A new concept of glycan signaling for cell regulation

• Project/Area Number: 21K18251
• Research Category: Grant-in-Aid for Challenging Research (Pioneering)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 48:Biomedical structure and function and related fields
• Research Institution: Nagoya University
• Principal Investigator: Kadomatsu Kenji 名古屋大学, 糖鎖生命コア研究所, 所長 (80204519)
• Project Period (FY): 2021-07-09 – 2024-03-31
• Project Status: Completed (Fiscal Year 2023)
• Budget Amount: ¥26,000,000 (Direct Cost: ¥20,000,000、Indirect Cost: ¥6,000,000); Fiscal Year 2023: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000); Fiscal Year 2022: ¥6,630,000 (Direct Cost: ¥5,100,000、Indirect Cost: ¥1,530,000); Fiscal Year 2021: ¥12,870,000 (Direct Cost: ¥9,900,000、Indirect Cost: ¥2,970,000)
• Keywords: ヘパラン硫酸 / ALK / PTPRσ / LAR / 糖鎖

Outline of Research at the Start

糖鎖はタンパク質と比べてゆらぎが大きく、X線やMRIの解析により平均的立体構造を得ることは難しい。最近糖鎖に対する受容体酵素が見つかったが、糖鎖によるその酵素活性の生物学的意義は不明であった。研究代表者の所属するグループはその糖鎖のリガンドとしてのコア構造を決定し、受容体酵素の基質を含む下流シグナル、そしてそれによる神経軸索再生制御を解明した。この発見は例外的な糖鎖のシグナル経路とは考えにくく、新しいコンセプトが隠されている可能性が高い。本研究の眼目は、多面的アプローチによって、糖鎖シグナル伝達という新コンセプトを樹立することにある。これによって糖鎖受容体の発掘が本格化すると期待される。

Outline of Final Research Achievements

It has been believed that intracellular signaling via receptors, like proteins, is not possible for glycans. We have determined the downstream signals of recently discovered glycan receptors and the core structure of their glycan ligands, and elucidated the regulation of neuronal axon regeneration by them. The focus of this study was to establish a new concept of “glycan signaling” by taking a multifaceted approach. We found that in addition to the receptor tyrosine phosphatase PTPσthe receptor tyrosine kinase ALK acts as a glycan receptor, and that the long glycans chondroitin sulfate and heparan sulfate send opposite intracellular signals via a common substrate under these receptors and show opposite phenotypes for axon regeneration.

Academic Significance and Societal Importance of the Research Achievements

本研究課題でカバーされた一連の研究により、機能性糖鎖リガンドが明確に存在し、複層的な分子スイッチとしての役割さえも果たしている実態を示すことができた。加えて、本研究は長鎖ヘパリンの受傷後神経回復促進や糖脂質の運動学習への貢献などの予期せぬ発見ももたらした。成果の一部は臨床的にも応用が可能と期待されるものが含まれている。さらに、糖鎖の期待以上の様々な生物学的活性を示すことができ、現在、我が国を起点にうねりが起きようとしている、第３の生命鎖である糖鎖を軸とした生命科学の新しい展開への一助となった。

