SU1498, an inhibitor of vascular endothelial growth factor receptor 2, causes accumulation of phosphorylated ERK kinases and inhibits their activity in vivo and in vitro
SU1498, an inhibitor of vascular endothelial growth factor receptor 2, causes accumulation of phosphorylated ERK kinases and inhibits their activity in vivo and in vitro
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DOI：
10.1074/jbc.m308625200
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发表时间：
2004-02-13
影响因子：
4.8
通讯作者：
Kovala, AT
中科院分区：
文献类型：
--
作者：
Boguslawski, G;McGlynn, PW;Kovala, AT
血管内皮生长因子受体2的抑制剂SU1498已成功地用于研究受体功能的生理表现。在此，我们报道，除了其抗受体活性外，SU1498还刺激人脐静脉内皮细胞和人主动脉内皮细胞中磷酸化ERKs的积累，这种方式依赖于MAPK途径的上游成分B-Raf和MEK激酶的功能。只有在鞘氨醇1-磷酸或蛋白质生长因子刺激的细胞中，才能观察到磷酸化ERKs的增强积累；SU1498本身是无效的。我们表明，该抑制剂通过阻断磷酸化ERK的活性，在直接测定和免疫沉淀物处理的细胞与该化合物。这些数据揭示了一种新颖而独特的方式来阻断人内皮细胞中的MAPK信号通路。
SU1498, an inhibitor of vascular endothelial growth factor receptor 2, has been used successfully to study the physiological manifestations of receptor functions. Here we report that in addition to its anti-receptor activity, SU1498 stimulates accumulation of phosphorylated ERKs in human umbilical vein endothelial cells and in human aortic endothelial cells in a manner that is dependent on the functioning of the upstream components of the MAPK pathway, B-Raf, and MEK kinases. The enhanced accumulation of phospho-ERKs is observed only in cells that have been stimulated with sphingosine 1-phosphate or protein growth factors; SU1498 by itself is ineffective. We show that the inhibitor acts by blocking the kinase activity of phospho-ERK both in a direct assay and in immunoprecipitates from cells treated with the compound. The data reveal a novel and unique way in which MAPK signaling pathway may be blocked in human endothelial cells.