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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
Mondru, A.K. Aljasir, M.A. Alrumayh, A. Nithianandarajah, G.N. Ahmed, K. Muller, Jurgen Goldring, C.E.P. Wilm, B. Cross, M.J.
Mondru, A.K.
Aljasir, M.A.
Alrumayh, A.
Nithianandarajah, G.N.
Ahmed, K.
Muller, Jurgen
Goldring, C.E.P.
Wilm, B.
Cross, M.J.
Publication Date
2023-03
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© 2023 by the authors.
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2023-03-18
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Abstract
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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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.
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