Research Products

• [Journal Article] Detecting and exploring kidney-derived extracellular vesicles in plasma. (2024)
  • Author(s): Komatsu S, Kato N, Kitai H, Funahashi Y, Noda Y, Tsubota S, Tanaka A, Sato Y, Maeda K, Saito S, Furuhashi K, Ishimoto T, Kosugi T, Maruyama S, Kadomatsu K.
  • Journal Title: Clin Exp Nephrol. Volume: - Issue: 7 Pages: 617-628
  • DOI: 10.1007/s10157-024-02464-z
  • Peer Reviewed
• [Journal Article] Towards the in vivo identification of protein-protein interactions. (2023)
  • Author(s): Suzuki, Y., Kadomatsu, K., Sakamoto, K.
  • Journal Title: J Biochem Volume: 23 Issue: 6 Pages: 013-013
  • DOI: 10.1093/jb/mvad013
  • Peer Reviewed
• [Journal Article] Glypican-2 defines age-dependent axonal response to chondroitin sulfate (2023)
  • Author(s): Ouchida Jun、Ozaki Tomoya、Segi Naoki、Suzuki Yuji、Imagama Shiro、Kadomatsu Kenji、Sakamoto Kazuma
  • Journal Title: Experimental Neurology Volume: 366 Pages: 114444-114444
  • DOI: 10.1016/j.expneurol.2023.114444
  • Peer Reviewed
• [Journal Article] Regulation of lipid synthesis in myelin modulates neural activity and is required for motor learning (2023)
  • Author(s): Kato D, Aoyama Y, Nishida K, Takahashi Y, Sakamoto T, Takeda I, Tatematsu T, Go S, Saito Y, Kunishima S, Cheng J, Hou L, Tachibana Y, Sugio S, Kondo R, Eto F, Sato S, Moorhouse AJ, Yao I, Kadomatsu K, Setou M, and Wake H.
  • Journal Title: Glia Volume: 71 Issue: 11 Pages: 2591-2608
  • DOI: 10.1002/glia.24441
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Single-cell Glycogenomics Deciphers Links Between Altered Transcriptional Regulation and Aberrant Glycosylation in Alzheimer's Disease. (2023)
  • Author(s): Matsui Y, Togayachi A, Sakamoto K, Angata K, Kadomatsu K, Nishihara S.
  • Journal Title: bioRxiv [Preprint]. Volume: - Pages: 573290-573290
  • DOI: 10.1101/2023.12.25.573290
  • Peer Reviewed
• [Journal Article] Mitotic Dysregulation at Tumor Initiation Creates a Therapeutic Vulnerability to Combination Anti-Mitotic and Pro-Apoptotic Agents for MYCN-Driven Neuroblastoma. (2023)
  • Author(s): Zhai L, Balachandran A, Larkin R, Seneviratne JA, Chung SA, Lalwani A, Tsubota S, Beck D, Kadomatsu K, Beckers A, Durink K, De Preter K, Speleman F, Haber M, Norris MD, Swarbrick A, Cheung BB, Marshall GM, Carter DR
  • Journal Title: Int J Mol Sci. Volume: 24 Issue: 21 Pages: 15571-15571
  • DOI: 10.3390/ijms242115571
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Basigin is released in extracellular vesicles derived from the renal tubular epithelium in response to albuminuria. (2023)
  • Author(s): Watanabe T, Maeda K, Kato N, Seko H, Sugimura M, Sato Y, Ryuge A, Kato S, Kadomatsu K, Maruyama S, Kosugi T.
  • Journal Title: Nephrology (Carlton). Volume: 28 Issue: 11 Pages: 629-638
  • DOI: 10.1111/nep.14227
  • Peer Reviewed
• [Journal Article] Close association of polarization and LC3, a marker of autophagy, in axon determination in mouse hippocampal neurons. (2022)
