Analysis of the mechanism of suppression of lung cancer cell proliferation signals by N-glycan of MET

2021 Fiscal Year Final Research Report

• Project/Area Number: 20K17218
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 53030:Respiratory medicine-related
• Research Institution: Sapporo Medical University
• Principal Investigator: SAITOU ATSUSHI 札幌医科大学, 医学部, 訪問研究員 (90836446)
• Project Period (FY): 2020-04-01 – 2022-03-31
• Keywords: 糖鎖 / MET / HGF / 肺癌 / EGFR-TKI耐性

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.

Free Research Field

糖鎖

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。