| Project/Area Number |
21K06083
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Review Section |
Basic Section 43030:Functional biochemistry-related
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| Research Institution | Sapporo Medical University |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
藤谷 直樹 札幌医科大学, 医学部, 講師 (10374191)
上原 康昭 札幌医科大学, 医学部, 助教 (40882907)
長谷川 喜弘 札幌医科大学, 医学部, 講師 (90643180)
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| Project Period (FY) |
2021-04-01 – 2024-03-31
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| Project Status |
Completed (Fiscal Year 2023)
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| Budget Amount *help |
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2023: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2022: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2021: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
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| Keywords | 糖鎖 / ErbB4 / ErbB / 増殖因子受容体 / シグナル伝達 / 質量分析 / EGFR / Glycosylation / N-glycan |
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| Outline of Research at the Start |
本研究ではErbB4の部位特異的糖鎖構造解析を行い、糖鎖によるErbB4シグナル制御機構を明らかにする。
受容体の多くは糖鎖を持っており、糖鎖による機能制御を受けている。これまでにEGFRとErbB3の糖鎖解析を行い、特定の糖鎖構造が機能と関係している可能性について検討してきた。本研究でErbB4の糖鎖機能を明らかにし、ErbB受容体ファミリー全体の糖鎖機能メカニズムの解明をめざす。
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| Outline of Final Research Achievements |
We have been examining the mechanisms of functional regulation of growth factor receptor by N-glycans. In this study, N-glycans of ErbB4 were examined. We analyzed the site-specific glycosylation status and glycan structures of ErbB4, and found that the glycan occupancies of N146 and N448 were low as less than 50%, whereas occupancies of other sites were rather high, and those of N113 and N333 were especially high as 100%. We also found that most N-glycans on N113, N228 and N523 were oligomannose-type and those on other eight sites were complex type. We examined CHOK1 cells transfected with glycan deficient mutants of ErbB4, and found that N-glycan on N333 was involved in receptor activation: the levels and duration of heregulin-induced receptor phosphorylation were upregulated in ErbB4 N333Q mutant. The results suggested that the occupancies, structures and functions of N-glycans of ErbB4 were regulated site-specifically, and the N-glycan on N333 was involved in activation of ErbB4.
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| Academic Significance and Societal Importance of the Research Achievements |
増殖因子受容体はがん治療の標的であり、その制御機構を明らかにすることは社会的にも重要である。研究代表者等は糖鎖によるErbB4の制御機構を検討した。ErbB4の部位特異的な糖鎖解析を行った結果、部位によって糖鎖付加率が異なること、また糖鎖のプロセシングの程度が異なることがわかった。これらは、ErbBファミリーの全てに共通するが、METやFGFRファミリーではみられない特徴であった。一方で、機能的に重要な糖鎖は100%の付加率を示す点は、これまで調べた全ての分子に共通していた。以上の結果は受容体の糖鎖付加、そして糖鎖のプロセシングを部位特異的に決定する機構の解明につながると考えている。
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