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Protein kinase C phosphorylates AMP-activated protein kinase α1 Ser487
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 inhibi...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Portland Press Ltd.
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5147050/ https://www.ncbi.nlm.nih.gov/pubmed/27784766 http://dx.doi.org/10.1042/BCJ20160211 |
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author | Heathcote, Helen R. Mancini, Sarah J. Strembitska, Anastasiya Jamal, Kunzah Reihill, James A. Palmer, Timothy M. Gould, Gwyn W. Salt, Ian P. |
author_facet | Heathcote, Helen R. Mancini, Sarah J. Strembitska, Anastasiya Jamal, Kunzah Reihill, James A. Palmer, Timothy M. Gould, Gwyn W. Salt, Ian P. |
author_sort | Heathcote, Helen R. |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-5147050 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Portland Press Ltd. |
record_format | MEDLINE/PubMed |
spelling | pubmed-51470502016-12-23 Protein kinase C phosphorylates AMP-activated protein kinase α1 Ser487 Heathcote, Helen R. Mancini, Sarah J. Strembitska, Anastasiya Jamal, Kunzah Reihill, James A. Palmer, Timothy M. Gould, Gwyn W. Salt, Ian P. Biochem J Research Articles 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. Portland Press Ltd. 2016-12-15 2016-12-09 /pmc/articles/PMC5147050/ /pubmed/27784766 http://dx.doi.org/10.1042/BCJ20160211 Text en © 2016 The Author(s) https://creativecommons.org/licenses/by/4.0/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) (https://creativecommons.org/licenses/by/4.0) . |
spellingShingle | Research Articles Heathcote, Helen R. Mancini, Sarah J. Strembitska, Anastasiya Jamal, Kunzah Reihill, James A. Palmer, Timothy M. Gould, Gwyn W. Salt, Ian P. Protein kinase C phosphorylates AMP-activated protein kinase α1 Ser487 |
title | Protein kinase C phosphorylates AMP-activated protein kinase α1 Ser487 |
title_full | Protein kinase C phosphorylates AMP-activated protein kinase α1 Ser487 |
title_fullStr | Protein kinase C phosphorylates AMP-activated protein kinase α1 Ser487 |
title_full_unstemmed | Protein kinase C phosphorylates AMP-activated protein kinase α1 Ser487 |
title_short | Protein kinase C phosphorylates AMP-activated protein kinase α1 Ser487 |
title_sort | protein kinase c phosphorylates amp-activated protein kinase α1 ser487 |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5147050/ https://www.ncbi.nlm.nih.gov/pubmed/27784766 http://dx.doi.org/10.1042/BCJ20160211 |
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