Role of Tspan18 in the intracellular trafficking of VEGF receptor

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K07389
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 49010:Pathological biochemistry-related
• Research Institution: Keio University
• Principal Investigator: Tai Ikue 慶應義塾大学, 医学部(信濃町), 講師 (90749508)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: 血管新生 / 血管形成 / リンパ管新生 / tetraspanin / Tspan18

Outline of Final Research Achievements

We are analyzing effects of Tspan18, a membrane protein with four transmembrane regions, on shedding of VEGFR2, as a mechanism by which Tspan18 contributes to normal retinal vascular development and development of tumor blood vessels. Though nuclear localization of VEGFR2 fragments was not detected, we have shown that Tspan18 increases the amount of VEGFR2 fragments and phosphorylation of full length VEGFR2 by overexpression and knockdown experiments using HUVECs. The amount of VEGFR2 fragments were normal in the postnatal retina, lung and mesentery endothelial cells of endothelial-cell-specific Tspan18 KO mice, but phosphorylation of full-length VEGFR2 was suppressed in those mice. We additionally identified a novel gene important for development of blood vessels and lymphatic vessels, and developed and analyzed its knockout mice.

Free Research Field

血管生物学

Academic Significance and Societal Importance of the Research Achievements

より効果的で副作用の少ない、抗腫瘍血管新生療法の新たな分子標的を探索するため、VEGFシグナルの詳細を基礎研究により徹底的に見直そうという機運が世界的に高まっている。その中で、Tetraspaninというまだ知見の乏しいタンパク質によるVEGF受容体のtruncationという切り口はユニークと言える。特に、ノックアウトマウスの解析からTspan18のin vivoでの重要性は既に示されていることから、上記のVEGFシグナルの詳細の解明、次世代の抗腫瘍血管新生療法の開拓へ本研究が寄与するところは大きいと考えられる。