Naoyuki Taniguchi

RIKEN, Вако, Saitama, Japan

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Publications (794)3007.13 Total impact

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    ABSTRACT: E-cadherin is a central molecule in the process of gastric carcinogenesis and its posttranslational modifications by N-glycosylation have been described to induce a deleterious effect on cell adhesion associated with tumor cell invasion. However, the role that site-specific glycosylation of E-cadherin has in its defective function in gastric cancer cells needs to be determined. Using transgenic mice models and human clinical samples, we demonstrated that N-acetylglucosaminyltransferase V (GnT-V)-mediated glycosylation causes an abnormal pattern of E-cadherin expression in the gastric mucosa. In vitro models further indicated that, among the four potential N-glycosylation sites of E-cadherin, Asn-554 is the key site that is selectively modified with β1,6 GlcNAc-branched N-glycans catalyzed by GnT-V. This aberrant glycan modification on this specific asparagine site of E-cadherin was demonstrated to affect its critical functions in gastric cancer cells by affecting E-cadherin cellular localization, cis-dimer formation, molecular assembly and stability of the adherens junctions and cell-cell aggregation, which was further observed in human gastric carcinomas. Interestingly, manipulating this site-specific glycosylation, by preventing Asn-554 from receiving the deleterious branched structures, either by a mutation or by silencing GnT-V, resulted in a protective effect on E-cadherin, precluding its functional dysregulation and contributing to tumor suppression.Oncogene advance online publication, 20 July 2015; doi:10.1038/onc.2015.225.
    Oncogene 07/2015; DOI:10.1038/onc.2015.225 · 8.46 Impact Factor
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    ABSTRACT: Biological significance: It has been proposed that serum SP-D concentrations are predictive of COPD pathogenesis, but distinguishing between COPD patients and healthy individuals to establish a clear cut-off value is difficult because smoking status highly affects circulating SP-D levels. Herein, we focused on N-glycosylation in SP-D and examined whether or not N-glycosylation patterns in SP-D are associated with the pathogenesis of COPD. We performed an N-glycomic analysis of human serum SP-D and the results show that a core-fucose is present in its N-glycan. We also found that the N-glycosylation in serum SP-D was indeed altered in COPD, that is, fucosylation levels including core-fucosylation are significantly increased in COPD patients compared with non-COPD smokers. The severity of emphysema was positively associated with fucosylation levels in serum SP-D in smokers. Our findings shed new light on the discovery and/or development of a useful biomarker based on glycosylation changes for diagnosing COPD.
    Journal of proteomics 07/2015; DOI:10.1016/j.jprot.2015.07.011 · 3.89 Impact Factor
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    ABSTRACT: Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases that degrade many extracellular matrix components and that have been implicated in the pathogenesis of various human diseases including cancer metastasis. Here, we screened MMP-9 inhibitors using photo-cross-linked chemical arrays, which can detect small-molecule ligand-protein interactions on a chip in a high-throughput manner. The array slides were probed sequentially with His-MMP-9, anti-His antibody, and a Cy5-labeled secondary antibody and then scanned with a microarray scanner. We obtained 27 hits among 24,275 compounds from the NPDepo library; 2 of the identified compounds (isoxazole compound 1 and naphthofluorescein) inhibited MMP-9 enzyme activity in vitro. We further explored 17 analogs of 1 and found that compound 18 had the strongest inhibitory activity. Compound 18 also inhibited other MMPs, including MMP-2, MMP-12, and MMP-13 and significantly inhibited cell migration in human fibrosarcoma HT1080 cells. These results suggest that 18 is a broad-spectrum MMP inhibitor.