  • Author(s): Segi, N., Ozaki, T., Suzuki, Y., Ouchida, J., Imagama, S, Kadomatsu, K., Sakamoto, K.
  • Journal Title: Exp Neurol. Volume: 354 Pages: 114112-114112
  • DOI: 10.1016/j.expneurol.2022.114112
  • Peer Reviewed
• [Journal Article] Damage and Cell Survival in Hippo Pathway Kinase LATS2-Inactivated Malignant Mesothelioma (2022)
  • Author(s): Suzuki K,Tange M,Yamagishi R, Hanada H, Mukai S, Sato T, Tanaka T, Akashi T, Kadomatsu K, Maeda T, Miida T, Takeuchi T, Murakami H, Sekido Y, Murakami-Tonami Y
  • Journal Title: Cell Death Discovery Volume: 8 Issue: 1 Pages: 446-446
  • DOI: 10.1038/s41420-022-01232-w
  • Peer Reviewed / Open Access
• [Journal Article] Metabolome and transcriptome analysis on muscle of sporadic inclusion body myositis. (2022)
  • Author(s): Murakami, A., Noda, S., Kazuta, T., Hirano, S., Kimura, S., Nakanishi, H., Matsuo, K., Tsujikawa, K., Iida, M., Koike, H., Sakamoto, K., Hara, Y., Kuru, S., Kadomatsu, K., Shimamura, T., Ogi, T., Katsuno, M.
  • Journal Title: Ann Clin Transl Neurol. Volume: 9 Issue: 10 Pages: 1602-1615
  • DOI: 10.1002/acn3.51657
  • Peer Reviewed / Open Access
• [Journal Article] Systematic characterization of seed overlap microRNA cotargeting associated with lupus pathogenesis (2022)
  • Author(s): Kitai Hiroki、Kato Noritoshi、Ogami Koichi、Komatsu Shintaro、Watanabe Yu、Yoshino Seiko、Koshi Eri、Tsubota Shoma、Funahashi Yoshio、Maeda Takahiro、Furuhashi Kazuhiro、Ishimoto Takuji、Kosugi Tomoki、Maruyama Shoichi、Kadomatsu Kenji、Suzuki Hiroshi I.
  • Journal Title: BMC Biology Volume: 20 Issue: 1 Pages: 248-248
  • DOI: 10.1186/s12915-022-01447-4
  • Peer Reviewed / Open Access
• [Journal Article] Reform of Journal of Biochemistry (2022)
  • Author(s): Kadomatsu, K
  • Journal Title: J Biochem Volume: 172 Issue: 3 Pages: 141-141
  • DOI: 10.1093/jb/mvac037
  • Peer Reviewed
• [Journal Article] Identification of PTPRσ-interacting proteins by proximity-labelling assay. (2021)
  • Author(s): Gong Y, Abudureyimu S, Kadomatsu K, Sakamoto K.
  • Journal Title: J Biochem. Volume: 162 Issue: 2 Pages: 187-194
  • DOI: 10.1093/jb/mvaa141
  • NAID: 40022513442
  • Peer Reviewed / Open Access
• [Journal Article] Enoxaparin promotes functional recovery after spinal cord injury by antagonizing PTPRσ (2021)
  • Author(s): Ito S, Ozaki T, Morozumi M, Imagama S, Kadomatsu K, Sakamoto K.
  • Journal Title: Exp. Neurol. Volume: 340 Pages: 113679-113679
  • DOI: 10.1016/j.expneurol.2021.113679
  • Peer Reviewed / Open Access
• [Journal Article] Type IIa RPTPs and Glycans: Roles in Axon Regeneration and Synaptogenesis (2021)
  • Author(s): Sakamoto Kazuma、Ozaki Tomoya、Suzuki Yuji、Kadomatsu Kenji
  • Journal Title: International Journal of Molecular Sciences Volume: 22 Issue: 11 Pages: 5524-5524
  • DOI: 10.3390/ijms22115524
  • Peer Reviewed / Open Access
