007)
  43. Goto H et al. Complex formation of Plk1 and INCENP required for metaphase-anaphase transition. Nature Cell Biol. 8: 180-187 (2006)
  44. Zhang Q et al. Metastatic potential of mouse Lewis lung cancer cells is regulated via ganglioside GM1 by modulating the matrix metalloprotease-9 localization in lipid rafts. J. Biol. Chem. 281: 18145-18155 (2006)
  45. Okuda T et al. Targeted disruption of Gb3/CD77 synthase gene resulted in the complete deletion of globo-series glycosphingolipids and loss of sensitivity to verotoxins. J. Biol. Chem. 281: 10230-10235 (2006)
  46. Aixinjueluo W et al. Mechanisms for the apoptosis of small cell lung cancer cells induced by anti-GD2 monoclonal antibodies: Roles of anoikis. J. Biol. Chem. 280: 29828-29836 (2005)
  47. Hamamura K et al. Ganglioside GD3 promotes cell growth and invasion through p130Cas and paxillin in malignant melanoma cells. Proc. Natl. Acad. Sci. USA 102: 11041-11046 (2005)
  48. Kato H et al. RNA polymerase II is required for siRNA generation and peri-centromeric heterochromatin formation in fission yeast. Science 309: 467-469 (2005)
  49. Yuki N et al. Carbohydrate Mimicry between Human Ganglioside GM1 and Campylobacter jejuni Lipo-oligosaccharide Causes Guillain-Barré Syndrome. Proc. Natl. Acad. Sci. USA. 101: 11404-11409 (2004)
  50. Nishio M et al. Over-expressed GM1 suppresses NGF signals by modulating the intra-cellular localization of NGF receptors and membrane fluidity in PC12 cells. J. Biol. Chem. 279: 33368-33378 (2004)
  51. Tsuchida A et al. Synthesis of disialyl Lewis a structure in colon cancer cell lines by a sialyltransferase ST6GalNAc VI responsible for the synthesis of a-series gangliosides. J. Biol. Chem. 278: 22787-22794 (2003)
  52. Mitsuda T et al. Over-expression of ganglioside GM1 results in the dispersion of platelet derived growth factor receptor from glycolipid-enriched micro-domains and in the suppression of cell growth signals. J. Biol. Chem. 277: 11239-11246 (2002)
  53. Furukawa K et al. Expression of the Gb3/CD77 synthase gene in megakaryoblastic leukemia cells: implication in the sensitivity to verotoxins. J. Biol. Chem. 277: 11247-11254 (2002)
  54. Okada M et al. b-series ganglioside deficiency exhibits no definite changes in the neurogenesis and the sensitivity to Fas-mediated apotosis, but impairs regeneration of the lesioned hypoglossal nerve. J. Biol. Chem. 277: 1633-1636 (2002)
  55. Kojima Y et al. Molecular cloning of Gb3/CD77 synthase, a glycosyl-transferase that initiate the synthesis of globo-series glycosphingolipids. J. Biol. Chem. 275: 15152-15156 (2000)
  56. Becker JC et al. Long-lived and transferable tumor immunity in mice following targeted interleukin 2 therapy. J. Clin. Invest. 98: 2801-2804 (1996)
  57. Takamiya K et al. Mice with disrupted GM2/GD2 synthase gene lack complex gangliosides, but exhibit only subtle defects in their nervous system. Proc. Natl. Acad. Sci. USA. 93: 10662-10667 (1996)

受賞

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