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p110alpha hot spot mutations E545K and H1047R exert metabolic reprogramming independently of p110alpha kinase activity

Journal article
Authors Aditi Chaudhari
Daniel Krumlinde
Annika Lundqvist
Levent Akyürek
Sashidar Bandaru
Kristina Skålen
Marcus Ståhlman
Jan Borén
Yvonne Wettergren
Katarina Ejeskär
Victoria Rotter Sopasakis
Published in Molecular and Cellular Biology
Volume 35
Issue 19
Pages 3258-3273
ISSN 0270-7306
Publication year 2015
Published at Wallenberg Laboratory
Institute of Biomedicine, Department of Medical and Clinical Genetics
Institute of Clinical Sciences, Department of Surgery
Institute of Biomedicine, Department of Medical Biochemistry and Cell Biology
Institute of Medicine, Department of Molecular and Clinical Medicine
Pages 3258-3273
Language en
Subject categories Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy), Clinical Laboratory Medicine, Cell and Molecular Biology


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.

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