• [Journal Article] Chondroitin 6-sulfate represses keratinocyte proliferation in mouse skin, which is associated with psoriasis. (2021)
  • Author(s): Kitazawa, K., Nadanaka, S., Kadomatsu, K., and Kitagawa, H.
  • Journal Title: Commun. Biol. Volume: 4 Issue: 1 Pages: 114-114
  • DOI: 10.1038/s42003-020-01618-5
  • Peer Reviewed / Open Access
• [Journal Article] Screening of novel Midkine binding protein by BioID2-based proximity labeling (2021)
  • Author(s): Komata Y, Tsubota S, Sakamoto K, Ikematsu S, Kadomatsu K.
  • Journal Title: Nagoya Journal of Medical Science Volume: 83 Issue: 3 Pages: 495-508
  • DOI: 10.18999/nagjms.83.3.495
  • NAID: 120007147353
  • ISSN: 0027-7622
  • URL: https://nagoya.repo.nii.ac.jp/records/2001441
  • Peer Reviewed
• [Journal Article] Dermatan sulphate is an activating ligand of anaplastic lymphoma kinase (2021)
  • Author(s): Machino Masaaki、Gong Yuanhao、Ozaki Tomoya、Suzuki Yuji、Watanabe Eri、Imagama Shiro、Kadomatsu Kenji、Sakamoto Kazuma
  • Journal Title: The Journal of Biochemistry Volume: 170 Issue: 5 Pages: 631-637
  • DOI: 10.1093/jb/mvab085
  • Peer Reviewed / Open Access
• [Journal Article] High-throughput identification and determination of aminoglycoside antibiotics in human plasma using UPLC?Q-ToF-MS (2021)
  • Author(s): Minohara Sawa、Fujishiro Masaya、Lee Xiao-Pen、Imai Ayumi、Hashimoto Mari、Hasegawa Chika、Kuroki Tomoaki、Kadomatsu Koichi、Kumazawa Takeshi、Kato Akihito、Matsuyama Takaaki
  • Journal Title: European Journal of Mass Spectrometry Volume: 21 Issue: 1 Pages: 63-70
  • DOI: 10.1177/14690667211003196
  • Peer Reviewed
• [Journal Article] Midkine Interaction with Chondroitin Sulfate Model Synthetic Tetrasaccharides and Their Mimetics: The Role of Aromatic Interactions (2021)
  • Author(s): Garca‐Jimenez Maria Jose、Gil‐Caballero Sergio、Maza Susana、Corzana Francisco、Juarez‐Vicente Francisco、Miles Jonathan R.、Sakamoto Kazuma、Kadomatsu Kenji、Garciao Dominguez Mario、Paz Jose L.、Nieto Pedro M.
  • Journal Title: Chemistry A European Journal Volume: 27 Issue: 48 Pages: 12395-12409
  • DOI: 10.1002/chem.202101674
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Basigin deficiency prevents anaplerosis and ameliorates insulin resistance and hepatosteatosis. (2021)
  • Author(s): Ryuge A, Kosugi T, Maeda K, Banno R, Gou Y, Zaitsu K,Ito T, Sato Y, Hirayama A, Tsubota S, Honda T, Nakajima K, Ozaki T, Kondoh K, Takahashi K, Kato N, Ishimoto T, Soga T, Nakagawa T, Koike T, Arima H, Yuzawa Y, Minokoshi Y, Maruyama S, Kadomatsu K.
  • Journal Title: JCI Insight. Volume: 6 Issue: 20
  • DOI: 10.1172/jci.insight.142464
  • Peer Reviewed / Open Access
• [Journal Article] Combination of tumor necrosis factor‐α and epidermal growth factor induces the adrenergic‐to‐mesenchymal transdifferentiation in SH‐SY5Y neuroblastoma cells (2020)
  • Author(s): Huang Yue、Tsubota Shoma、Nishio Nobuhiro、Takahashi Yoshiyuki、Kadomatsu Kenji
  • Journal Title: Cancer Science Volume: 112 Issue: 2 Pages: 715-724
