@article{fec28d17ac7d465cbaa4d57d77a244d1,
title = "The endosomal RIN2/Rab5C machinery prevents VEGFR2 degradation to control gene expression and tip cell identity during 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 {\textquoteleft}tip{\textquoteright} and {\textquoteleft}stalk{\textquoteright} 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.",
keywords = "Early endosomes, Endolysosomal trafficking, Notch signaling, Rab GTPases, Rab5C, Sprouting angiogenesis, Tip cells, VEGF signaling, VEGFR2",
author = "Lanette Kempers and Yuki Wakayama and {van der Bijl}, Ivo and Charita Furumaya and {de Cuyper}, {Iris M.} and Aldo Jongejan and Marije Kat and {van Stalborch}, {Anne-Marieke D.} and {van Boxtel}, {Antonius L.} and Marvin Hubert and Dirk Geerts and {van Buul}, {Jaap D.} and {de Korte}, Dirk and Wiebke Herzog and Coert Margadant",
note = "Funding Information: We thank Arnoud Sonnenberg (Department of Cell Biology, Netherlands Cancer Institute, Amsterdam), Ben Morris and Roderick Beijersbergen (Robotics and Screening Center, Netherlands Cancer Institute, Amsterdam) and Nathan Lawson (UMass Medical School, Worcester, MA) for their kind gifts of materials. We gratefully acknowledge technical support from Paul Verkuijlen (Sanquin Research, Amsterdam), Simon Tol, Mark Hoogenboezen, and Erik Mul (Central Facility, Sanquin Research, Amsterdam), Lenny Brocks and Marjolijn Mertz (Digital microscopy facility, Netherlands Cancer Institute, Amsterdam), and Linda Koster (Sequencing core facility, Amsterdam University Medical Centers, Amsterdam). We thank Arnoud Sonnenberg for critical reading. This work was supported by research grants from the Netherlands Organisation for Scientific Research (ZonMW Veni 016.146.160) and the Dutch Thrombosis Foundation (2017-01) awarded to CM, Sanquin (PPOC 14-43) awarded to DdK, the Japan Society for the Promotion of Science Overseas Researcher Fellowships awarded to YW, and the Deutsche Forschungsgemeinschaft (HE4585/3-1), awarded to WH. We further acknowledge support from the Dutch Society for Cell Biology. Funding Information: We thank Arnoud Sonnenberg (Department of Cell Biology, Netherlands Cancer Institute, Amsterdam), Ben Morris and Roderick Beijersbergen (Robotics and Screening Center, Netherlands Cancer Institute, Amsterdam) and Nathan Lawson (UMass Medical School, Worcester, MA) for their kind gifts of materials. We gratefully acknowledge technical support from Paul Verkuijlen (Sanquin Research, Amsterdam), Simon Tol, Mark Hoogenboezen, and Erik Mul (Central Facility, Sanquin Research, Amsterdam), Lenny Brocks and Marjolijn Mertz (Digital microscopy facility, Netherlands Cancer Institute, Amsterdam), and Linda Koster (Sequencing core facility, Amsterdam University Medical Centers, Amsterdam). We thank Arnoud Sonnenberg for critical reading. This work was supported by research grants from the Netherlands Organisation for Scientific Research (ZonMW Veni 016.146.160) and the Dutch Thrombosis Foundation (2017-01) awarded to CM, Sanquin (PPOC 14-43) awarded to DdK, the Japan Society for the Promotion of Science Overseas Researcher Fellowships awarded to YW, and the Deutsche Forschungsgemeinschaft (HE4585/3-1), awarded to WH. We further acknowledge support from the Dutch Society for Cell Biology. Publisher Copyright: {\textcopyright} 2021, The Author(s). Copyright: Copyright 2021 Elsevier B.V., All rights reserved.",
year = "2021",
month = aug,
doi = "https://doi.org/10.1007/s10456-021-09788-4",
language = "English",
volume = "24",
pages = "695--714",
journal = "Angiogenesis",
issn = "0969-6970",
publisher = "Springer Netherlands",
number = "3",
}