Mechanistic elucidation of angiogenesis mediated by Tspan18

• Project/Area Number: 17K15625
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Pathological medical chemistry
• 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): 2017-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2018: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2017: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: VEGF受容体 / angiogenesis / Tetraspanin18 / VEGFR2 / shedding / 血管新生 / 血管内皮細胞 / Tetraspanin / Tspan18 / メタロプロテアーゼ / tetraspanin18 / VEGF signaling / 血管 / テトラスパニン / 網膜血管

Outline of Final Research Achievements

Tspan18-dificient mice show abnormality in retinal vascular development. To understand how this phenotype is induced, binding of Tspan18 to VEGFRs was evaluated by co-immunoprecipitation assay. As a result, binding of Tspan18 to proteolytic fragments of VEGFR2, 130-kDa and 75-kDa fragments, was detected. Experiments using protease inhibitors showed that metalloprotease is necessary for the production of the 130-kDa fragment. Furthermore, it was shown that knockdown of Tspan18 in blood endothelial cells results in a shift in turnover of the fragments, including enhanced production of 130-kDa fragment and delayed production of 75-kDa fragment after VEGF treatment. Tumor blood vessels in Tspan18-deficient mice showed normalization of vascular structure, including absence of hemorrhage.

Academic Significance and Societal Importance of the Research Achievements

血管形成において最も重要な受容体といえるVEGFR2はプロテアーゼにより断片へと切断されるが、この切断にどのような意味があるかはわかっていなかった。我々の研究により、Tspan18を欠損するマウスが血管形成に異常を示すことに加え、Tsapn18がVEGFR2の断片と結合することが明らかになり、VEGFR2の切断過程や断片の制御が正常な血管形成に重要であることが示唆された。

Research Products

• [Journal Article] TAK1 Prevents Endothelial Apoptosis and Maintains Vascular Integrity. (2018)
  • Author(s): Naito H, Iba T, Wakabayashi T, Tai-Nagara I, Suehiro JI, Jia W, Eino D, Sakimoto S, Muramatsu F, Kidoya H, Sakurai H, Satoh T, Akira S, Kubota Y, Takakura N.
  • Journal Title: Dev Cell. Volume: 48 Issue: 2 Pages: 151-166
  • DOI: 10.1016/j.devcel.2018.12.002
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Placental labyrinth formation in mice requires endothelial FLRT2/UNC5B signaling (2017)
  • Author(s): Tai-Nagara Ikue、Yoshikawa Yusuke、Numata Naoko、Ando Tomofumi、Okabe Keisuke、Sugiura Yuki、Ieda Masaki、Takakura Nobuyuki、Nakagawa Osamu、Zhou Bin、Okabayashi Koji、Suematsu Makoto、Kitagawa Yuko、Bastmeyer Martin、Sato Kohji、Klein R?diger、Navankasattusas Sutip、Li Dean Y.、Yamagishi Satoru、Kubota Yoshiaki
  • Journal Title: Development Volume: 144 Pages: 2392-2401
  • DOI: 10.1242/dev.149757
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] 血管とリンパ管の独立性を規定する分子機構とその破綻 (2019)
  • Author(s): 田井育江
  • Organizer: 第一回医学会連合リトリート
• [Presentation] 血管とリンパ管の独立性を規定する分子機構とその破綻 (2019)
  • Author(s): 田井育江
  • Organizer: 第124回日本解剖学会総会・全国学術集会
  • Invited