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A new ligand for ALK and its activation mechanism

Research Project

Project/Area Number 19H03415
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Review Section Basic Section 48040:Medical biochemistry-related
Research InstitutionNagoya University

Principal Investigator

Kadomatsu Kenji  名古屋大学, 医学系研究科, 教授 (80204519)

Co-Investigator(Kenkyū-buntansha) 坂元 一真  名古屋大学, 医学系研究科, 准教授 (60612801)
Project Period (FY) 2019-04-01 – 2022-03-31
Project Status Completed (Fiscal Year 2021)
Budget Amount *help
¥17,550,000 (Direct Cost: ¥13,500,000、Indirect Cost: ¥4,050,000)
Fiscal Year 2021: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
Fiscal Year 2020: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
Fiscal Year 2019: ¥7,410,000 (Direct Cost: ¥5,700,000、Indirect Cost: ¥1,710,000)
KeywordsALK / 受容体型チロシンキナーゼ / デルマタン硫酸 / 神経軸索再生 / 受容体型チロシンフォスファターゼ
Outline of Research at the Start

ALKの中枢神経での機能はほとんど分かっていない。また、その生理的リガンドが未だ不明である。
神経軸索再生を阻害する受容体型チロシンフォスファターゼPTPRσに対抗する新しいキナーゼを探索し、ALKに強い神経軸索再生能を発見した。PTPRσリガンドとのアナロジーを想定して硫酸化糖鎖をスクリーニングすると、硫酸化糖鎖の一つデルマタン硫酸(DS)が強力にALKを活性化し、ALK依存的に神経軸索再生を促進することが分かった。本研究はALKの新リガンドDSの生理的意義を明らかにし、DSによるALK活性化機構を解明する。

Outline of Final Research Achievements

The principal investigators searched for a new kinase that opposes the receptor-type tyrosine phosphatase PTPRσ, which inhibits neuroaxonal regeneration, and discovered that ALK (anaplastic lymphoma kinase) promotes neuroaxonal regeneration. In addition, the study found that dermatan sulfate (DS), a sulfated glycan, strongly activates ALK and promotes neuroaxonal regeneration in an ALK-dependent manner. In the current study, we demonstrated that DS has sufficient affinity for ALK and induces its clustering. Furthermore, we identified a group of molecules interacting with ALK and PTPRσ by the proximity-dependent labeling method BioID. The results revealed that there is a group of substrate molecules common to these two enzymes with opposing functions. Future studies can be developed on the physiological significance of these molecular switches.

Academic Significance and Societal Importance of the Research Achievements

受容体型チロシンキナーゼと受容体型テロシンキナーゼと受容体型チロシンフォスファターゼのクロストークは予想はされてきたが、その具合を示す例は少ない。本研究によって光が見えはじめたALKとPTPRσのクロストークは、新しい生命制御機構の1つを提示するものである。既に研究代表者らは、神経系でその生物学的意味についてもアドレスできる立場にあるが、両者は、神経発達・回路形成・再編などに関わる可能性があり、関連する疾病の病態解明、治療法開発につながる可能性がある。

Report

(4 results)
  • 2021 Annual Research Report   Final Research Report ( PDF )
  • 2020 Annual Research Report
  • 2019 Annual Research Report
  • Research Products

    (35 results)

All 2022 2021 2020 2019 Other

All Journal Article (18 results) (of which Int'l Joint Research: 3 results,  Peer Reviewed: 18 results,  Open Access: 10 results) Presentation (9 results) (of which Int'l Joint Research: 4 results,  Invited: 9 results) Book (5 results) Remarks (3 results)

  • [Journal Article] Enoxaparin promotes functional recovery after spinal cord injury by antagonizing PTPRσ2021

    • 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

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [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

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Type IIa RPTPs and Glycans: Roles in Axon Regeneration and Synaptogenesis2021

    • 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

    • Related Report
      2021 Annual Research Report
    • 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

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Screening of novel Midkine binding protein by BioID2-based proximity labeling2021

