The endosomal RIN2/Rab5C machinery prevents VEGFR2 degradation to control gene expression and tip cell identity during angiogenesis

Lanette Kempers, Yuki Wakayama, Ivo van der Bijl, Charita Furumaya, Iris M. de Cuyper, Aldo Jongejan, Marije Kat, Anne-Marieke D. van Stalborch, Antonius L. van Boxtel, Marvin Hubert, Dirk Geerts, Jaap D. van Buul, Dirk de Korte, Wiebke Herzog, Coert Margadant*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

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.
Original languageEnglish
JournalAngiogenesis
Early online date2021
DOIs
Publication statusE-pub ahead of print - 2021
Externally publishedYes

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