    Bioscience Biotechnology and Biochemistry 05/2015; 79(10):1-6. DOI:10.1080/09168451.2015.1045829 · 1.06 Impact Factor
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    ABSTRACT: Core fucosylation is catalyzed by α1,6-fucosyltransferase (Fut8), which transfers a fucose residue to the innermost GlcNAc residue via α1,6-linkage on N-glycans in mammals. We previously reported that Fut8 knockout (Fut8-/-) mice showed a schizophrenia-like phenotype and a decrease in working memory. To understand the underlying molecular mechanism, we analyzed early-form long-term potentiation (E-LTP), which is closely related to learning and memory in the hippocampus. The scale of E-LTP induced by high frequency stimulation was significantly decreased in Fut8-/- mice. Tetraethylammonium-induced LTP showed no significant differences, suggesting that the decline in E-LTP was caused by post-synaptic events. Unexpectedly, the phosphorylation levels of calcium/calmodulin-dependent protein kinase II (CaMKII), an important mediator of learning and memory in post-synapses, were greatly increased in Fut8-/- mice. The expression levels of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate receptors (AMPARs) in the postsynaptic density were enhanced in Fut8-/- mice, although there were no significant differences in the total expression levels, implicating that AMPARs without core fucosylation might exist in an active state. The activation of AMPARs was further confirmed by Fura-2 calcium imaging using primary cultured neurons. Taken together, loss of core fucosylation on AMPARs enhanced their heteromerization, which might increase sensitivity for postsynaptic depolarization, and persistently activate N-methyl-D-aspartate receptors as well as Ca2+ influx and CaMKII, and then impair LTP. Copyright © 2015, The American Society for Biochemistry and Molecular Biology.
    Journal of Biological Chemistry 05/2015; 290(28). DOI:10.1074/jbc.M114.579938 · 4.57 Impact Factor
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    ABSTRACT: While many examples have been reported that glycoclusters interact with target lectins more strongly than single molecules of glycans, through multivalency effects, literature examples to support lectin interactions/modulations on cell surface and in live animals is quite rare. Our N-glycoclusters, which were efficiently prepared by immobilizing 16 molecules of the asparagine-linked glycans (N-glycans) onto a lysine-based dendron template through histidine-mediated Huisgen cycloaddition, were shown to efficiently detect platelet endothelial cell adhesion molecule (PECAM) on human umbilical vein endothelial cells (HUVEC) as a α(2-6)-sialylated oligosaccharides recognizing lectin. Furthermore, the identity of the N-glycans on our N-glycoclusters allowed control over organ-selective accumulation and serum clearance properties when intravenously injected into mice.
    Glycoconjugate Journal 05/2015; DOI:10.1007/s10719-015-9594-6 · 2.52 Impact Factor
  • Yasuhiko Kizuka · Shinobu Kitazume · Keiko Sato · Naoyuki Taniguchi
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    ABSTRACT: β-Site amyloid precursor protein cleaving enzyme-1 (BACE1) is a central molecule in Alzheimer's disease (AD). It cleaves amyloid precursor protein (APP) to produce the toxic amyloid-β (Aβ) peptides. Thus, a novel BACE1 modulator could offer a new therapeutic strategy for AD. We report that C-type lectin-like domain family 4, member g (Clec4g, also designated as LSECtin) interacts with BACE1 in mouse brain and cultured cells. Overexpression of Clec4g suppressed BACE1-mediated Aβ generation, and affected the intracellular distribution of BACE1 but not its catalytic activity. These results highlight a novel role of Clec4g in negatively regulating BACE1 function. Copyright © 2015. Published by Elsevier B.V.
    FEBS letters 05/2015; 589(13). DOI:10.1016/j.febslet.2015.04.060 · 3.17 Impact Factor
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    ABSTRACT: ZG16p is a soluble mammalian lectin that interacts with mannose and heparan sulfate. Here we describe detailed analyses of the interactions of human ZG16p with mycobacterial phosphatidylinositol mannosides (PIMs), using glycan microarray and NMR. Pathogen-related glycan microarray analysis identified phosphatidylinositol mono- and di-mannosides (PIM1 and PIM2) as novel ligand candidates of ZG16p. Saturation Transfer Difference (STD) NMR and transferred NOE experiments with chemically synthesized PIM glycans indicate that PIMs preferentially interacts with ZG16p using the mannose residues. Binding site of PIMs is identified by chemical shift perturbation experiments using uniformly 15N-labeled ZG16p. NMR results with docking simulations suggest a binding mode of ZG16p and PIM glycan, which would help to consider the physiological role of ZG16p. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
    ChemBioChem 04/2015; 16(10). DOI:10.1002/cbic.201500103 · 3.09 Impact Factor
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    ABSTRACT: O-GlcNAcylation is a reversible post-translational modification. O-GlcNAc addition and removal is catalyzed by O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA), respectively. More recent evidence indicates that regulation of O-GlcNAcylation is important for inflammatory diseases and tumorigenesis. In this study, we revealed that O-GlcNAcylation was increased in the colonic tissues of dextran sodium sulfate (DSS)-induced colitis and azoxymethane (AOM)/DSS-induced colitis-associated cancer (CAC) animal models. Moreover, the O-GlcNAcylation level was elevated in human CAC tissues compared with matched normal counterparts. To investigate the functional role of O-GlcNAcylation in colitis, we used OGA heterozygote mice, which have an increased level of O-GlcNAcylation. OGA+/- mice have higher susceptibility to DSS-induced colitis than OGA+/+ mice. OGA +/- mice exhibited a higher incidence of colon tumors than OGA+/+ mice. In molecular studies, elevated O-GlcNAc levels were shown to enhance the activation of NF-κB signaling through increasing the binding of RelA/p65 to its target promoters. We also found that Thr-322 and Thr352 in the p65-O-GlcNAcylation sites are critical for p65 promoter binding. These results suggest that the elevated O-GlcNAcylation level in colonic tissues contributes to the development of colitis and CAC by disrupting regulation of NF-κB-dependent transcriptional activity.
