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Open AccessArticle

RhoGEF17—An Essential Regulator of Endothelial Cell Death and Growth

1
Experimental Pharmacology Mannheim (EPM), European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Ludolf-Krehl-Str. 13-17, 68167 Mannheim, Germany
2
Institute of Pharmacology and Toxicology, University Medical Center Göttingen, Robert-Koch-Strasse 40, 37075 Göttingen, Germany
3
DZHK (German Center for Cardiovascular Research) Partner Site Göttingen, Göttingen, Germany
4
Institute for Clinical Chemistry, Medical Faculty Mannheim, Heidelberg University, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany
5
DZHK (German Center for Cardiovascular Research) Partner Site Heidelberg/Mannheim, Mannheim, Germany
*
Authors to whom correspondence should be addressed.
These authors share senior authorship.
Academic Editors: Alexander E. Kalyuzhny and Cord Brakebusch
Cells 2021, 10(4), 741; https://doi.org/10.3390/cells10040741
Received: 15 February 2021 / Revised: 15 March 2021 / Accepted: 20 March 2021 / Published: 27 March 2021
(This article belongs to the Section Cell Signaling and Regulated Cell Death)
The Rho guanine nucleotide exchange factor RhoGEF17 was described to reside in adherens junctions (AJ) in endothelial cells (EC) and to play a critical role in the regulation of cell adhesion and barrier function. The purpose of this study was to analyze signal cascades and processes occurring subsequent to AJ disruption induced by RhoGEF17 knockdown. Primary human and immortalized rat EC were used to demonstrate that an adenoviral-mediated knockdown of RhoGEF17 resulted in cell rounding and an impairment in spheroid formation due to an enhanced proteasomal degradation of AJ components. In contrast, β-catenin degradation was impaired, which resulted in an induction of the β-catenin-target genes cyclin D1 and survivin. RhoGEF17 depletion additionally inhibited cell adhesion and sheet migration. The RhoGEF17 knockdown prevented the cells with impeded cell–cell and cell–matrix contacts from apoptosis, which was in line with a reduction in pro-caspase 3 expression and an increase in Akt phosphorylation. Nevertheless, the cells were not able to proliferate as a cell cycle block occurred. In summary, we demonstrate that a loss of RhoGEF17 disturbs cell–cell and cell–substrate interaction in EC. Moreover, it prevents the EC from cell death and blocks cell proliferation. Non-canonical β-catenin signaling and Akt activation could be identified as a potential mechanism. View Full-Text
Keywords: rho guanine nucleotide exchange factor; adherens junction complex; endothelial cell; non-canonical β-catenin signaling; anchorage-dependent cell death rho guanine nucleotide exchange factor; adherens junction complex; endothelial cell; non-canonical β-catenin signaling; anchorage-dependent cell death
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MDPI and ACS Style

Weber, P.; Baltus, D.; Jatho, A.; Drews, O.; Zelarayan, L.C.; Wieland, T.; Lutz, S. RhoGEF17—An Essential Regulator of Endothelial Cell Death and Growth. Cells 2021, 10, 741. https://doi.org/10.3390/cells10040741

AMA Style

Weber P, Baltus D, Jatho A, Drews O, Zelarayan LC, Wieland T, Lutz S. RhoGEF17—An Essential Regulator of Endothelial Cell Death and Growth. Cells. 2021; 10(4):741. https://doi.org/10.3390/cells10040741

Chicago/Turabian Style

Weber, Pamina; Baltus, Doris; Jatho, Aline; Drews, Oliver; Zelarayan, Laura C.; Wieland, Thomas; Lutz, Susanne. 2021. "RhoGEF17—An Essential Regulator of Endothelial Cell Death and Growth" Cells 10, no. 4: 741. https://doi.org/10.3390/cells10040741

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