    • 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

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Dermatan sulphate is an activating ligand of anaplastic lymphoma kinase2021

    • 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

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] High-throughput identification and determination of aminoglycoside antibiotics in human plasma using UPLC?Q-ToF-MS2021

    • 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

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed
  • [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

    • Related Report
      2021 Annual Research Report
    • 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 cells2020

    • 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

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Chondroitin sulfate N-acetylgalactosyltransferase-1 knockout shows milder phenotype in experimental autoimmune encephalomyelitis than in wild type2020

    • Author(s)
      Inada Rino、Miyamoto Katsuichi、Tanaka Noriko、Moriguchi Kota、Kadomatsu Kenji、Takeuchi Kosei、Igarashi Michihiro、Kusunoki Susumu
    • Journal Title

      Glycobiology

      Volume: 31 Issue: 3 Pages: 260-265

    • DOI

      10.1093/glycob/cwaa072

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Thymidylate synthase inhibitor raltitrexed can induce high levels of DNA damage in MYCN ‐amplified neuroblastoma cells2020

    • Author(s)
      Yamashita Ken、Kiyonari Shinichi、Tsubota Shoma、Kishida Satoshi、Sakai Ryuichi、Kadomatsu Kenji
    • Journal Title

      Cancer Science

      Volume: 111 Issue: 7 Pages: 2431-2439

    • DOI

      10.1111/cas.14485

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Growth Factor Midkine Aggravates Pulmonary Arterial Hypertension via Surface Nucleolin.2020

    • Author(s)
      Kinoshita D, Shishido T, Takahashi T, Yokoyama M, Sugai T, Watanabe K, Tamura H, Nishiyama S, Takahashi H, Arimoto T, Miyamoto T, Watanabe T, Kishida S, Kadomatsu K, Abe JI, Takeishi Y, Konta T, Kubota I, Watanabe M.
    • Journal Title

      Sci Rep.

      Volume: 10 Issue: 1 Pages: 10354-10354

    • DOI

      10.1038/s41598-020-67217-w

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Systemic treatment with a novel basic fibroblast growth factor mimic small-molecule compound boosts functional recovery after spinal cord injury.2020

    • Author(s)
      Imagama S, Ogino R, Ueno S, Murayama N, Takemoto N, Shimmyo Y, Kadoshima T, Tamura S, Kuroda M, Matsuyama Y, Kadomatsu K, Morita Y, Inoue T, Ishiguro N.
    • Journal Title

      PLoS One.

      Volume: 15

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed
  • [Journal Article] miR-146a targeted to splenic macrophages prevents sepsis-induced multiple organ injury.2019

    • Author(s)
      Funahashi Y, Kato N, Masuda T, Nishio F, Kitai H, Ishimoto T, Kosugi T, Tsuboi N, Matsuda N, Maruyama S, Kadomatsu K.
    • Journal Title

      Lab. Invest.

      Volume: - Issue: 8 Pages: 1130-1142

    • DOI

      10.1038/s41374-019-0190-4

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] GlcNAc6ST3 is a keratan sulfate sulfotransferase for the protein-tyrosine phosphatase PTPRZ in the adult brain2019

    • Author(s)
      Narentuya、Takeda-Uchimura Yoshiko、Foyez Tahmina、Zhang Zui、Akama Tomoya O.、Yagi Hirokazu、Kato Koichi、Komatsu Yukio、Kadomatsu Kenji、Uchimura Kenji
    • Journal Title

      Scientific Reports

      Volume: 9 Issue: 1 Pages: 4387-4387

    • DOI

      10.1038/s41598-019-40901-2

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] CD147/Basigin Deficiency Prevents the Development of Podocyte Injury through FAK Signaling.2019

    • Author(s)
      Yoshioka T, Kosugi T, Masuda T, Watanabe T , Ryuge A, Nagaya H, Kayaho M, Sato Y, Katsuno T, Kato N, Ishimoto T, Yuzawa Y, Maruyama S, Kadomatsu K.
    • Journal Title

      Am J Pathol.