    Oncotarget 03/2015; 6(14). DOI:10.18632/oncotarget.3725 · 6.36 Impact Factor
  • Naoyuki Taniguchi · Yasuhiko Kizuka
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    ABSTRACT: Glycosylation is catalyzed by various glycosyltransferase enzymes which are mostly located in the Golgi apparatus in cells. These enzymes glycosylate various complex carbohydrates such as glycoproteins, glycolipids, and proteoglycans. The enzyme activity of glycosyltransferases and their gene expression are altered in various pathophysiological situations including cancer. Furthermore, the activity of glycosyltransferases is controlled by various factors such as the levels of nucleotide sugars, acceptor substrates, nucleotide sugar transporters, chaperons, and endogenous lectin in cancer cells. The glycosylation results in various functional changes of glycoproteins including cell surface receptors and adhesion molecules such as E-cadherin and integrins. These changes confer the unique characteristic phenotypes associated with cancer cells. Therefore, glycans play key roles in cancer progression and treatment. This review focuses on glycan structures, their biosynthetic glycosyltransferases, and their genes in relation to their biological significance and involvement in cancer, especially cancer biomarkers, epithelial-mesenchymal transition, cancer progression and metastasis, and therapeutics. Major N-glycan branching structures which are directly related to cancer are β1,6-GlcNAc branching, bisecting GlcNAc, and core fucose. These structures are enzymatic products of glycosyltransferases, GnT-V, GnT-III, and Fut8, respectively. The genes encoding these enzymes are designated as MGAT5 (Mgat5), MGAT3 (Mgat3), and FUT8 (Fut8) in humans (mice in parenthesis), respectively. GnT-V is highly associated with cancer metastasis, whereas GnT-III is associated with cancer suppression. Fut8 is involved in expression of cancer biomarker as well as in the treatment of cancer. In addition to these enzymes, GnT-IV and GnT-IX (GnT-Vb) will be also discussed in relation to cancer. © 2015 Elsevier Inc. All rights reserved.
    Advances in Cancer Research 03/2015; 126:11-51. DOI:10.1016/bs.acr.2014.11.001 · 5.32 Impact Factor
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    ABSTRACT: Ag recognition and Ab production in B cells are major components of the humoral immune response. In the current study, we found that the core fucosylation catalyzed by α1,6-fucosyltransferase (Fut8) was required for the Ag recognition of BCR and the subsequent signal transduction. Moreover, compared with the 3-83 B cells, the coalescing of lipid rafts and Ag-BCR endocytosis were substantially reduced in Fut8-knockdown (3-83-KD) cells with p31 stimulation and then completely restored by reintroduction of the Fut8 gene to the 3-83-KD cells. Indeed, Fut8-null (Fut8(-/-)) mice evoked a low immune response following OVA immunization. Also, the frequency of IgG-producing cells was significantly reduced in the Fut8(-/-) spleen following OVA immunization. Our results clearly suggest an unexpected mode of BCR function, in which the core fucosylation of IgG-BCR mediates Ag recognition and, concomitantly, cell signal transduction via BCR and Ab production. Copyright © 2015 by The American Association of Immunologists, Inc.
