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    Protein kinase C phosphorylates AMP-activated protein kinase α1 Ser487

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    Publication date
    2016
    Author
    Heathcote, H.R.
    Mancini, S.J.
    Strembitska, A.
    Jamal, K.
    Reihill, J.A.
    Palmer, Timothy M.
    Gould, G.W.
    Salt, I.P.
    Keyword
    AMP-activated protein kinase (AMPK); AMPKα1/α2 catalytic subunit isoforms; Ser487/491
    Rights
    © 2016 The Authors. This is an open access article published by Portland Press Limited on behalf of the Biochemical Society and distributed under the Creative Commons Attribution License 4.0 (CC BY).
    Peer-Reviewed
    yes
    
    Metadata
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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.
    URI
    http://hdl.handle.net/10454/10904
    Version
    Published version
    Citation
    Heathcote HR, Mancini SJ, Strembitska A, Jamala K, Reihill JA, Palmer TM, Gould GW, Salt IP (2016) Protein kinase C phosphorylates AMP-activated protein kinase α1 Ser487. Biochemical Journal. 473: 4681–4697.
    Link to publisher’s version
    http://dx.doi.org/10.1042/BCJ20160211
    Type
    Article
    Collections
    Life Sciences Publications

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