Department of Ecological Environment Conservation, Kyungpook National University, Gyeongsangbuk-do, Seoul, Korea.
Mol Cancer Res. 2012 Aug;10(8):1010-20. doi: 10.1158/1541-7786.MCR-11-0600. Epub 2012 Jun 18.
It is known that VEGF receptors (VEGFR) and integrins interact with each other to regulate angiogenesis. We reported previously that the fasciclin 1 (FAS1) domain-containing protein, TGFBIp/βig-h3 (TGF-β-induced protein) is an angiogenesis regulator that inhibits both endothelial cell migration and growth via αvβ3 integrin. In an attempt to target the interaction between VEGFR-2 and αvβ3 integrin, we determined whether the FAS1 domain region of TGFBIp/βig-h3 (FAS1 domain protein) can block the interaction between the two receptors, leading to the suppression of angiogenesis. In this study, we showed that FAS1 domain protein inhibits VEGF165-induced endothelial cell proliferation and migration via αvβ3 integrin, resulting in the inhibition of VEGF165-induced angiogenesis. We also defined a molecular mechanism by which FAS1 domain protein blocks the association between αvβ3 integrin and VEGFR-2, showing that it binds to αvβ3 integrin but not to VEGFR-2. Blocking the association of these major angiogenic receptors with FAS1 domain protein inhibits signaling pathways downstream of VEGFR-2. Collectively, our results indicate that FAS1 domain protein, in addition to its inhibitory effect on αvβ3 integrin-mediated angiogenesis, also inhibits VEGF165-induced angiogenesis. Thus, FAS1 domain protein can be further developed into a potent anticancer drug that targets two principal angiogenic pathways.
已知血管内皮生长因子受体 (VEGFR) 和整合素相互作用，共同调节血管生成。我们之前曾报道过，富含 fasciiclin1（FAS1）结构域的蛋白 TGFBIp/βig-h3（TGF-β诱导蛋白）是一种血管生成调节剂，通过αvβ3 整合素抑制内皮细胞的迁移和生长。为了靶向 VEGFR-2 和 αvβ3 整合素之间的相互作用，我们确定 TGFBIp/βig-h3（TGF-β诱导蛋白）的 FAS1 结构域区域（FAS1 结构域蛋白）是否可以阻断两个受体之间的相互作用，从而抑制血管生成。在这项研究中，我们表明 FAS1 结构域蛋白通过 αvβ3 整合素抑制 VEGF165 诱导的内皮细胞增殖和迁移，从而抑制 VEGF165 诱导的血管生成。我们还定义了 FAS1 结构域蛋白阻断 αvβ3 整合素与 VEGFR-2 之间的关联的分子机制，表明它与 αvβ3 整合素结合而不是与 VEGFR-2 结合。阻断这些主要血管生成受体与 FAS1 结构域蛋白的关联抑制了 VEGFR-2 下游的信号通路。总之，我们的结果表明，FAS1 结构域蛋白除了对 αvβ3 整合素介导的血管生成具有抑制作用外，还抑制 VEGF165 诱导的血管生成。因此，FAS1 结构域蛋白可以进一步开发为针对两种主要血管生成途径的有效抗癌药物。