    The Journal of Immunology 02/2015; 194(6). DOI:10.4049/jimmunol.1402678 · 4.92 Impact Factor
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    ABSTRACT: Core fucosylation is an important post-translational modification, which is catalyzed by α1,6-fucosyltransferase (Fut8). Increased expression of Fut8 has been shown in diverse carcinomas including hepatocarcinoma. In this study, we investigated the role of Fut8 expression in liver regeneration by using the 70% partial hepatectomy (PH) model, and found that Fut8 is also critical for the regeneration of liver. Interestingly, we show that the Fut8 activities were significantly increased in the beginning of PH (~4d), but returned to the basal level in the late stage of PH. Lacking Fut8 led to delayed liver recovery in mice. This retardation mainly resulted from suppressed hepatocyte proliferation, as supported not only by a decreased phosphorylation level of epidermal growth factor (EGF) receptor and hepatocyte growth factor (HGF) receptor in the liver of Fut8(-/-) mice in vivo, but by the reduced response to exogenous EGF and HGF of the primary hepatocytes isolated from the Fut8(-/-) mice. Furthermore, an administration of L-fucose, which can increase GDP-fucose synthesis through a salvage pathway, significantly rescued the delayed liver regeneration of Fut8(+/-) mice. Overall, our study provides the first direct evidence for the involvement of Fut8 in liver regeneration.
    Scientific Reports 02/2015; 5:8264. DOI:10.1038/srep08264 · 5.58 Impact Factor
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    ABSTRACT: The β-site amyloid precursor protein cleaving enzyme-1 (BACE1), an essential protease for the generation of amyloid-β (Aβ) peptide, is a major drug target for Alzheimer's disease (AD). However, there is a concern that inhibiting BACE1 could also affect several physiological functions. Here, we show that BACE1 is modified with bisecting N-acetylglucosamine (GlcNAc), a sugar modification highly expressed in brain, and demonstrate that AD patients have higher levels of bisecting GlcNAc on BACE1. Analysis of knockout mice lacking the biosynthetic enzyme for bisecting GlcNAc, GnT-III (Mgat3), revealed that cleavage of Aβ-precursor protein (APP) by BACE1 is reduced in these mice, resulting in a decrease in Aβ plaques and improved cognitive function. The lack of this modification directs BACE1 to late endosomes/lysosomes where it is less colocalized with APP, leading to accelerated lysosomal degradation. Notably, other BACE1 substrates, CHL1 and contactin-2, are normally cleaved in GnT-III-deficient mice, suggesting that the effect of bisecting GlcNAc on BACE1 is selective to APP. Considering that GnT-III-deficient mice remain healthy, GnT-III may be a novel and promising drug target for AD therapeutics. © 2015 The Authors. Published under the terms of the CC BY 4.0 license.
    EMBO Molecular Medicine 02/2015; 7(2). DOI:10.15252/emmm.201404438 · 8.67 Impact Factor
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    ABSTRACT: Unlabelled: Objecitive: Fucosyltransferase 8 (FUT8), the only enzyme responsible for the core α1,6-fucosylation of asparagine-linked oligosaccharides of glycoproteins, is a vital enzyme in cancer development and progression. We examined FUT8 expression in non-small cell lung cancers (NSCLCs) to analyze its clinical significance. We also examined the expression of guanosine diphosphate-mannose-4,6-dehydratase (GMD), which is imperative for the synthesis of fucosylated oligosaccharides. Methods: Using immunohistochemistry, we evaluated the expression of FUT8 and GMD in relation to patient survival and prognosis in potentially curatively resected NSCLCs. Results: High expression of FUT8 was found in 67 of 129 NSCLCs (51.9%) and was significantly found in non-squamous cell carcinomas (p = 0.008). High expression of FUT8 was associated with poor survival (p = 0.03) and was also a significant and independent unfavorable prognostic factor in patients with potentially curatively resected NSCLCs (p = 0.047). High expression of GMD was significantly associated with high FUT8 expression (p = 0.04). Conclusions: High expression of FUT8 is associated with an unfavorable clinical outcome in patients with potentially curatively resected NSCLCs, suggesting that FUT8 can be a prognostic factor. The analysis of FUT8 expression and its core fucosylated products may provide new insights for the therapeutic targets of NSCLCs.
