Regulation of intracellular membrane trafficking by atypical RabGAPs

2022 Fiscal Year Final Research Report

• Project/Area Number: 17K07327
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Functional biochemistry
• Research Institution: University of Tsukuba
• Principal Investigator: Funakoshi Yuji 筑波大学, 医学医療系, 准教授 (30415286)
• Project Period (FY): 2017-04-01 – 2023-03-31
• Keywords: RabGAP / クラスリン非依存性エンドサイトーシス / TRE17/USP6 / TBC1D3 / TBC1D24 / recycling

Outline of Final Research Achievements

Endocytosis and following intracellular trafficking of the plasma membrane proteins are regulated by various Rab small GTPases. Rab proteins hydrolyze GTP by its intrinsic GTPase activities with the aid of RabGAPs, which have the conserved TBC domains. Interestingly, TBC domains of some RabGAPs lack the arginine/glutamine residues essential for their RabGAP activities. In this study, we investigated the roles of the atypical RabGAP members, TRE17, TBC1D3 and TBC1D24, and obtained the following results; first, TRE17 accelerates tumor cell invasion through the promotion of the recycling of CD147, which in turn induces matrix metalloproteinase production; second, TBC1D3 and TBC1D24 promote formation of tubular recycling endosomes, which are critical compartments for the recycling of membrane proteins that enter cells through clathrin-independent endocytosis (CIE). Our findings give insights into the mechanism of CIE cargo trafficking and pathogenesis of diseases related to these RabGAPs.

Free Research Field

分子細胞生物学

Academic Significance and Societal Importance of the Research Achievements

エンドサイトーシスやその後の細胞内輸送は、受容体などの細胞膜蛋白質の膜上での局在や発現量を規定し、様々な細胞機能を制御する。本研究では、3つの非定型RabGAPが、Clathrin-independent endocytosis（CIE）によって取り込まれる膜蛋白質のリサイクリングを、それぞれ異なる機構で促進することを明らかにしており、未解明な部分の多いCIEカーゴ輸送の分子機構と、その輸送を介した生理機能の解明に大きく貢献するものである。また、これらRabGAPは、腫瘍や腫瘍性病変、がんの悪性化、脳神経系疾患などに深く関わっており、それらの病態解明、治療法開発に貢献できるものと期待される。