A new ligand for ALK and its activation mechanism
| Project/Area Number |
19H03415
|
|---|
| Research Category |
Grant-in-Aid for Scientific Research (B)
|
| Allocation Type | Single-year Grants |
|---|
| Section | 一般 |
|---|
| Review Section |
Basic Section 48040:Medical biochemistry-related
|
|---|
| Research Institution | Nagoya University |
|---|
Principal Investigator |
|
|---|
| 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)
|
|---|
| Keywords | ALK / 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)
Research Products
(35 results)
-
-
-
-
-
-
-
-
[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
Related 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
Related 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
Related 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
Related Report
Peer Reviewed / Int'l Joint Research
-
-
[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
Related 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
Related 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
Related Report
Peer Reviewed / Int'l Joint Research
-
-
-
-
-
-
-
-
-
-
-
-
-
-
[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
-
-
-
