Vascular endothelial growth factor (VEGF)/VEGF-C mosaic molecules reveal specificity determinants and feature novel receptor binding patterns
Vascular endothelial growth factor (VEGF)/VEGF-C mosaic molecules reveal specificity determinants and feature novel receptor binding patterns
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DOI：
10.1074/jbc.m511593200
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发表时间：
2006-04-28
影响因子：
4.8
通讯作者：
Alitalo, K
中科院分区：
文献类型：
--
作者：
Jeltsch, M;Karpanen, T;Alitalo, K
血管内皮生长因子（VEGF）及其受体在血管生成和淋巴管生成中起着关键作用。VEGF激活VEGF受体-1（VEGFR-1）和VEGFR-2，而VEGF-C激活VEGFR-2和VEGFR-3。我们已经创建了VEGF/VEGF-C嵌合分子的文库，其包含具有新受体结合谱的因子，特别是与所有三种VEGF受体（“超级VEGF”）结合的蛋白质。所分析的super-VEGF在体内显示血管生成和淋巴管生成作用，尽管比亲本分子弱。VEGFR-3结合分子的组成和扫描诱变揭示了受体结合和特异性的决定因素。VEGFR-2和VEGFR-3对VEGF-C结合的需求存在显著差异; VEGFR-2的胞外结构域2就足够了，而在VEGFR-3中，结构域1和2都是必需的。
Vascular endothelial growth factors (VEGFs) and their receptors play key roles in angiogenesis and lymphangiogenesis. VEGF activates VEGF receptor-1 (VEGFR-1) and VEGFR-2, whereas VEGF-C activates VEGFR-2 and VEGFR-3. We have created a library of VEGF/VEGF-C mosaic molecules that contains factors with novel receptor binding profiles, notably proteins binding to all three VEGF receptors ("super-VEGFs"). The analyzed super-VEGFs show both angiogenic and lymphangiogenic effects in vivo, although weaker than the parental molecules. The composition of the VEGFR-3 binding molecules and scanning mutagenesis revealed determinants of receptor binding and specificity. VEGFR-2 and VEGFR-3 showed striking differences in their requirements for VEGF-C binding; extracellular domain 2 of VEGFR-2 was sufficient, whereas in VEGFR-3, both domains 1 and 2 were necessary.