VEGF controls endothelial-cell permeability by promoting the β-arrestin-dependent endocytosis of VE-cadherin
VEGF controls endothelial-cell permeability by promoting the β-arrestin-dependent endocytosis of VE-cadherin
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DOI：
10.1038/ncb1486
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发表时间：
2006-11-01
影响因子：
21.3
通讯作者：
Gutkind, J. Silvio
中科院分区：
文献类型：
--
作者：
Gavard, Julie;Gutkind, J. Silvio
血管内皮生长因子（VEGF）如何诱导血管通透性，它的第一个描述的功能，仍然知之甚少。在这里，我们提供了一种新的信号通路的证据，通过这种信号通路，VEGF刺激促进了一种关键的内皮细胞粘附分子VE-钙粘蛋白的快速内吞作用，从而破坏了内皮屏障功能。该过程是由VEGFR-2通过鸟嘌呤核苷酸交换因子Vav 2的Src依赖性磷酸化激活小GTPase Rac而启动的。Rac激活，反过来，促进p21激活激酶（PAK）介导的高度保守的基序内的VE-钙粘蛋白的细胞内尾部的磷酸化。令人惊讶的是，这导致β-抑制蛋白2被丝氨酸磷酸化的VE-钙粘蛋白募集，从而促进其内化到网格蛋白包被的囊泡中，并随后分解细胞间连接。最终，这种新的生物化学途径，通过VEGF促进内皮细胞渗透性通过β-arrestin 2依赖性内吞VE-钙粘蛋白可能有助于确定新的治疗靶点，用于治疗许多人类疾病的特点是血管渗漏。
How vascular endothelial growth factor (VEGF) induces vascular permeability, its first described function, remains poorly understood. Here, we provide evidence of a novel signalling pathway by which VEGF stimulation promotes the rapid endocytosis of a key endothelial cell adhesion molecule, VE-cadherin, thereby disrupting the endothelial barrier function. This process is initiated by the activation of the small GTPase Rac by VEGFR-2 through the Src-dependent phosphorylation of Vav2, a guanine nucleotide-exchange factor. Rac activation, in turn, promotes the p21-activated kinase (PAK)-mediated phosphorylation of a highly conserved motif within the intracellular tail of VE-cadherin. Surprisingly, this results in the recruitment of beta-arrestin2 to serine-phosphorylated VE-cadherin, thereby promoting its internalization into clathrin-coated vesicles and the consequent disassembly of intercellular junctions. Ultimately, this novel biochemical route by which VEGF promotes endothelial permeability through the beta-arrestin2-dependent endocytosis of VE-cadherin may help identify new therapeutic targets for the treatment of many human diseases that are characterized by vascular leakage.