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 investigate roles of disialyl-gangliosides in cell proliferation, invasion and metastasis with focus on malignant melanomas.

B. Results: It has been clarified that GD3 expression resulted in the cluster formation of integrins in lipid rafts and enhancement of adhesion signals from interaction with collagen type I. Consequently, phosphorylation of Akt as well as of FAK, p130Cas and paxillin is enhanced probably due to the involvement of ILK. Relation between signals via growth factor/receptors and those via integrins has been clearly shown, i.e. melanoma cells under suspension did not respond to serum in terms of tyrosine phosphorylation of p130Cas, FAK or paxillin, indicating that integrin-mediated adhesion signals are essential in the growth signal induction. On the other hand, complete removal of serum resulted in the disappearance of ERK phosphorylation with adhesion to collagen type I, while tyrosine phosphorylation of p130Cas and paxillin could be still observed. These results indicate that co-existence of signals from growth factor receptors and from integrins is essential for the cell proliferation and activation, and that expression of ganglioside GD3 enhances both signaling pathways by regulating them at lipid rafts.

Regulatory mechanisms of nervous systems with acidic glycosphingolipids:

 

A. Purpose: To clarify roles of gangliosides in nervous tissues.

B. Results: Complex knockout (KO) mice in which remaining gangliosides can not compensate the lost functions have been generated. Abnormal phenotypes of double KO mice of GM2/GD2 synthase and GD3 synthase genes and their mechanisms have been analyzed. Among up-regulated genes related to inflammation and immune reaction, significance of complement system has been focused. Majority of complement-associated genes were up-regulated, and inflammatory glia proliferation and cytokine secretion increased with aging. In the analyses of lipid rafts, it was shown that complement regulatory proteins such as CD59 and CD55 as well as raft markers Caveolin-1 and Flotillin-1 disappeared from lipid rafts. Together with immunohistochemistry, dislocation of complement regulatory proteins in cell membrane might induce functional disorders, complement activation and subsequent inflammation, leading to neurodegeneration. This conclusion was confirmed by making triple KO mice based on cross-mating between DKO mice and C3-deficient mice, in which inflammatory reaction almost subsided, and neurodegeneration largely improved. All these results indicate that gangliosides are essential in the correct architecture and function of lipid rafts, and also play important roles in the maintenance of integrity of nervous systems.

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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