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Protein kinase C phosphorylates AMP-Activated protein kinase α1 Ser487

Heathcote, H. R.; Mancini, S. J.; Strembitska, A.; Jamal, K.; Reihill, J. A.; Palmer, T. M.; Gould, G. W.; Salt, I. P.

Authors

H. R. Heathcote

S. J. Mancini

A. Strembitska

K. Jamal

J. A. Reihill

G. W. Gould

I. P. Salt



Contributors

Abstract

The key metabolic regulator, AMP-activated protein kinase (AMPK), is reported to be down-regulated in metabolic disorders, but the mechanisms are poorly characterised. Recent studies have identified phosphorylation of the AMPKα1/α2 catalytic subunit isoforms at Ser487/491, respectively, as an inhibitory regulation mechanism. Vascular endothelial growth factor (VEGF) stimulates AMPK and protein kinase B (Akt) in cultured human endothelial cells. As Akt has been demonstrated to be an AMPKα1 Ser487 kinase, the effect of VEGF on inhibitory AMPK phosphorylation in cultured primary human endothelial cells was examined. Stimulation of endothelial cells with VEGF rapidly increased AMPKα1 Ser487 phosphorylation in an Akt-independent manner, without altering AMPKα2 Ser491 phosphorylation. In contrast, VEGF-stimulated AMPKα1 Ser487 phosphorylation was sensitive to inhibitors of protein kinase C (PKC) and PKC activation using phorbol esters or overexpression of PKC-stimulated AMPKα1 Ser487 phosphorylation. Purified PKC and Akt both phosphorylated AMPKα1 Ser487 in vitro with similar efficiency. PKC activation was associated with reduced AMPK activity, as inhibition of PKC increased AMPK activity and phorbol esters inhibited AMPK, an effect lost in cells expressing mutant AMPKα1 Ser487Ala. Consistent with a pathophysiological role for this modification, AMPKα1 Ser487 phosphorylation was inversely correlated with insulin sensitivity in human muscle. These data indicate a novel regulatory role of PKC to inhibit AMPKα1 in human cells. As PKC activation is associated with insulin resistance and obesity, PKC may underlie the reduced AMPK activity reported in response to overnutrition in insulin-resistant metabolic and vascular tissues.

Citation

Heathcote, H. R., Mancini, S. J., Strembitska, A., Jamal, K., Reihill, J. A., Palmer, T. M., …Salt, I. P. (2016). Protein kinase C phosphorylates AMP-Activated protein kinase α1 Ser487. Biochemical Journal, 473(24), 4681-4697. https://doi.org/10.1042/BCJ20160211

Journal Article Type Article
Acceptance Date Oct 25, 2016
Online Publication Date Dec 9, 2016
Publication Date Dec 15, 2016
Deposit Date Oct 30, 2018
Publicly Available Date Mar 29, 2024
Journal Biochemical Journal
Print ISSN 1470-8728
Electronic ISSN 1470-8728
Publisher Portland Press
Peer Reviewed Peer Reviewed
Volume 473
Issue 24
Pages 4681-4697
DOI https://doi.org/10.1042/BCJ20160211
Keywords AMPK; Protein kinase C; Vascular endothelial growth factor
Public URL https://hull-repository.worktribe.com/output/1137505
Publisher URL http://www.biochemj.org/content/473/24/4681

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