title: p110α Hot Spot Mutations E545K and H1047R Exert Metabolic Reprogramming Independently of p110α Kinase Activity.
abstract: 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.
authors.affiliation: Wallenberg Laboratory, Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Aditi
authors.initials: A
authors.lastname: Chaudhari
authors.affiliation: Wallenberg Laboratory, Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Daniel
authors.initials: D
authors.lastname: Krumlinde
authors.affiliation: Wallenberg Laboratory, Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Annika
authors.initials: A
authors.lastname: Lundqvist
authors.affiliation: Department of Medical Chemistry and Cell Biology, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Levent M
authors.initials: LM
authors.lastname: Akyürek
authors.affiliation: Department of Medical Chemistry and Cell Biology, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Sashidhar
authors.initials: S
authors.lastname: Bandaru
authors.affiliation: Wallenberg Laboratory, Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Kristina
authors.initials: K
authors.lastname: Skålén
authors.affiliation: Wallenberg Laboratory, Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Marcus
authors.initials: M
authors.lastname: Ståhlman
authors.affiliation: Wallenberg Laboratory, Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Jan
authors.initials: J
authors.lastname: Borén
authors.affiliation: Department of Surgery, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Wettergren
authors.affiliation: Department of Medical and Clinical Genetics, University of Gothenburg, Gothenburg, Sweden Systems Biology Research Center, University of Skövde, Skövde, Sweden.
authors.forename: Katarina
authors.initials: K
authors.lastname: Ejeskär
authors.affiliation: Wallenberg Laboratory, Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden victoria.rotter@wlab.gu.se.
authors.forename: Victoria
authors.initials: V
authors.lastname: Rotter Sopasakis
mesh_terms: D000818:Animals; D058534:Class I Phosphatidylinositol 3-Kinases / Q000235:genetics* / Q000378:metabolism; D004734:Energy Metabolism; D004789:Enzyme Activation; D005227:Fatty Acids / Q000378:metabolism; D005234:Fatty Liver / Q000201:enzymology; D018149:Glucose Intolerance; D006003:Glycogen / Q000378:metabolism; D006019:Glycolysis; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D018345:Mice, Knockout; D020125:Mutation, Missense; D010084:Oxidation-Reduction; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D005227:Fatty Acids; D006003:Glycogen; C509622:1-phosphatidylinositol 3-kinase p110 subunit, mouse; D058534:Class I Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt