VEGF induces signalling and angiogenesis by directing VEGFR2 internalisation through macropinocytosis
VEGF induces signalling and angiogenesis by directing VEGFR2 internalisation through macropinocytosis
复制标题
DOI：
10.1242/jcs.188219
复制
发表时间：
2016-11-01
影响因子：
4
通讯作者：
Christoforidis, Savvas
中科院分区：
文献类型：
--
作者：
Basagiannis, Dimitris;Zografou, Sofia;Christoforidis, Savvas
内吞作用在受体信号传导中起着至关重要的作用。VEGFR2（也称为KDR）及其配体VEGFA是新生血管形成的基础。然而，我们对VEGFR2信号转导中内吞作用的理解仍然有限。尽管存在多种内化途径，但VEGFR2的唯一已知内吞途径是网格蛋白介导的途径。在这里，我们表明，这一途径是主要的内化途径VEGFR2只有在配体的情况下。有趣的是，VEGFA诱导VEGFR2的一个新的内化路线，巨胞饮途径，这成为配体存在下受体的普遍内吞途径，而网格蛋白介导的途径的贡献变得很小。VEGFR2的巨胞饮细胞内化，其机制是通过小的GTdR CDC42介导的，通过在膜的皱褶区域产生的巨胞饮体发生。有趣的是，巨胞饮在VEGF诱导的信号传导、体外内皮细胞功能和体内血管生成中起着至关重要的作用，而网格蛋白介导的内吞作用对于VEGF信号传导不是必需的。这些发现扩展了我们对VEGFR2内吞途径的了解，并表明VEGF通过巨胞饮作用驱动的VEGFR2内化对内皮细胞信号传导和血管生成至关重要。
Endocytosis plays a crucial role in receptor signalling. VEGFR2 (also known as KDR) and its ligand VEGFA are fundamental in neovascularisation. However, our understanding of the role of endocytosis in VEGFR2 signalling remains limited. Despite the existence of diverse internalisation routes, the only known endocytic pathway for VEGFR2 is the clathrin-mediated pathway. Here, we show that this pathway is the predominant internalisation route for VEGFR2 only in the absence of ligand. Intriguingly, VEGFA induces a new internalisation itinerary for VEGFR2, the pathway of macropinocytosis, which becomes the prevalent endocytic route for the receptor in the presence of ligand, whereas the contribution of the clathrin-mediated route becomes minor. Macropinocytic internalisation of VEGFR2, which mechanistically is mediated through the small GTPase CDC42, takes place through macropinosomes generated at ruffling areas of the membrane. Interestingly, macropinocytosis plays a crucial role in VEGFAinduced signalling, endothelial cell functions in vitro and angiogenesis in vivo, whereas clathrin-mediated endocytosis is not essential for VEGFA signalling. These findings expand our knowledge on the endocytic pathways of VEGFR2 and suggest that VEGFA-driven internalisation of VEGFR2 through macropinocytosis is essential for endothelial cell signalling and angiogenesis.