The interaction of endoglin with β-arrestin2 regulates transforming growth factor-β-mediated ERK activation and migration in endothelial cells
The interaction of endoglin with β-arrestin2 regulates transforming growth factor-β-mediated ERK activation and migration in endothelial cells
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DOI：
10.1074/jbc.m700176200
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发表时间：
2007-07-20
影响因子：
4.8
通讯作者：
Blobe, Gerard C.
中科院分区：
文献类型：
--
作者：
Lee, Nam Y.;Blobe, Gerard C.
在内皮细胞中，转化生长因子β（TGF-β）通过两种不同的途径（ALK-1/Smads 1/5/8途径和ALK-5/Smads 2/3途径）发出信号，调节内皮细胞增殖和迁移。通过这些途径的TGF-β信号传导在内皮细胞中由内皮特异性TGF-β超家族共受体内皮糖蛋白进一步调节。内皮糖蛋白、ALK-1和ALK-5在内皮生物学中的重要性通过小鼠中由于血管生成缺陷而敲除的胚胎致死表型以及在人类血管疾病中这些基因中存在致病突变而得到强调。然而，内皮糖蛋白的作用机制尚未明确。在这里，我们定义了一个新的内皮糖蛋白和支架蛋白β-arrestin 2之间的相互作用。免疫共沉淀和荧光共聚焦研究都证明了内皮糖蛋白和β-抑制蛋白2在内皮细胞中的特异性相互作用，ALK-1和II型TGF-β受体在较小程度上增强了这种相互作用。内皮糖蛋白/β-抑制蛋白2相互作用导致内皮糖蛋白内化以及内皮糖蛋白和β-抑制蛋白2在内吞囊泡中的共积累。尽管内皮糖蛋白对Smad 2/3或Smad 1/5/8的活化没有直接影响，但内皮糖蛋白拮抗TGF-β介导的ERK信号传导，改变活化的ERK的亚细胞分布，并以依赖于内皮糖蛋白与β-arrestin 2相互作用的能力的方式抑制内皮细胞迁移。反过来，小干扰RNA介导的内源性β-arrestin 2表达沉默恢复了TGF-β介导的ERK激活，并以内皮素依赖性方式增加了内皮细胞迁移。这些研究定义了endoglin的新功能，并进一步扩展了普遍存在的支架蛋白β-arrestin 2介导的作用。
In endothelial cells, transforming growth factor beta (TGF-beta) signals through two distinct pathways to regulate endothelial cell proliferation and migration, the ALK-1/Smads 1/5/8 pathway and the ALK-5/Smads 2/3 pathway. TGF-beta signaling through these pathways is further regulated in endothelial cells by the endothelial specific TGF-beta superfamily co-receptor, endoglin. The importance of endoglin, ALK-1, and ALK-5 in endothelial biology is underscored by the embryonic lethal phenotypes of knock-outs in mice due to defects in angiogenesis, and by the presence of disease-causing mutations in these genes in human vascular diseases. However, the mechanism of action of endoglin is not well defined. Here we define a novel interaction between endoglin and the scaffolding protein beta-arrestin2. Both co-immunoprecipitation and fluorescence confocal studies demonstrate the specific interaction between endoglin and beta-arrestin2 in endothelial cells, enhanced by ALK-1 and to a lesser extent by the type II TGF-beta receptor. The endoglin/beta-arrestin2 interaction results in endoglin internalization and co-accumulation of endoglin and beta-arrestin2 in endocytic vesicles. Whereas endoglin did not have a direct impact on either Smad 2/3 or Smad 1/5/8 activation, endoglin antagonized TGF-beta-mediated ERK signaling, altered the subcellular distribution of activated ERK, and inhibited endothelial cell migration in a manner dependent on the ability of endoglin to interact with beta-arrestin2. Reciprocally, small interfering RNA-mediated silencing of endogenous beta-arrestin2 expression restored TGF-beta-mediated ERK activation and increased endothelial cell migration in an endoglin-dependent manner. These studies define a novel function for endoglin, and further expand the roles mediated by the ubiquitous scaffolding protein beta-arrestin2.