VEGF stimulates activation of ERK5 in the absence of C-terminal phosphorylation preventing nuclear localization and facilitating AKT activation in endothelial cells
| Autor: | 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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| Jazyk: | angličtina |
| Rok vydání: | 2023 |
| Předmět: | |
| Druh dokumentu: | Článek |
| DOI: | 10.3390/cells12060967 |
| Popis: | Yes 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. This research was funded by grants from: North West Cancer Research (NWCR): M.J.C. and A.K.M.; Medical Research Council (MRC DiMeN PhD): M.J.C. and K.A.; Biotechnology and Biological Sciences Research Council (BBSRC DTG Studentship): M.J.C., C.E.P.G., B.W. and G.N.N.; and Wellcome Trust Institutional Strategic Fund: M.J.C. and A.K.M. |
| Databáze: | Networked Digital Library of Theses & Dissertations |
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