| Project/Area Number |
20K17218
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| Research Category |
Grant-in-Aid for Early-Career Scientists
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| Allocation Type | Multi-year Fund |
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| Review Section |
Basic Section 53030:Respiratory medicine-related
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| Research Institution | Sapporo Medical University |
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Principal Investigator |
SAITOU ATSUSHI 札幌医科大学, 医学部, 訪問研究員 (90836446)
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| Project Period (FY) |
2020-04-01 – 2022-03-31
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| Project Status |
Completed (Fiscal Year 2021)
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| Budget Amount *help |
¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000)
Fiscal Year 2021: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2020: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
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| Keywords | 糖鎖 / MET / HGF / 肺癌 / EGFR-TKI耐性 / N型糖鎖 / プロセシング / シグナル伝達 / 肺がん / EGFR-TKI |
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| Outline of Research at the Start |
・METの細胞外ドメインを用いてWestern Blotting法でMETシグナルの抑制作用を評価する。
・全長METの糖鎖欠損変異体導入細胞を精製し上記同様にシグナルを評価する。
・MET細胞外ドメインの糖鎖欠損変異体を精製し、そのMETシグナル抑制作用を評価する。
・ヒト肺がん細胞株のMETをKnock Outし、MET糖鎖欠損変異体を導入し上記同様にMETシグナルを評価する。
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| Outline of Final Research Achievements |
In this study, we show that N-glycans have essential roles in MET processing and downstream signaling. By using N-glycan deletion mutants, we demonstrated that N-glycans are involved in the processing of MET. The findings also suggest that the N-glycans of the SEMA domain of MET positively regulate HGF signaling, and the N-glycans of the region other than the SEMA domain negatively regulate
HGF signaling. In the all-N-glycan deletion mutant, processing and signaling were significantly suppressed. The cell surface expression levels of the all-N-glycan deletion mutant were significantly reduced, and the phosphorylation levels of the receptors expressed on the cell surface were also suppressed. We also identified the structures of the N-glycans of MET and demonstrated that the occupancy of most of the N-glycosylation sites was considerably high, and the dominant population were complex type with sialic acids and core fucoses.
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| Academic Significance and Societal Importance of the Research Achievements |
METの部位特異的な糖鎖構造解析や糖鎖欠損変異体を用いた糖鎖機能解析についての報告は本研究が初めてであり、糖鎖がMETの機能制御に関与していることが示唆された。
糖鎖がMETを制御する詳細な機序を解明することは、肺がんの主要治療薬であるEGFR-TKIの薬剤耐性に関与する重要な分子であるMETの機能を制御する新しい方法を確立するための手がかりとなる可能性がある。
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