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The inhibition of Bax activation-induced apoptosis by RasGRP2 via R-Ras-PI3K-Akt signaling pathway in the endothelial cells

Apoptosis of endothelial cells is a very important event in various diseases and angiogenesis. We recently reported that ras guanyl nucleotide releasing protein 2 (RasGRP2), which is a guanine nucleotide exchange factor, was expressed in the human umbilical vein endothelial cells (HUVECs) and that R...

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Autores principales: Takino, Jun-ichi, Sato, Takuma, Nagamine, Kentaro, Hori, Takamitsu
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6854084/
https://www.ncbi.nlm.nih.gov/pubmed/31723205
http://dx.doi.org/10.1038/s41598-019-53419-4
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author Takino, Jun-ichi
Sato, Takuma
Nagamine, Kentaro
Hori, Takamitsu
author_facet Takino, Jun-ichi
Sato, Takuma
Nagamine, Kentaro
Hori, Takamitsu
author_sort Takino, Jun-ichi
collection PubMed
description Apoptosis of endothelial cells is a very important event in various diseases and angiogenesis. We recently reported that ras guanyl nucleotide releasing protein 2 (RasGRP2), which is a guanine nucleotide exchange factor, was expressed in the human umbilical vein endothelial cells (HUVECs) and that Rap1 activation by its overexpression inhibited apoptosis by suppressing tumor necrosis factor-α induced-reactive oxygen species (ROS) production. However, other signaling pathways and roles of RasGRP2 not mediated via Rap1 are not well understood. Therefore, we compared the Mock (M) and the RasGRP2-stable overexpression (R) immortalized HUVECs using BAM7 and anisomycin, which are apoptosis inducers. BAM7 and anisomycin induced apoptosis without causing ROS production, and such apoptosis was significantly increased in M cells, but not in R cells. RasGRP2 suppressed BAM7- and anisomycin-induced apoptosis, but not via the Rap1 pathway as observed using Rap1 knockdown. Furthermore, RasGRP2 activated not only Rap1 but also R-Ras, and suppressed apoptosis by activating R-Ras-phosphoinositide 3-kinase (PI3K)-Akt signaling pathway. The phosphorylation of Akt by RasGRP2 inhibited Bax translocation by promoting translocation of hexokinase-2 (HK-2) from cytoplasm to mitochondria. Taken together, it was suggested that RasGRP2 suppresses the Bax activation-induced apoptosis by promoting HK-2 translocation to mitochondria via R-Ras-PI3K-Akt signaling pathway.
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spelling pubmed-68540842019-11-19 The inhibition of Bax activation-induced apoptosis by RasGRP2 via R-Ras-PI3K-Akt signaling pathway in the endothelial cells Takino, Jun-ichi Sato, Takuma Nagamine, Kentaro Hori, Takamitsu Sci Rep Article Apoptosis of endothelial cells is a very important event in various diseases and angiogenesis. We recently reported that ras guanyl nucleotide releasing protein 2 (RasGRP2), which is a guanine nucleotide exchange factor, was expressed in the human umbilical vein endothelial cells (HUVECs) and that Rap1 activation by its overexpression inhibited apoptosis by suppressing tumor necrosis factor-α induced-reactive oxygen species (ROS) production. However, other signaling pathways and roles of RasGRP2 not mediated via Rap1 are not well understood. Therefore, we compared the Mock (M) and the RasGRP2-stable overexpression (R) immortalized HUVECs using BAM7 and anisomycin, which are apoptosis inducers. BAM7 and anisomycin induced apoptosis without causing ROS production, and such apoptosis was significantly increased in M cells, but not in R cells. RasGRP2 suppressed BAM7- and anisomycin-induced apoptosis, but not via the Rap1 pathway as observed using Rap1 knockdown. Furthermore, RasGRP2 activated not only Rap1 but also R-Ras, and suppressed apoptosis by activating R-Ras-phosphoinositide 3-kinase (PI3K)-Akt signaling pathway. The phosphorylation of Akt by RasGRP2 inhibited Bax translocation by promoting translocation of hexokinase-2 (HK-2) from cytoplasm to mitochondria. Taken together, it was suggested that RasGRP2 suppresses the Bax activation-induced apoptosis by promoting HK-2 translocation to mitochondria via R-Ras-PI3K-Akt signaling pathway. Nature Publishing Group UK 2019-11-13 /pmc/articles/PMC6854084/ /pubmed/31723205 http://dx.doi.org/10.1038/s41598-019-53419-4 Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Takino, Jun-ichi
Sato, Takuma
Nagamine, Kentaro
Hori, Takamitsu
The inhibition of Bax activation-induced apoptosis by RasGRP2 via R-Ras-PI3K-Akt signaling pathway in the endothelial cells
title The inhibition of Bax activation-induced apoptosis by RasGRP2 via R-Ras-PI3K-Akt signaling pathway in the endothelial cells
title_full The inhibition of Bax activation-induced apoptosis by RasGRP2 via R-Ras-PI3K-Akt signaling pathway in the endothelial cells
title_fullStr The inhibition of Bax activation-induced apoptosis by RasGRP2 via R-Ras-PI3K-Akt signaling pathway in the endothelial cells
title_full_unstemmed The inhibition of Bax activation-induced apoptosis by RasGRP2 via R-Ras-PI3K-Akt signaling pathway in the endothelial cells
title_short The inhibition of Bax activation-induced apoptosis by RasGRP2 via R-Ras-PI3K-Akt signaling pathway in the endothelial cells
title_sort inhibition of bax activation-induced apoptosis by rasgrp2 via r-ras-pi3k-akt signaling pathway in the endothelial cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6854084/
https://www.ncbi.nlm.nih.gov/pubmed/31723205
http://dx.doi.org/10.1038/s41598-019-53419-4
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