A molecular mechanism of phosphoinositides transport to the plasma membrane outer leaflet and its function in cancer progression

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K06563
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 43030:Functional biochemistry-related
• Research Institution: Tokyo University of Pharmacy and Life Science
• Principal Investigator: YONEDA ATSUKO 東京薬科大学, 生命科学部, 講師 (80590372)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: イノシトールリン脂質 / 癌 / 細胞接着

Outline of Final Research Achievements

The plasma membranes comprise lipid bilayers with distinct lipid composition. Transient transport of the lipids from the inner leaflet of the plasma membrane to the outer leaflet has been known in cell death (apoptosis). However, it is not known whether phosphoinositides in the inner leaflet can be transported to the outer leaflet. We found the presence of phosphatidylinositol 4,5-bisphosphates (PIP2) in the outer leaflet of plasma membrane and that the PIP2 in the outer leaflet supports cell adhesion and migration of human cancer cells, which are characteristics of malignant cancer cells. Additionally, we identified an enzyme A to transport PIP2 to the plasma membrane outer leaflet. Moreover, candidate receptors to support outer PIP2-dependent cell adhesion were found. Some of these results were published in an international journal and presented at the international meeting. This study would lead to develop tools to treat diseases that outer PIP2 is involved in.

Free Research Field

細胞生物学

Academic Significance and Societal Importance of the Research Achievements

本研究では、細胞膜内葉で様々な細胞応答に関わるPIP2が、外葉にも局在することを初めて見出した。また、外葉 PIP2 が悪性癌細胞の性質である細胞接着や遊走に関わることを見出し、国際誌に発表した。さらに、PIP2の反転に関わる酵素を同定し、PIP2が細胞膜外葉に露出する機構の一端を明らかにした。外葉PIP2依存的細胞接着に関わる候補因子も絞り込んでおり、外葉PIP2が制御する新しい形式のがん細胞の接着と遊走の機構解明につながる。本研究は、外葉PIP2依存的細胞接着や遊走が関わる疾病の発見や、これらの現象を阻害する方法の開発の基礎形成に繋がる。