Heathcote, H. R., Mancini, S. J., Strembitska, A., Jamal, K., Reihill, J. A., Palmer, T. M., Gould, G. W. and Salt, I. P. (2016) Protein kinase C phosphorylates AMP-activated protein kinase α1 Ser487. Biochemical Journal, 473(24), pp. 4681-4697. (doi: 10.1042/BCJ20160211) (PMID:27784766) (PMCID:PMC5147050)
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Abstract
The key metabolic regulator, AMP-activated protein kinase (AMPK) is reported to be downregulated 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.
Item Type: | Articles |
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Status: | Published |
Refereed: | Yes |
Glasgow Author(s) Enlighten ID: | Palmer, Dr Timothy and Mancini, Dr Sarah and Gould, Professor Gwyn and Salt, Dr Ian and Strembitska, Anastasiya |
Authors: | Heathcote, H. R., Mancini, S. J., Strembitska, A., Jamal, K., Reihill, J. A., Palmer, T. M., Gould, G. W., and Salt, I. P. |
College/School: | College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health College of Medical Veterinary and Life Sciences > School of Molecular Biosciences |
Journal Name: | Biochemical Journal |
Publisher: | Portland Press Ltd. |
ISSN: | 0264-6021 |
ISSN (Online): | 1470-8728 |
Published Online: | 26 October 2016 |
Copyright Holders: | Copyright © 2016 The Authors |
First Published: | First published in Biochemical Journal 473(24):4681-4697 |
Publisher Policy: | Reproduced under a Creative Commons License |
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