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FGD5 sustains vascular endothelial growth factor A (VEGFA) signaling through inhibition of proteasome-mediated VEGF receptor 2 degradation
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. (Farmaceutisk cellbiologi och bioteknologi)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.ORCID iD: 0000-0003-3117-5367
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
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2017 (English)In: Cellular Signalling, ISSN 0898-6568, E-ISSN 1873-3913, Vol. 40, p. 125-132Article in journal (Refereed) Published
Abstract [en]

The complete repertoire of endothelial functions elicited by FGD5, a guanine nucleotide exchange factor activating the Rho GTPase Cdc42, has yet to be elucidated. Here we explore FGD5's importance during vascular endothelial growth factor A (VEGFA) signaling via VEGF receptor 2 (VEGFR2) in human endothelial cells. In microvascular endothelial cells, FGD5 is located at the inner surface of the cell membrane as well as at the outer surface of EEAl-positive endosomes carrying VEGFR2. The latter finding prompted us to explore if FGD5 regulates VEGFR2 dynamics. We found that depletion of FGD5 in microvascular cells inhibited their migration towards a stable VEGFA gradient. Furthermore, depletion of FGD5 resulted in accelerated VEGFR2 degradation, which was reverted by lactacystin-mediated proteasomal inhibition. Our results thus suggest a mechanism whereby FGD5 sustains VEGFA signaling and endothelial cell chemotaxis via inhibition of proteasome-dependent VEGFR2 degradation.

Place, publisher, year, edition, pages
2017. Vol. 40, p. 125-132
Keywords [en]
Angiogenesis, Cdc42, FGD5, Vascular biology, VEGFR2, Degradation
National Category
Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:uu:diva-341984DOI: 10.1016/j.cellsig.2017.09.009ISI: 000414620900013PubMedID: 28927665OAI: oai:DiVA.org:uu-341984DiVA, id: diva2:1183773
Available from: 2018-02-19 Created: 2018-02-19 Last updated: 2018-02-19Bibliographically approved

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Heldin, JohanO'Callaghan, PaulHernández Vera, RodrigoFredlund Fuchs, PederGerwins, PärKreuger, Johan

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Heldin, JohanO'Callaghan, PaulHernández Vera, RodrigoFredlund Fuchs, PederGerwins, PärKreuger, Johan
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Department of Pharmaceutical BiosciencesDepartment of Medical Cell Biology
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Cellular Signalling
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