    Oncology 01/2015; 88(5). DOI:10.1159/000369495 · 2.42 Impact Factor
  • Kazuki Nakajima · Naoyuki Taniguchi
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    ABSTRACT: Cellular glycosylation plays an important role in many biological processes, as well as in disease states such as diabetes and cancer. Nucleotide sugar s are donor substrates of glycosyltransferases and their availability and localization regulate glycosylation status. The nucleotide sugar level is controlled by cellular metabolic states. To investigate the fate of nucleotide sugars in glycosylation, two methods for monitoring nucleotide sugar metabolism, namely, ion-pair reversed-phase HPLC and LC-MS, have been previously described (Nakajima et al., Glycobiology 20(7):865–871, 2010; Mol Cell Proteomics (9):2468–2480, 2013). Using the HPLC method, cellular levels of eight unique nucleotide sugars were simultaneously determined. Using the LC-MS method, which is based on mass isotopomer analysis of nucleotide sugars metabolically labeled with 13C6-glucose, the metabolic pathways governing UDP-GlcNAc synthesis and utilization were characterized. Here, these strategies are reviewed and the biochemical significance of nucleotide sugars in cellular glycosylation is discussed.
    Glycoscience: Biology and Medicine, 01/2015: pages 103-110; , ISBN: 978-4-431-54840-9
  • Chi-Huey Wong · Naoyuki Taniguchi
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    ABSTRACT: This overview summarizes the current status and future perspectives in the field of glycoscience, with the focus on the integration of current knowledge obtained from genome and proteome research and the impact of such findings on human health and disease. The pathophysiological significance of glycan changes has been reported, and most of these findings can be found in the many chapters in this book. The roles of glycans in infectious diseases, differentiation and development, immune responses, cancer progression, neural communication, and many other intercellular recognition processes are the major topics in this book. Biomarker discovery and its validation of various diseases including cancer are a new challenge in this field. Therapeutics such as vaccines using glycan mimics, recombinant glycoproteins, or the modification of glycans are also new perspective for various diseases. In order to address these challenges, the chemo-enzymatic synthesis of glycans and more sensitive methods for glycan analysis by using NMR, mass spectrometry, imaging techniques, and bioinformatics are needed for the advancement of glycoscience. Finally, major future challenges of glycoscience are also listed in this overview.
    Glycoscience: Biology and Medicine, 01/2015: pages 11-14; , ISBN: 978-4-431-54840-9
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    ABSTRACT: Nutrient transporters are critical gate-keepers of extracellular metabolite entry into the cell. As integral membrane proteins, most transporters are N-glycosylated, and the N-glycans are remodeled in the Golgi apparatus. The Golgi branching enzymes N-acetylglucosaminyltransferases I, II, IV, V and avian VI (encoded by Mgat1, Mgat2, Mgat4a/b/c Mgat5 and Mgat6), each catalyze the addition of acetylglucosamine (GlcNAc) in N-glycans. Here, we asked whether N-glycan branching promotes nutrient transport and metabolism in immortal human HeLa carcinoma and non-malignant HEK293 embryonic kidney cells. Mgat6 is absent in mammals, but ectopic expression can be expected to add an additional β1,4-linked branch to N-glycans, and may provide evidence for functional redundancy of the N-glycan branches. Tetracycline (tet)-induced overexpression of Mgat1, Mgat5 and Mgat6 resulted in increased enzyme activity and increased N-glycan branching concordant with the known specificities of these enzymes. Tet-induced Mgat1, Mgat5 and Mgat6 combined with stimulation of hexosamine biosynthesis pathway (HBP) to UDP-GlcNAc, increased cellular metabolite levels, lactate and oxidative metabolism in an additive manner. We then tested the hypothesis that N-glycan branching alone might promote nutrient uptake when glucose (Glc) and glutamine are limiting. In low glutamine and Glc medium, tet-induced Mgat5 alone increased amino acids uptake, intracellular levels of glycolytic and TCA intermediates, as well as HEK293 cell growth. More specifically, tet-induced Mgat5 and HBP elevated the import rate of glutamine, although transport of other metabolites may be regulated in parallel. Our results suggest that N-glycan branching cooperates with HBP to regulate metabolite import in a cell autonomous manner, and can enhance cell growth in low-nutrient environments.
