VEGF stimulates activation of ERK5 in the absence of C-terminal phosphorylation preventing nuclear localization and facilitating AKT activation in endothelial cells
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2023-03Author
Mondru, A.K.Aljasir, M.A.
Alrumayh, A.
Nithianandarajah, G.N.
Ahmed, K.
Muller, Jurgen
Goldring, C.E.P.
Wilm, B.
Cross, M.J.
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© 2023 by the authors. 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/).Peer-Reviewed
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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.Version
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Mondru AK, Aljasir MA, Alrumayh A et al (2023) VEGF stimulates activation of ERK5 in the absence of C-terminal phosphorylation preventing nuclear localization and facilitating AKT activation in endothelial cells. Cells. 12(6): 967.Link to Version of Record
https://doi.org/10.3390/cells12060967Type
Articleae974a485f413a2113503eed53cd6c53
https://doi.org/10.3390/cells12060967