Jeltsch Michael, Karpanen Terhi, Strandin Tomas, Aho Kukka, Lankinen Hilkka, Alitalo Kari
Molecular/Cancer Biology Laboratory and Ludwig Institute for Cancer Research, Biomedicum Helsinki, Haartman Institute and Helsinki University Central Hospital, P.O. Box 63 (Haartmaninkatu 8), University of Helsinki, Helsinki 00014, Finland.
J Biol Chem. 2006 Apr 28;281(17):12187-95. doi: 10.1074/jbc.M511593200. Epub 2006 Feb 27.
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.
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关键作用。VEGF激活血管内皮生长因子受体-1（VEGFR-1）和VEGFR-2，而VEGF-C激活VEGFR-2和VEGFR-3。我们构建了一个VEGF/VEGF-C嵌合分子文库，其中包含具有新型受体结合谱的因子，特别是能与所有三种VEGF受体结合的蛋白（“超级VEGF”）。分析的超级VEGF在体内显示出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在VEGF-C结合需求上表现出显著差异；VEGFR-2的胞外结构域2就足够了，而在VEGFR-3中，结构域1和2都必不可少。