  • DOI: 10.1111/cas.14760
  • Peer Reviewed
• [Presentation] ヒューマングライコームプロジェクト～プロジェクトの開始と将来の展望～ (2024)
  • Author(s): 門松健治
  • Organizer: PIフォーラム
  • Invited
• [Presentation] 硫酸化糖鎖と軸索再生. (2024)
  • Author(s): 門松健治
  • Organizer: 第23回日本再生医療学会総会
  • Invited
• [Presentation] ヒューマングライコームプロジェクトと疾患. (2023)
  • Author(s): 門松健治
  • Organizer: 日本生化学会大会
  • Invited
• [Presentation] ヒューマングライコームプロジェクト始動と開く未来. (2023)
  • Author(s): 門松健治
  • Organizer: 第17回 多糖の未来フォーラム
  • Invited
• [Presentation] ヒューマングライコームプロジェクト～プロジェクトの開始と将来の展望～ (2023)
  • Author(s): 門松健治
  • Organizer: Science Pioneers Consortium 2023
  • Invited
• [Presentation] Crosstalk of glycosaminoglycans and cell surface receptors in neural wiring/rewiring. (2023)
  • Author(s): Kenji Kadomatsu
  • Organizer: 26th International Symposium on Glycoconjugates.
  • Int'l Joint Research / Invited
• [Presentation] Glycans in neural wiring/rewiring. (2022)
  • Author(s): Kenji Kadomatsu
  • Organizer: SfG 2022 Annual Meeting
  • Int'l Joint Research / Invited
• [Presentation] Glycans in neural wiring/rewiring. (2022)
  • Author(s): Kenji Kadomatsu
  • Organizer: Commemorative Symposium on the 30th Anniversary of Mizutani Foundation for Glycoscience.
  • Invited
• [Presentation] 「糖鎖バイオマーカーの開発」糖鎖バイオマーカーの開発 (2022)
  • Author(s): 門松健治
  • Organizer: 第65回 日本腎臓学会学術総会
  • Invited
• [Presentation] 生命科学の未来：糖鎖がもたらす革新 (2022)
  • Author(s): 門松健治
  • Organizer: 第63回 日本生化学会中国・四国支部例会
  • Invited
• [Presentation] 糖鎖に関する生命科学研究～ヒト糖鎖プロジェクト～ (2022)
  • Author(s): 門松健治
  • Organizer: 日本集中治療医学会第6回東海北陸支部学術集会
  • Invited
• [Presentation] 糖鎖って何？～「糖鎖、ゲノム、タンパク質」命（いのち）を紡ぐ3つの鎖～ (2021)
  • Author(s): 門松健治
  • Organizer: 第1回 iGCOREサイエンスカフェ
  • Invited
• [Presentation] 基礎医学から産学官民連携まで～老化との包括的な対峙 (2021)
  • Author(s): 門松健治
  • Organizer: 第63回 日本老年医学会
  • Invited
• [Presentation] ヒト糖鎖プロジェクトと医療 (2021)
  • Author(s): 門松健治
  • Organizer: 第2回生体防御医学セミナー
  • Invited
• [Presentation] 生命科学の中のヒューマングライコームプロジェクト (2021)
  • Author(s): 門松健治
  • Organizer: 第40回日本糖質学会年会
  • Invited
• [Presentation] Chondroitin sulefate, heparan sulfate and PTP σ; :Roles in axon regeneration and synaptogenesis. (2021)
  • Author(s): Kadomatsu Kenji
  • Organizer: 3rd Australasian Glycoscience Symposium (3rd AGS).
  • Int'l Joint Research / Invited
• [Book] 「神経回路再生ならびに小児がん神経芽腫の研究」 最先端ナノライフシステム研究第Ⅱ編 マイクロ・ナノメカトロニクス研究 (2022)
  • Author(s): 坂元一真 尾崎智也 坪田庄真 郷詩織 鈴木佑治 門松健治
  • Total Pages: 6
  • Publisher: 丸善プラネット
• [Book] 「神経回路再生ならびに小児がん神経芽腫の研究」最先端ナノライフシステム研究第Ⅱ編 マイクロ・ナ ノメカトロニクス研究 3章 (2022)
  • Author(s): 坂元一真 尾崎智也 坪田庄真 郷詩織 鈴木佑治 門松健治
  • Total Pages: 7
  • Publisher: 丸善プラネット
• [Book] 細胞のメカニズムと神経疾患～オートファジーと軸索、神経変性疾患～ (2021)
  • Author(s): 門松健治
  • Total Pages: 4
  • Publisher: Clinical Neuroscience
• [Remarks] 糖鎖生命コア研究所
  • URL: https://igcore.thers.ac.jp
• [Remarks] 糖鎖生命コア研究所
  • URL: https://igcore.thers.ac.jp/
• [Remarks] 名古屋大学大学院医学系研究科 生物化学講座分子生物学
  • URL: https://www.med.nagoya-u.ac.jp/biochem/