      Volume: 189 Issue: 7 Pages: 1338-1350

    • DOI

      10.1016/j.ajpath.2019.04.003

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Glycan sulfation patterns define autophagy flux at axon tip via PTPRσ-cortactin axis2019

    • Author(s)
      Kazuma Sakamoto, Tomoya Ozaki, Yen-Chun Ko, Cheng-Fang Tsai, Yuanhao Gong, Masayoshi Morozumi, Yoshimoto Ishikawa, Kenji Uchimura, Satomi Nadanaka, Hiroshi Kitagawa, Medel Manuel L. Zulueta, Anandaraju Bandaru, Jun-ichi Tamura, Shang-Cheng Hung, and Kenji Kadomatsu
    • Journal Title

      Nat. Chem. Biol.

      Volume: 15 Issue: 7 Pages: 699-699

    • DOI

      10.1038/s41589-019-0274-x

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Fructose Increases the Activity of Sodium Hydrogen Exchanger in Renal Proximal Tubules that is Dependent on Ketohexokinase.2019

    • Author(s)
      Takahiro Hayasaki, Takuji Ishimoto, Tomohito Doke, Akiyoshi Hirayama, Tomoyoshi Soga, Kazuhiro Furuhashi, Noritoshi Kato, Tomoki Kosugi, Naotake Tsuboi, Miguel A Lanaspa, Richard J Johnson, Shoichi Maruyama, Kenji Kadomatsu
    • Journal Title

      J Nutr Biochem

      Volume: 71 Pages: 54-62

    • DOI

      10.1016/j.jnutbio.2019.05.017

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [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
    • Related Report
      2021 Annual Research Report
    • 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
    • Related Report
      2021 Annual Research Report
    • 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
    • Related Report
      2021 Annual Research Report
    • 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
    • Related Report
      2021 Annual Research Report
    • 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).
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] 傷ついた神経はなぜ再生しないのか2019

    • Author(s)
      門松健治
    • Organizer
      第11回 形態科学シンポジウム
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] Future of Glycoscience.2019

    • Author(s)
      Kadomatsu K.
    • Organizer
      Glyco-Neuroscience Workdhop
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Chondroitin Sulfate as a Ligand Glycan that Disrupts Autophagy Flux at Axon Tips.2019

    • Author(s)
      Kadomatsu K.
    • Organizer
      G-Chain国際シンポジウム(生命の鎖)
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Chondroitin sulfate as a ligand that disrupts autophagy flux at axon tips.2019

    • Author(s)
      Kadomatsu K.
    • Organizer
      Proteoglycans 2019
    • Related Report
      2019 Annual Research Report
    • 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 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
    • Related Report
      2021 Annual Research Report
  • [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
    • Related Report
      2021 Annual Research Report
  • [Book] 「糖鎖生物学」 神経と糖鎖(I)-神経発生と再生2020

    • Author(s)
      北島健 佐藤ちひろ 門松健治 加藤晃一
    • Total Pages
      16
    • Publisher
      名古屋大学出版会
    • Related Report
      2020 Annual Research Report
  • [Book] Human Glycome Project への世界と日本の動き~本特集の序に代えて~2020

    • Author(s)
      門松健治
    • Total Pages
      4
    • Publisher
      生化学
    • Related Report
      2020 Annual Research Report
  • [Book] 「糖鎖生物学」2020

    • Author(s)
      北島健 佐藤ちひろ 門松健治 加藤晃一
    • Total Pages
      16
    • Publisher
      名古屋大学出版会
    • Related Report
      2019 Annual Research Report
  • [Remarks] 名古屋大学大学院医学系研究科生物化学講座分生物学

    • URL

      https://www.med.nagoya-u.ac.jp/biochem/

    • Related Report
      2021 Annual Research Report
  • [Remarks] https://www.med.nagoya-u.ac.jp/biochem/

    • Related Report
      2020 Annual Research Report
  • [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/

    • Related Report
      2019 Annual Research Report

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Published: 2019-04-18   Modified: 2023-01-30  

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