RhoGEF17—An Essential Regulator of Endothelial Cell Death and Growth

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 subse...

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Autores principales: Weber, Pamina, Baltus, Doris, Jatho, Aline, Drews, Oliver, Zelarayan, Laura C., Wieland, Thomas, Lutz, Susanne
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8067313/
https://www.ncbi.nlm.nih.gov/pubmed/33801779
http://dx.doi.org/10.3390/cells10040741
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author Weber, Pamina
Baltus, Doris
Jatho, Aline
Drews, Oliver
Zelarayan, Laura C.
Wieland, Thomas
Lutz, Susanne
author_facet Weber, Pamina
Baltus, Doris
Jatho, Aline
Drews, Oliver
Zelarayan, Laura C.
Wieland, Thomas
Lutz, Susanne
author_sort Weber, Pamina
collection PubMed
description 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.
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spelling pubmed-80673132021-04-25 RhoGEF17—An Essential Regulator of Endothelial Cell Death and Growth Weber, Pamina Baltus, Doris Jatho, Aline Drews, Oliver Zelarayan, Laura C. Wieland, Thomas Lutz, Susanne Cells Article 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. MDPI 2021-03-27 /pmc/articles/PMC8067313/ /pubmed/33801779 http://dx.doi.org/10.3390/cells10040741 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) ).
spellingShingle Article
Weber, Pamina
Baltus, Doris
Jatho, Aline
Drews, Oliver
Zelarayan, Laura C.
Wieland, Thomas
Lutz, Susanne
RhoGEF17—An Essential Regulator of Endothelial Cell Death and Growth
title RhoGEF17—An Essential Regulator of Endothelial Cell Death and Growth
title_full RhoGEF17—An Essential Regulator of Endothelial Cell Death and Growth
title_fullStr RhoGEF17—An Essential Regulator of Endothelial Cell Death and Growth
title_full_unstemmed RhoGEF17—An Essential Regulator of Endothelial Cell Death and Growth
title_short RhoGEF17—An Essential Regulator of Endothelial Cell Death and Growth
title_sort rhogef17—an essential regulator of endothelial cell death and growth
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8067313/
https://www.ncbi.nlm.nih.gov/pubmed/33801779
http://dx.doi.org/10.3390/cells10040741
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