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p110α hot spot mutations E545K and H1047R exert metabolic reprogramming independently of p110α kinase activity
Wallenberg Laboratory, Department of Molecular and Clinical Medicine, University of Gothenburg, Sweden.
Wallenberg Laboratory, Department of Molecular and Clinical Medicine, University of Gothenburg, Sweden.
Wallenberg Laboratory, Department of Molecular and Clinical Medicine, University of Gothenburg, Sweden.
Department of Medical Chemistry and Cell biology, University of Gothenburg, Sweden.
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2015 (English)In: Molecular and Cellular Biology, ISSN 0270-7306, E-ISSN 1098-5549, Vol. 35, no 19, 3258-3273 p.Article in journal (Refereed) Published
Abstract [en]

The phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) catalytic subunit p110α is the most frequently mutated kinase in human cancer, and the hot spot mutations E542K, E545K, and H1047R are the most common mutations in p110α. Very little is known about the metabolic consequences of the hot spot mutations of p110α in vivo. In this study, we used adenoviral gene transfer in mice to investigate the effects of the E545K and H1047R mutations on hepatic and whole-body glucose metabolism. We show that hepatic expression of these hot spot mutations results in rapid hepatic steatosis, paradoxically accompanied by increased glucose tolerance, and marked glycogen accumulation. In contrast, wild-type p110α expression does not lead to hepatic accumulation of lipids or glycogen despite similar degrees of upregulated glycolysis and expression of lipogenic genes. The reprogrammed metabolism of the E545K and H1047R p110α mutants was surprisingly not dependent on altered p110α lipid kinase activity.

Place, publisher, year, edition, pages
American Society for Microbiology , 2015. Vol. 35, no 19, 3258-3273 p.
National Category
Medical Genetics Cell and Molecular Biology
Research subject
Medical sciences
Identifiers
URN: urn:nbn:se:his:diva-11449DOI: 10.1128/MCB.00471-15PubMedID: 26169833ScopusID: 2-s2.0-84941052983OAI: oai:DiVA.org:his-11449DiVA: diva2:849373
Funder
Swedish Childhood Cancer FoundationSwedish Research CouncilKnowledge Foundation
Available from: 2015-08-28 Created: 2015-08-28 Last updated: 2015-11-30Bibliographically approved

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CiteExportLink to record
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Citation style
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