Grünewald Felix S, Prota Andrea E, Giese Alexandra, Ballmer-Hofer Kurt
Paul Scherrer Institut, Biomolecular Research, 5232 Villigen PSI, Switzerland.
Biochim Biophys Acta. 2010 Mar;1804(3):567-80. doi: 10.1016/j.bbapap.2009.09.002. Epub 2009 Sep 15.
Vascular endothelial growth factors (VEGFs) constitute a family of six polypeptides, VEGF-A, -B, -C, -D, -E and PlGF, that regulate blood and lymphatic vessel development. VEGFs specifically bind to three type V receptor tyrosine kinases (RTKs), VEGFR-1, -2 and -3, and to coreceptors such as neuropilins and heparan sulfate proteoglycans (HSPG). VEGFRs are activated upon ligand-induced dimerization mediated by the extracellular domain (ECD). A study using receptor constructs carrying artificial dimerization-promoting transmembrane domains (TMDs) showed that receptor dimerization is necessary, but not sufficient, for receptor activation and demonstrates that distinct orientation of receptor monomers is required to instigate transmembrane signaling. Angiogenic signaling by VEGF receptors also depends on cooperation with specific coreceptors such as neuropilins and HSPG. A number of VEGF isoforms differ in binding to coreceptors, and ligand-specific signal output is apparently the result of the specific coreceptor complex assembled by a particular VEGF isoform. Here we discuss the structural features of VEGF family ligands and their receptors in relation to their distinct signal output and angiogenic potential.
血管内皮生长因子（VEGF）由六种多肽组成，即VEGF-A、-B、-C、-D、-E和胎盘生长因子（PlGF），它们调节血管和淋巴管的发育。VEGF特异性结合三种V型受体酪氨酸激酶（RTK），即VEGFR-1、-2和-3，以及诸如神经纤毛蛋白和硫酸乙酰肝素蛋白聚糖（HSPG）等共受体。VEGFR在由细胞外结构域（ECD）介导的配体诱导二聚化后被激活。一项使用携带人工二聚化促进跨膜结构域（TMD）的受体构建体的研究表明，受体二聚化对于受体激活是必要的，但不是充分的，并证明受体单体的不同取向是启动跨膜信号传导所必需的。VEGF受体的血管生成信号传导还取决于与特定共受体（如神经纤毛蛋白和HSPG）的合作。许多VEGF异构体在与共受体的结合上存在差异，并且配体特异性信号输出显然是由特定VEGF异构体组装的特定共受体复合物的结果。在这里，我们讨论VEGF家族配体及其受体的结构特征与其独特的信号输出和血管生成潜力之间的关系。
