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. 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
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Mancini, Dr Sarah and Gould, Professor Gwyn and Strembitska, Anastasiya and Salt, Dr Ian and Palmer, Dr Timothy
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 > Institute of Cardiovascular and Medical Sciences
College of Medical Veterinary and Life Sciences > Institute of Molecular Cell and Systems Biology
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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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
492453BHF 4 Year PhD ProgrammeAnna DominiczakBritish Heart Foundation (BHF)FS/11/79/29329RI CARDIOVASCULAR & MEDICAL SCIENCES
641891Inhibition of endothelial mitogen-activated protein kinases by amp-activated protein kinaseIan SaltBritish Heart Foundation (BHF)PG/13/82/30483RI CARDIOVASCULAR & MEDICAL SCIENCES
580311The sensitive assessment of the activity of cellular signalling pathways regulating insulin action and the cardiovascular complications of diabetesIan SaltDiabetes UK (DIABETESUK)11/0004309RI CARDIOVASCULAR & MEDICAL SCIENCES