    Glycobiology 10/2014; 25(2). DOI:10.1093/glycob/cwu105 · 3.15 Impact Factor
  • Shinobu Kitazume · Rie Imamaki · Kazuko Ogawa · Naoyuki Taniguchi
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    ABSTRACT: The vascular endothelial glycocalyx contains several anionic sugars, one of which is a sialic acid attached to both N- and O-glycans. Platelet endothelial cell adhesion molecule (PECAM), a member of the Ig superfamily that plays multiple roles in cell adhesion, mechanical stress sensing, antiapoptosis and angiogenesis, has recently been shown to recognize α2,6-sialic acid. In endothelial cells that lack α2,6-sialic acid because of sialyltransferase ST6Gal I deficiency, impairment of the homophilic PECAM interaction and PECAM-dependent cell survival signaling is observed. In this review, we will introduce part of the biological role of PECAM, and discuss how the lectin activity of PECAM is related to angiogenesis.
    Glycobiology 09/2014; 24(12). DOI:10.1093/glycob/cwu094 · 3.15 Impact Factor
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    ABSTRACT: N-Acetylglucosaminyltransferase (GnT) III is a glycosyltransferase which produces bisected N-glycans by transferring GlcNAc to the 4-position of core mannose. Bisected N-glycans are involved in physiological and pathological processes through the functional regulation of their carrier proteins. An understanding of the biological functions of bisected glycans will be greatly accelerated by use of specific inhibitors of GnT-III. Thus far, however, such inhibitors have not been developed and even the substrate-binding mode of GnT-III is not fully understood. To gain insight into structural features required of the substrate, we systematically synthesized four N-glycan units, the branching parts of the bisected and non-bisected N-glycans. The series of syntheses were achieved from a common core trimannose, giving bisected tetra- and hexasaccharides as well as non-bisected tri- and pentasaccharides. A competitive GnT-III inhibition assay using the synthetic substrates revealed a vital role for the Manβ(1-4)GlcNAc moiety. In keeping with previous reports, GlcNAc at the α1,3-branch is also involved in the interaction. The structural requirements of GnT-III elucidated in this study will provide a basis for rational inhibitor design.
    Bioorganic & Medicinal Chemistry Letters 09/2014; 24(18). DOI:10.1016/j.bmcl.2014.07.074 · 2.42 Impact Factor
  • Yasuhiko Kizuka · Kenji Kanekiyo · Shinobu Kitazume · Naoyuki Taniguchi
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    ABSTRACT: In the nervous system, various unique glycans not found in other tissues are expressed on glycoproteins, and their expression/functions have been studied using specific antibodies/lectins. Among brain-specific glycans in mammals, we focus on human natural killer-1 (HNK-1) and related Cat-315 epitopes, which can be detected using specific antibodies. It is known that the HNK-1 epitope is expressed on N- and O-mannosylated glycans and that Cat-315 mAb preferentially recognizes the HNK-1 epitope on brain-specific "branched O-mannose glycan." The β1,6-branched O-mannose structure is synthesized by a brain-specific glycosyltransferase, N-acetylglucosaminyltransferase-IX (GnT-IX, also designated as GnT-Vb). Using GnT-IX gene-deficient mice and specific antibodies/lectins, the function of GnT-IX was found to be quite different from that of its ubiquitous homologue, GnT-V. Using Cat-315 mAb, the receptor protein tyrosine phosphatase-beta (RPTPβ) was identified as an in vivo target glycoprotein for GnT-IX. Analysis of the function of branched O-mannose glycan on RPTPβ indicated that its loss promoted the recovery process after myelin injury (called remyelination) in brain and that this phenomenon is probably caused in vivo by reduced activation of astrocytes in GnT-IX-deficient brain.
    Advances in neurobiology 08/2014; 9:117-127. DOI:10.1007/978-1-4939-1154-7_6
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    ABSTRACT: The luminal sides of vascular endothelial cells are heavily covered with a so-called glycocalyx, but the precise role of the endothelial glycocalyx remains unclear. Our previous study showed that N-glycan α2,6-sialylation regulates the cell surface residency of an anti-apoptotic molecule, platelet endothelial cell adhesion molecule (PECAM), as well as the sensitivity of endothelial cells toward apoptotic stimuli. As PECAM itself was shown to be modified with biantennary N-glycans having α2,6-sialic acid, we expected that PECAM would possess lectin-like activity toward α2,6-sialic acid to ensure its homophilic interaction. To verify this, a series of oligosaccharides were initially added to observe their inhibitory effects on the homophilic PECAM interaction in vitro. We found that a longer α2,6-sialylated oligosaccharide exhibited strong inhibitory activity. Furthermore, we found that a cluster-type α2,6-sialyl N-glycan probe specifically bound to PECAM-immobilized beads. Moreover, the addition of the α2,6-sialylated oligosaccharide to endothelial cells enhanced the internalization of PECAM as well as the sensitivity to apoptotic stimuli. Collectively, these findings suggest that PECAM is a sialic acid binding lectin and that this binding property supports endothelial cell survival. Notably, our findings that α2,6-sialylated glycans influenced the susceptibility to endothelial cell apoptosis shed light on the possibility of using a glycan-based method to modulate angiogenesis.
