Endorepellin, the Angiostatic Module of Perlecan, Interacts with Both the α2β1 Integrin and Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) A DUAL RECEPTOR ANTAGONISM
Endorepellin, the Angiostatic Module of Perlecan, Interacts with Both the α2β1 Integrin and Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) A DUAL RECEPTOR ANTAGONISM
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DOI：
10.1074/jbc.m111.243626
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发表时间：
2011-07-22
影响因子：
4.8
通讯作者：
Iozzo, Renato V.
中科院分区：
文献类型：
--
作者：
Goyal, Atul;Pal, Nutan;Iozzo, Renato V.
endorepelin，串珠素的C-末端模块，负调控血管生成的反其促血管生成的亲本分子。内皮排斥素（串珠素的C-末端结构域V）结合内皮细胞上的α 2 β 1整联蛋白并触发导致肌动蛋白细胞骨架破坏的信号级联。在这里，我们表明，串珠素和endorepelin直接结合，并具有高亲和力的VEGF受体1和2，在一个区域，从VEGF结合位点不同。在人和猪内皮细胞中，这种相互作用引起α 2 β 1整联蛋白和VEGFR 2的物理下调，同时激活酪氨酸磷酸酶SHP-1和下游VEGFA转录的减弱。我们证明，内排斥素需要α 2 β 1整合素和VEGFR 2的血管抑制活性。表达α 2 β 1整联蛋白但缺乏VEGFR 2的内皮细胞对内皮排斥素治疗没有反应。因此，我们提供了一个新的范例的抗血管生成蛋白的活性和机械解释内皮细胞，同时表达两种受体的唯一细胞的特异性endorepelin。我们推测，一种机制，如双重受体拮抗作用，可以为其他血管抑制片段。
Endorepellin, the C-terminal module of perlecan, negatively regulates angiogenesis counter to its proangiogenic parental molecule. Endorepellin (the C-terminal domain V of perlecan) binds the alpha 2 beta 1 integrin on endothelial cells and triggers a signaling cascade that leads to disruption of the actin cytoskeleton. Here, we show that both perlecan and endorepellin bind directly and with high affinity to both VEGF receptors 1 and 2, in a region that differs from VEGFA-binding site. In both human and porcine endothelial cells, this interaction evokes a physical down-regulation of both the alpha 2 beta 1 integrin and VEGFR2, with concurrent activation of the tyrosine phosphatase SHP-1 and downstream attenuation of VEGFA transcription. We demonstrate that endorepellin requires both the alpha 2 beta 1 integrin and VEGFR2 for its angiostatic activity. Endothelial cells that express alpha 2 beta 1 integrin but lack VEGFR2, do not respond to endorepellin treatment. Thus, we provide a new paradigm for the activity of an antiangiogenic protein and mechanistically explain the specificity of endorepellin for endothelial cells, the only cells that simultaneously express both receptors. We hypothesize that a mechanism such as dual receptor antagonism could operate for other angiostatic fragments.