The endosomal RIN2/Rab5C machinery prevents VEGFR2 degradation to control gene expression and tip cell identity during angiogenesis.
Animals
Carrier Proteins
/ genetics
Gene Expression Regulation
Guanine Nucleotide Exchange Factors
/ genetics
Human Umbilical Vein Endothelial Cells
/ metabolism
Humans
Neovascularization, Physiologic
Proteolysis
Vascular Endothelial Growth Factor Receptor-2
/ genetics
Zebrafish
/ genetics
rab5 GTP-Binding Proteins
/ genetics
Early endosomes
Endolysosomal trafficking
Notch signaling
Rab GTPases
Rab5C
Sprouting angiogenesis
Tip cells
VEGF signaling
VEGFR2
Journal
Angiogenesis
ISSN: 1573-7209
Titre abrégé: Angiogenesis
Pays: Germany
ID NLM: 9814575
Informations de publication
Date de publication:
08 2021
08 2021
Historique:
received:
28
11
2020
accepted:
05
03
2021
pubmed:
14
5
2021
medline:
15
1
2022
entrez:
13
5
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 33983539
doi: 10.1007/s10456-021-09788-4
pii: 10.1007/s10456-021-09788-4
pmc: PMC8292304
doi:
Substances chimiques
Carrier Proteins
0
Guanine Nucleotide Exchange Factors
0
RIN2 protein, human
0
KDR protein, human
EC 2.7.10.1
Vascular Endothelial Growth Factor Receptor-2
EC 2.7.10.1
RAB5C protein, human
EC 3.6.1.-
Rab5c protein, zebrafish
EC 3.6.1.-
rab5 GTP-Binding Proteins
EC 3.6.5.2
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
695-714Subventions
Organisme : NCI NIH HHS
ID : P30 CA008748
Pays : United States
Informations de copyright
© 2021. The Author(s).
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