Search: WFRF:(Morrice Nicholas) >
GFAT1 phosphorylati...
GFAT1 phosphorylation by AMPK promotes VEGF-induced angiogenesis
-
- Zibrova, Darya (author)
- Universitätsklinikum Jena
-
- Vandermoere, Franck (author)
- University of Montpellier
-
- Göransson, Olga (author)
- Lund University,Lunds universitet,Proteinfosforylering,Forskargrupper vid Lunds universitet,Protein Phosphorylation,Lund University Research Groups
-
show more...
-
- Peggie, Mark (author)
- University of Dundee
-
- Mariño, Karina V. (author)
- Experimental Medicine and Biology Institute (IByME)
-
- Knierim, Anne (author)
- Universitätsklinikum Jena
-
- Spengler, Katrin (author)
- Universitätsklinikum Jena
-
- Weigert, Cora (author)
- German Center for Diabetes Research,University of Tübingen
-
- Viollet, Benoit (author)
- Paris Descartes University,Institut Cochin
-
- Morrice, Nicholas A. (author)
- AB Sciex
-
- Sakamoto, Kei (author)
- University of Dundee
-
- Heller, Regine (author)
- Universitätsklinikum Jena
-
show less...
-
(creator_code:org_t)
- 2017
- 2017
- English 19 s.
-
In: Biochemical Journal. - 0264-6021. ; 474:6, s. 983-1001
- Related links:
-
http://dx.doi.org/10...
-
show more...
-
https://lup.lub.lu.s...
-
https://doi.org/10.1...
-
show less...
Abstract
Subject headings
Close
- Activation of AMP-activated protein kinase (AMPK) in endothelial cells regulates energy homeostasis, stress protection and angiogenesis, but the underlying mechanisms are incompletely understood. Using a label-free phosphoproteomic analysis, we identified glutamine:fructose-6-phosphate amidotransferase 1 (GFAT1) as an AMPK substrate. GFAT1 is the rate-limiting enzyme in the hexosamine biosynthesis pathway (HBP) and as such controls the modification of proteins by O-linked β-N-acetylglucosamine (O-GlcNAc). In the present study, we tested the hypothesis that AMPK controls O-GlcNAc levels and function of endothelial cells via GFAT1 phosphorylation using biochemical, pharmacological, genetic and in vitro angiogenesis approaches. Activation of AMPK in primary human endothelial cells by 5-aminoimidazole-4-carboxamide riboside (AICAR) or by vascular endothelial growth factor (VEGF) led to GFAT1 phosphorylation at serine 243. This effect was not seen when AMPK was down-regulated by siRNA. Upon AMPK activation, diminished GFAT activity and reduced O-GlcNAc levels were observed in endothelial cells containing wild-type (WT)-GFAT1 but not in cells expressing non-phosphorylatable S243A-GFAT1. Pharmacological inhibition or siRNA-mediated down-regulation of GFAT1 potentiated VEGF-induced sprouting, indicating that GFAT1 acts as a negative regulator of angiogenesis. In cells expressing S243A-GFAT1, VEGF-induced sprouting was reduced, suggesting that VEGF relieves the inhibitory action of GFAT1/HBP on angiogenesis via AMPK-mediated GFAT1 phosphorylation. Activation of GFAT1/HBP by high glucose led to impairment of vascular sprouting, whereas GFAT1 inhibition improved sprouting even if glucose level was high. Our findings provide novel mechanistic insights into the role of HBP in angiogenesis. They suggest that targeting AMPK in endothelium might help to ameliorate hyperglycaemia-induced vascular dysfunction associated with metabolic disorders.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Läkemedelskemi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Medicinal Chemistry (hsv//eng)
Publication and Content Type
- art (subject category)
- ref (subject category)
Find in a library
To the university's database
- By the author/editor
-
Zibrova, Darya
-
Vandermoere, Fra ...
-
Göransson, Olga
-
Peggie, Mark
-
Mariño, Karina V ...
-
Knierim, Anne
-
show more...
-
Spengler, Katrin
-
Weigert, Cora
-
Viollet, Benoit
-
Morrice, Nichola ...
-
Sakamoto, Kei
-
Heller, Regine
-
show less...
- About the subject
-
- MEDICAL AND HEALTH SCIENCES
-
MEDICAL AND HEAL ...
-
and Basic Medicine
-
and Medicinal Chemis ...
- Articles in the publication
-
Biochemical Jour ...
- By the university
-
Lund University