Vascular endothelial growth factor (VEGF)-receptor2: Its biological functions, major signaling pathway, and specific ligand VEGF-E
Vascular endothelial growth factor (VEGF)-receptor2: Its biological functions, major signaling pathway, and specific ligand VEGF-E
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DOI：
10.1080/10623320600697955
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发表时间：
2006-03-01
影响因子：
--
通讯作者：
Shibuya, Masabumi
中科院分区：
文献类型：
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作者：
Shibuya, Masabumi
血管内皮生长因子(VEGF)-A的两个高亲和力受体VEGFR1和VEGFR2在胚胎发生过程中协同进行生理性血管发生和血管生成。VEGFR2通过其强大的酪氨酸激酶活性转导血管生成的主要信号。然而，与其他代表性的酪氨酸激酶受体不同，VEGFR2不使用Ras途径作为主要的下游信号，而是使用磷脂酶C-蛋白激酶C途径来信号分裂原活化蛋白（MAP）激酶的激活和DNA合成。来自VEGFR2的细胞迁移信号最近被证明至少部分地依赖于来自VEGFR2激酶插入区域的衔接分子TSAd的途径。VEGFR2是病理性血管生成（包括癌症和糖尿病视网膜病变）的直接和主要信号传感器，与许多其他信号伙伴合作；因此，VEGFR2及其下游信号似乎是抑制这些疾病的关键靶点。超过10种VEGFR2拮抗剂，包括激酶抑制剂和中和抗体，目前正在临床试验中。最近，对vegfr2特异性配体VEGF-E（也称为Orf-VEGF）家族进行了广泛的表征。有趣的是，体内通过VEGF-E激活VEGFR2会在小鼠体内产生强烈的血管生成反应，与VEGF-A相比，对炎症和血管高通透性的影响较小，这表明VEGF-E是促进血管生成治疗缺血性疾病的有用工具。
Two high-affinity receptors for vascular endothelial growth factor (VEGF)-A, VEGFR1 and VEGFR2, cooperate for physiological vasculogenesis and angiogenesis in embryogenesis. VEGFR2 transduces the major signals for angiogenesis via its strong tyrosine kinase activity. However, unlike other representative tyrosine kinase receptors, VEGFR2 does not use the Ras pathway as a major downstream signaling but rather uses the phospholipase C-protein kinase C pathway to signal mitogen-activated protein (MAP)-kinase activation and DNA synthesis. Cell migration signals from VEGFR2 were recently shown to use, at least partly, a pathway dependent on the adaptor molecule TSAd from the kinase-insert region of VEGFR2. VEGFR2 is a direct and major signal transducer for pathological angiogenesis, including cancer and diabetic retinopathy, in cooperation with many other signaling partners; thus, VEGFR2 and its downstream signaling appear to be critical targets for the suppression of these diseases. More than 10 antagonists of VEGFR2, including kinase inhibitors and neutralizing antibodies, are now under clinical trials. Recently, the VEGFR2-specific ligand VEGF-E (also known as Orf-VEGF) family was extensively characterized. Interestingly, activation of VEGFR2 via VEGF-E in vivo results in a strong angiogenic response in mice, with minor effects on inflammation and hypervascular permeability compared with VEGF-A, suggesting that VEGF-E is a useful tool for proangiogenic therapy in ischemic diseases.