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VEGF Stimulates Activation of ERK5 in the Absence of C-Terminal Phosphorylation Preventing Nuclear Localization and Facilitating AKT Activation in Endothelial Cells

Extracellular-signal-regulated kinase 5 (ERK5) is critical for normal cardiovascular development. Previous studies have defined a canonical pathway for ERK5 activation, showing that ligand stimulation leads to MEK5 activation resulting in dual phosphorylation of ERK5 on Thr218/Tyr220 residues within...

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Autores principales: Mondru, Anil Kumar, Aljasir, Mohammad A., Alrumayh, Ahmed, Nithianandarajah, Gopika N., Ahmed, Katie, Muller, Jurgen, Goldring, Christopher E. P., Wilm, Bettina, Cross, Michael J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10047687/
https://www.ncbi.nlm.nih.gov/pubmed/36980305
http://dx.doi.org/10.3390/cells12060967
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author Mondru, Anil Kumar
Aljasir, Mohammad A.
Alrumayh, Ahmed
Nithianandarajah, Gopika N.
Ahmed, Katie
Muller, Jurgen
Goldring, Christopher E. P.
Wilm, Bettina
Cross, Michael J.
author_facet Mondru, Anil Kumar
Aljasir, Mohammad A.
Alrumayh, Ahmed
Nithianandarajah, Gopika N.
Ahmed, Katie
Muller, Jurgen
Goldring, Christopher E. P.
Wilm, Bettina
Cross, Michael J.
author_sort Mondru, Anil Kumar
collection PubMed
description Extracellular-signal-regulated kinase 5 (ERK5) is critical for normal cardiovascular development. Previous studies have defined a canonical pathway for ERK5 activation, showing that ligand stimulation leads to MEK5 activation resulting in dual phosphorylation of ERK5 on Thr218/Tyr220 residues within the activation loop. ERK5 then undergoes a conformational change, facilitating phosphorylation on residues in the C-terminal domain and translocation to the nucleus where it regulates MEF2 transcriptional activity. Our previous research into the importance of ERK5 in endothelial cells highlighted its role in VEGF-mediated tubular morphogenesis and cell survival, suggesting that ERK5 played a unique role in endothelial cells. Our current data show that in contrast to EGF-stimulated HeLa cells, VEGF-mediated ERK5 activation in human dermal microvascular endothelial cells (HDMECs) does not result in C-terminal phosphorylation of ERK5 and translocation to the nucleus, but instead to a more plasma membrane/cytoplasmic localisation. Furthermore, the use of small-molecule inhibitors to MEK5 and ERK5 shows that instead of regulating MEF2 activity, VEGF-mediated ERK5 is important for regulating AKT activity. Our data define a novel pathway for ERK5 activation in endothelial cells leading to cell survival.
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spelling pubmed-100476872023-03-29 VEGF Stimulates Activation of ERK5 in the Absence of C-Terminal Phosphorylation Preventing Nuclear Localization and Facilitating AKT Activation in Endothelial Cells Mondru, Anil Kumar Aljasir, Mohammad A. Alrumayh, Ahmed Nithianandarajah, Gopika N. Ahmed, Katie Muller, Jurgen Goldring, Christopher E. P. Wilm, Bettina Cross, Michael J. Cells Article Extracellular-signal-regulated kinase 5 (ERK5) is critical for normal cardiovascular development. Previous studies have defined a canonical pathway for ERK5 activation, showing that ligand stimulation leads to MEK5 activation resulting in dual phosphorylation of ERK5 on Thr218/Tyr220 residues within the activation loop. ERK5 then undergoes a conformational change, facilitating phosphorylation on residues in the C-terminal domain and translocation to the nucleus where it regulates MEF2 transcriptional activity. Our previous research into the importance of ERK5 in endothelial cells highlighted its role in VEGF-mediated tubular morphogenesis and cell survival, suggesting that ERK5 played a unique role in endothelial cells. Our current data show that in contrast to EGF-stimulated HeLa cells, VEGF-mediated ERK5 activation in human dermal microvascular endothelial cells (HDMECs) does not result in C-terminal phosphorylation of ERK5 and translocation to the nucleus, but instead to a more plasma membrane/cytoplasmic localisation. Furthermore, the use of small-molecule inhibitors to MEK5 and ERK5 shows that instead of regulating MEF2 activity, VEGF-mediated ERK5 is important for regulating AKT activity. Our data define a novel pathway for ERK5 activation in endothelial cells leading to cell survival. MDPI 2023-03-22 /pmc/articles/PMC10047687/ /pubmed/36980305 http://dx.doi.org/10.3390/cells12060967 Text en © 2023 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 (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Mondru, Anil Kumar
Aljasir, Mohammad A.
Alrumayh, Ahmed
Nithianandarajah, Gopika N.
Ahmed, Katie
Muller, Jurgen
Goldring, Christopher E. P.
Wilm, Bettina
Cross, Michael J.
VEGF Stimulates Activation of ERK5 in the Absence of C-Terminal Phosphorylation Preventing Nuclear Localization and Facilitating AKT Activation in Endothelial Cells
title VEGF Stimulates Activation of ERK5 in the Absence of C-Terminal Phosphorylation Preventing Nuclear Localization and Facilitating AKT Activation in Endothelial Cells
title_full VEGF Stimulates Activation of ERK5 in the Absence of C-Terminal Phosphorylation Preventing Nuclear Localization and Facilitating AKT Activation in Endothelial Cells
title_fullStr VEGF Stimulates Activation of ERK5 in the Absence of C-Terminal Phosphorylation Preventing Nuclear Localization and Facilitating AKT Activation in Endothelial Cells
title_full_unstemmed VEGF Stimulates Activation of ERK5 in the Absence of C-Terminal Phosphorylation Preventing Nuclear Localization and Facilitating AKT Activation in Endothelial Cells
title_short VEGF Stimulates Activation of ERK5 in the Absence of C-Terminal Phosphorylation Preventing Nuclear Localization and Facilitating AKT Activation in Endothelial Cells
title_sort vegf stimulates activation of erk5 in the absence of c-terminal phosphorylation preventing nuclear localization and facilitating akt activation in endothelial cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10047687/
https://www.ncbi.nlm.nih.gov/pubmed/36980305
http://dx.doi.org/10.3390/cells12060967
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