PUBLICATION

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

Authors
Kempers, L., Wakayama, Y., van der Bijl, I., Furumaya, C., De Cuyper, I.M., Jongejan, A., Kat, M., van Stalborch, A.D., van Boxtel, A.L., Hubert, M., Geerts, D., van Buul, J.D., de Korte, D., Herzog, W., Margadant, C.
ID
ZDB-PUB-210514-9
Date
2021
Source
Angiogenesis   24(3): 695-714 (Journal)
Registered Authors
Herzog, Wiebke
Keywords
Early endosomes, Endolysosomal trafficking, Notch signaling, Rab GTPases, Rab5C, Sprouting angiogenesis, Tip cells, VEGF signaling, VEGFR2
MeSH Terms
  • Animals
  • Carrier Proteins/genetics
  • Carrier Proteins/metabolism*
  • Gene Expression Regulation*
  • Guanine Nucleotide Exchange Factors/genetics
  • Guanine Nucleotide Exchange Factors/metabolism*
  • Human Umbilical Vein Endothelial Cells/metabolism*
  • Humans
  • Neovascularization, Physiologic*
  • Proteolysis*
  • Vascular Endothelial Growth Factor Receptor-2/genetics
  • Vascular Endothelial Growth Factor Receptor-2/metabolism*
  • Zebrafish/genetics
  • Zebrafish/metabolism*
  • rab5 GTP-Binding Proteins/genetics
  • rab5 GTP-Binding Proteins/metabolism*
PubMed
33983539 Full text @ Angiogenesis
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.
Genes / Markers
Figures
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Expression
Phenotype
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping
Errata and Notes