HOME > Members > GCOE Organizing Members > Koichi Furukawa, MD, PhD


Koichi Furukawa, MD, PhDProfessor, Department of Molecular Biochemistry, Nagoya University Graduate School of Medicine


Specialized field

Biochemistry

Career Summary

1975, 3
Graduated from Nagoya University School of Medicine
1975, 5
Internship at Nagoya Higashi Citizen Hospital
1976, 4
Resisdent of Internal Medicine at Nagoya National Hospital
1980, 10
Internist at the 1st Department of Internal Medicine, Nagoya University School of Medicine.
1984, 1
Research Associate, Sloan-Kettering Cancer Research Institute, New York
1989, 2
Assistant Professor, Department of Oncology, Nagasaki University School of Medicine
1990, 4
Associate Professor, Department of Oncology, Nagasaki University School of Medicine
1997, 3
Professor, Department of Biochemistry II, Nagoya University School of Medicine
2000, 4
Professor, Department of Biological Chemistry, Nagoya University Graduate School of Medicine

Research Theme

Regulatory mechanisms for signaling of cancer and neuronal cells with glycosylation

Research Summary

 

Mechanisms for the expression of malignant properties with cancer associated carbohydrate antigens in malignant tumor cells:

 

A. Purpose: To clarify the mechanisms for the complex carbohydrates involved in the evolution and development of pathogenesis of cancers and in the neurodegeneration, leading to the formation of basis to construct the strategy for the therapeutics.

B. Results: In order to clarify the mechanisms by which ganglioside GD3, specifically expressed in human melanoma cells, enhances malignant properties, we have established GD3-lacking mutants and their transfectant cells. Utilizing them, we have reported about the effects of GD3 expression on the activation of p130Cas, paxillin and FAK. Furthermore, it has been also demonstrated that adhesion activity mediated by integrins is enhanced by the shift of integrins to lipid rafts under GD3 expression. In addition, Yes among Src family kinases is constitutively activated in GD3+ cells, and this activation of Yes with GD3 has been recapitulated using a cell membrane reconstruction system of liposome.
Based on these results, we have tried to identify molecules interacting with GD3 on the cell surface using EMARS(enzyme-mediated activation of radical resources)reaction with an HRP-labeled anti-GD3 antibody. Consequently, a repulsion molecule, neogenin has been identified. This molecule is specifically detected in GD3+ cells, and its binding to GD3 has been shown. The cleavage products of neogenin might be transferred to nucleus and activate genes involved in the enhancement of malignant phenotypes in melanomas. This could be an evidence to indicate an actual role of GD3 in human malignant tumor cells.
We have tried to identify genes and molecules involved in the cancer metastasis by establishing high metastatic sublines using murine Lewis lung cancer. A gene, ppGalNAcT-13 was identified as a molecule markedly up-regulated in high metastatic sublines and in the GM1 synthase gene-silenced sublines. This gene product is a member of enzymes involved in the initiation step of O-glycan synthesis. This enzyme has been reported to be specifically expressed in nervous systems and brain tissues, and also to catalyze the synthesis of trimeric Tn antigen structure. Actually, cells over-expressing ppGalNAcT-13 cDNA showed enhanced cell growth and increased cell invasion, and also definite expression of trimeric Tn antigen on the cell surface. Furthermore, a carrier protein of the carbohydrate structure was searched and consequently Syndecan-1 was identified. In the metastasis experiments using grafts in mice, it was shown that the trimeric Tn structure on Syndecan-1 actually enhanced cancer metastasis. This finding is now being confirmed in human cancers.
 Gangliosides have been considered to be expressed in the nervous tissues, and be involved in the development, differentiation and functions. However, it has been clarified that they are involved in the maintenance of the integrity and regeneration activity in the nervous tissues based on the findings in the knockout (KO) mice of glycosyltransferases responsible for the synthesis of gangliosides. According to the results of double KO mice of GM2/GD2 synthase and GD3 synthase which have been analyzed for these several years, it was demonstrated that gangliosides play roles in the regulation of nervous systems by controlling the complement systems and by suppressing inflammation. However, in the triple KO mice lacking complement C3 as well as two ganglioside synthase genes, no improvement of astrocytosis could be observed, although accumulation of microglia and up-regulation of inflammatory cytokines were well improved. Thus, differential roles in neurodegeneration between two kind of glia were suspected, and now being investigated. On the other hand, we analyzed the significance of a gene named Wisp2/CCN5, showing up-regulation in DKO mice. In the analysis of its expression and function, its role in the enhancement of neurite extension and the resistance against induced apoptosis was demonstrated. More over, it was also elucidated that these functions of Wisp2/CCN5 are mediated by the activation of Akt. All these results suggested that some genes have been induced in DKO nervous tissues as a response to protect their brains from damages caused by the defects of gangliosides.

Principal Research Achievement

  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. Kondo Y, Shen L, Cheng AS, Ahmed S, Boumber Y, Charo C, Yamochi T, Urano T, Furukawa K, Kwabi-Addo B, Gold DL, Sekido Y, Huang TH, Issa JP. Gene silencing in cancer by histone H3 lysine 27 tri-methylation independent of promoter DNA methylation. Nat Genet, 40, 741-750 (2008)
  34. 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)
  35. 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)
  36. 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)
  37. 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)
  38. 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)
  39. 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)
  40. 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)
  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)

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