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The endosomal RIN2/Rab5C machinery prevents VEGFR2 degradation to control gene expression and tip cell identity during angiogenesis
Angiogenesis ( IF 9.2 ) Pub Date : 2021-05-13 , DOI: 10.1007/s10456-021-09788-4
Lanette Kempers 1 , Yuki Wakayama 2 , Ivo van der Bijl 1 , Charita Furumaya 1 , Iris M De Cuyper 1 , Aldo Jongejan 3 , Marije Kat 1 , Anne-Marieke D van Stalborch 1 , Antonius L van Boxtel 4, 5 , Marvin Hubert 6 , Dirk Geerts 7 , Jaap D van Buul 1 , Dirk de Korte 1, 8 , Wiebke Herzog 2, 6 , Coert Margadant 9
Affiliation  

Sprouting angiogenesis is key to many pathophysiological conditions, and is strongly regulated by vascular endothelial growth factor (VEGF) signaling through VEGF receptor 2 (VEGFR2). Here we report that the early endosomal GTPase Rab5C and its activator RIN2 prevent lysosomal routing and degradation of VEGF-bound, internalized VEGFR2 in human endothelial cells. Stabilization of endosomal VEGFR2 levels by RIN2/Rab5C is crucial for VEGF signaling through the ERK and PI3-K pathways, the expression of immediate VEGF target genes, as well as specification of angiogenic ‘tip’ and ‘stalk’ cell phenotypes and cell sprouting. Using overexpression of Rab mutants, knockdown and CRISPR/Cas9-mediated gene editing, and live-cell imaging in zebrafish, we further show that endosomal stabilization of VEGFR2 levels is required for developmental angiogenesis in vivo. In contrast, the premature degradation of internalized VEGFR2 disrupts VEGF signaling, gene expression, and tip cell formation and migration. Thus, an endosomal feedforward mechanism maintains receptor signaling by preventing lysosomal degradation, which is directly linked to the induction of target genes and cell fate in collectively migrating cells during morphogenesis.



中文翻译:

内体 RIN2/Rab5C 机制可防止 VEGFR2 降解以控制血管生成过程中的基因表达和提示细胞身份

发芽血管生成是许多病理生理状况的关键,并且受到血管内皮生长因子 (VEGF) 信号通过 VEGF 受体 2 (VEGFR2) 的强烈调节。在这里,我们报告早期内体 GTPase Rab5C 及其激活剂 RIN2 可防止溶酶体路径和人内皮细胞中 VEGF 结合的内化 VEGFR2 的降解。RIN2/Rab5C 稳定内体 VEGFR2 水平对于通过 ERK 和 PI3-K 通路的 VEGF 信号传导、直接 VEGF 靶基因的表达以及血管生成“尖端”和“茎”细胞表型和细胞发芽的规范至关重要。利用 Rab 突变体的过表达、敲低和 CRISPR/Cas9 介导的基因编辑以及斑马鱼的活细胞成像,我们进一步表明 VEGFR2 水平的内体稳定是体内发育性血管生成所必需的。相比之下,内化 VEGFR2 的过早降解会破坏 VEGF 信号传导、基因表达以及尖端细胞的形成和迁移。因此,内体前馈机制通过防止溶酶体降解来维持受体信号传导,这与形态发生过程中集体迁移细胞中靶基因的诱导和细胞命运直接相关。

更新日期:2021-05-13
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