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The NADPH oxidase NOX4 promotes the directed migration of endothelial cells by stabilizing vascular endothelial growth factor receptor 2 protein.
Journal of Biological Chemistry ( IF 4.0 ) Pub Date : 2020-08-14 , DOI: 10.1074/jbc.ra120.014723
Kei Miyano 1 , Shuichiro Okamoto 1 , Akira Yamauchi 2 , Chikage Kawai 2 , Mizuho Kajikawa 3 , Takuya Kiyohara 4 , Minoru Tamura 5 , Masahiko Taura 6 , Futoshi Kuribayashi 2
Affiliation  

Directed migration of endothelial cells (ECs) is an important process during both physiological and pathological angiogenesis. The binding of vascular endothelial growth factor (VEGF) to VEGF receptor-2 (VEGFR-2) on the EC surface is necessary for directed migration of these cells. Here, we used TAXIScan, an optically accessible real-time horizontal cell dynamics assay approach, and demonstrate that reactive oxygen species (ROS)-producing NADPH oxidase 4 (NOX4), which is abundantly expressed in ECs, mediates VEGF/VEGFR-2-dependent directed migration. We noted that a continuous supply of endoplasmic reticulum (ER)-retained VEGFR-2 to the plasma membrane is required to maintain VEGFR-2 at the cell surface. siRNA-mediated NOX4 silencing decreased the ER-retained form of VEGFR-2, resulting in decreased cell surface expression levels of the receptor. We also found that ER-localized NOX4 interacts with ER-retained VEGFR-2 and thereby stabilizes this ER-retained form at the protein level in the ER. We conclude that NOX4 contributes to the directed migration of ECs by maintaining VEGFR-2 levels at their surface.

中文翻译:

NADPH氧化酶NOX4通过稳定血管内皮生长因子受体2蛋白来促进内皮细胞的定向迁移。

内皮细胞 (EC) 的定向迁移是生理和病理血管生成过程中的一个重要过程。血管内皮生长因子 (VEGF) 与 EC 表面上的 VEGF 受体-2 (VEGFR-2) 的结合是这些细胞定向迁移所必需的。在这里,我们使用了 TAXIScan,一种光学可及的实时水平细胞动力学测定方法,并证明产生活性氧 (ROS) 的 NADPH 氧化酶 4 (NOX4),在 ECs 中大量表达,介导 VEGF/VEGFR-2-依赖定向迁移。我们注意到,需要向质膜持续供应内质网 (ER) 保留的 VEGFR-2,以将 VEGFR-2 维持在细胞表面。siRNA 介导的 NOX4 沉默减少了内质网保留形式的 VEGFR-2,导致受体的细胞表面表达水平降低。我们还发现 ER 定位的 NOX4 与 ER 保留的 VEGFR-2 相互作用,从而在 ER 的蛋白质水平上稳定这种 ER 保留的形式。我们得出结论,NOX4 通过维持其表面的 VEGFR-2 水平促进 EC 的定向迁移。
更新日期:2020-08-14
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