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p110α Hot Spot Mutations E545K and H1047R Exert Metabolic Reprogramming Independently of p110α Kinase Activity.
- Source :
-
Molecular and cellular biology [Mol Cell Biol] 2015 Oct; Vol. 35 (19), pp. 3258-73. Date of Electronic Publication: 2015 Jul 13. - Publication Year :
- 2015
-
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.<br /> (Copyright © 2015, American Society for Microbiology. All Rights Reserved.)
- Subjects :
- Animals
Class I Phosphatidylinositol 3-Kinases metabolism
Enzyme Activation
Fatty Acids metabolism
Fatty Liver enzymology
Glucose Intolerance
Glycogen metabolism
Glycolysis
Lipid Metabolism
Liver metabolism
Male
Mice, Knockout
Oxidation-Reduction
Phosphorylation
Protein Processing, Post-Translational
Proto-Oncogene Proteins c-akt metabolism
Signal Transduction
Class I Phosphatidylinositol 3-Kinases genetics
Energy Metabolism
Mutation, Missense
Subjects
Details
- Language :
- English
- ISSN :
- 1098-5549
- Volume :
- 35
- Issue :
- 19
- Database :
- MEDLINE
- Journal :
- Molecular and cellular biology
- Publication Type :
- Academic Journal
- Accession number :
- 26169833
- Full Text :
- https://doi.org/10.1128/MCB.00471-15