    Journal of Biological Chemistry 08/2014; 289(40). DOI:10.1074/jbc.M114.563585 · 4.57 Impact Factor

Publication Stats

21k Citations
3,007.13 Total Impact Points


  • 2008–2015
    • RIKEN
      • • Global Research Cluster
      • • RIKEN-Max Planck Joint Research Center for Systems Chemical Biology
      • • Chemical Biology Team
      Вако, Saitama, Japan
    • University of Massachusetts Medical School
      Worcester, Massachusetts, United States
    • Seikagaku Corporation
      Edo, Tōkyō, Japan
    • Institute of Microbial Chemistry
      Edo, Tōkyō, Japan
    • Macquarie University
      • Department of Chemistry and Biomolecular Sciences
      Sydney, New South Wales, Australia
  • 2013
    • Waseda University
      • Faculty of Human Sciences
      Edo, Tōkyō, Japan
  • 1970–2013
    • Osaka University
      • • Institute of Scientific and Industrial Research
      • • Department of Disease Glycomics
      • • Division of Biochemistry
      • • Department of Surgery
      • • Department of Internal Medicine
      Suika, Ōsaka, Japan
  • 1995–2011
    • Osaka City University
      • • Department of Biochemistry
      • • Graduate School of Medicine
      • • Second Department of Internal Medicine
      Ōsaka, Ōsaka, Japan
    • University of Tsukuba
      Tsukuba, Ibaraki, Japan
    • Osaka Medical Center and Research Institute for Maternal and Child Health
      Izumi, Ōsaka, Japan
    • Harvard Medical School
      Boston, Massachusetts, United States
  • 2006
    • Kochi University
      Kôti, Kōchi, Japan
  • 2005
    • Saga University
      • Department of Biomolecular Sciences
      Сага Япония, Saga, Japan
    • Hyogo College of Medicine
      • Department of Biochemistry
      Nishinomiya, Hyogo-ken, Japan
  • 2003
    • Yamagata University
      Ямагата, Yamagata, Japan
    • St. Jude Children's Research Hospital
      • Department of Developmental Neurobiology
      Memphis, Tennessee, United States
  • 2002
    • Georgetown University
      • Department of Oncology
      Washington, Washington, D.C., United States
    • Nagoya University
      • Division of Neurology
      Nagoya, Aichi, Japan
    • Yale-New Haven Hospital
      • Department of Pathology
      New Haven, Connecticut, United States
  • 1999
    • Nagasaki University
      Nagasaki, Nagasaki, Japan
    • Osaka Police Hospital
      Ōsaka, Ōsaka, Japan
    • Kyorin University
      Edo, Tōkyō, Japan
  • 1998
    • University of Helsinki
      Helsinki, Uusimaa, Finland
    • Osaka Rosai Hospital
      Ōsaka, Ōsaka, Japan
  • 1996
    • Aichi Cancer Center
      Ōsaka, Ōsaka, Japan
  • 1974–1995
    • Hokkaido University Hospital
      • • Division of Pediatrics
      • • Division of Neurosurgery
      • • Division of Internal Medicine II
      Sapporo-shi, Hokkaido, Japan
  • 1994
    • Niigata University
      Niahi-niigata, Niigata, Japan
    • Nara Medical University
      • Department of General Medicine
      Kashihara, Nara, Japan
  • 1992–1993
    • National Defense Medical College
      • Division of Hygiene
      Tokorozawa, Saitama, Japan
  • 1991
    • The University of Tokyo
      白山, Tōkyō, Japan
  • 1975–1990
    • Hokkaido University
      • • Department of Medicine II
      • • Laboratory of Biochemistry
      • • Cancer Institute
      • • Graduate School of Environmental Science
      Sapporo, Hokkaidō, Japan
  • 1982
    • Asahikawa Medical University
      Асахикава, Hokkaido, Japan
  • 1977
    • Hokkaido University of Education
      Sapporo, Hokkaidō, Japan