Global analysis of factors controlling GPCR endocytosis

2018 Fiscal Year Final Research Report

• Project/Area Number: 16K07303
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Functional biochemistry
• Research Institution: Tokyo University of Science
• Principal Investigator: Toshima Jiro 東京理科大学, 基礎工学部生物工学科, 教授 (00333831)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Keywords: GPCR / エンドサイトーシス / 膜小胞輸送

Outline of Final Research Achievements

GPCRs are expressed ubiquitously in eukaryote cells and play fundamental roles in many physiological processes. Additionally, GPCRs are related to many human diseases and therefore they have been the targets of medical therapeutics. Thus, elucidating the control mechanism of GPCR activity is essential for the more effective and safer therapeutic agents. We previously identified ~200 yeast mutants that have defect in GPCR endocytosis. Among these mutants, in this study, we focused at the genes controlling early stage of GPCR endocytosis and controlling transport between endosome and lysosome. By labeling early endocytic protein with GFP and monitoring the dynamics in mutants cells, we found four mutants, clc1, end3, las17, and sla2, that have remarkable defect in early stage endocytosis of GPCR. We also examined Rab5 and Rab7 proteins that are involved in GPCR transport from endosomes to lysosomes, and found that novel GPCR transport pathway, the Rab5-independent Rab7-mediated pathway.

Free Research Field

細胞生物学

Academic Significance and Societal Importance of the Research Achievements

GPCRはヒトの様々な生理現象を司る重要な因子であり、またGPCRの機能異常は多くの疾患の原因となることが明らかにされている。このため、GPCRは創薬の重要な標的分子となっており、GPCRシグナルの活性制御機構を明らかにすることは、基礎生命科学の分野のみならず、臨床応用の面からも重要である。エンドサイトーシスはGPCRの活性調節のための重要な機構の一つであり、本研究ではGPCRがエンドサイトーシスの初期過程でどのようにして細胞内に取り込まれるかを明らかにした。また、新しいリソソームへの輸送経路を見出しており、これらの成果は新しいGPCRシグナルの活性調節機構の解明につながることが期待される。