Endostatin blocks vascular endothelial growth factor-mediated signaling via direct interaction with KDR/Flk-1
Endostatin blocks vascular endothelial growth factor-mediated signaling via direct interaction with KDR/Flk-1
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DOI：
10.1074/jbc.m202771200
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发表时间：
2002-08-02
影响因子：
4.8
通讯作者：
Kwon, YG
中科院分区：
文献类型：
--
作者：
Kim, YM;Hwang, S;Kwon, YG
内皮抑素是胶原XVIII的一个片段，是一种有效的抗血管生成蛋白，但其作用的分子机制尚不清楚。我们研究了内皮抑素对血管内皮生长因子（VEGF）生物学和生化活性的影响。内皮抑素阻断VEGF诱导的人脐静脉内皮细胞KDR/Flk-1的酪氨酸磷酸化和ERK、p38 MAPK和p125（FAK）的激活。内皮抑制素还抑制VEGF（165）与内皮细胞和纯化的KDR/Flk-1胞外域的结合。此外，VEGF（121）与KDR/Flk-1的结合以及VEGF（121）刺激的ERK激活被内皮抑素阻断。亲和层析证实了内皮抑素与KDR/Flk-1的直接相互作用。然而，内皮抑素不结合VEGF。我们的研究结果表明，内皮抑素与KDR/Flk-1的直接相互作用可能参与内皮抑素对VEGF作用的抑制功能，并负责其有效的抗血管生成和抗肿瘤活性在体内。
Endostatin, a fragment of collagen XVIII, is a potent anti-angiogenic protein, but the molecular mechanism of its action is not yet clear. We examined the effects of endostatin on the biological and biochemical activities of vascular endothelial growth factor (VEGF). Endostatin blocked VEGF-induced tyrosine phosphorylation of KDR/Flk-1 and activation of ERK, p38 MAPK, and p125(FAK) in human umbilical vein endothelial cells. Endostatin also inhibited the binding of VEGF(165) to both endothelial cells and purified extracellular domain of KDR/Flk-1. Moreover, the binding of VEGF(121) to KDR/Flk-1 and VEGF(121)-stimulated ERK activation were blocked by endostatin. The direct interaction between endostatin and KDR/Flk-1 was confirmed by affinity chromatography. However, endostatin did not bind to VEGF. Our findings suggest that a direct interaction of endostatin with KDR/Flk-1 may be involved in the inhibitory function of endostatin toward VEGF actions and responsible for its potent anti-angiogenic and anti-tumor activities in vivo.