title: PI3K-C2γ is a Rab5 effector selectively controlling endosomal Akt2 activation downstream of insulin signalling.
abstract: In the liver, insulin-mediated activation of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway is at the core of metabolic control. Multiple PI3K and Akt isoenzymes are found in hepatocytes and whether isoform-selective interplays exist is currently unclear. Here we report that insulin signalling triggers the association of the liver-specific class II PI3K isoform γ (PI3K-C2γ) with Rab5-GTP, and its recruitment to Rab5-positive early endosomes. In these vesicles, PI3K-C2γ produces a phosphatidylinositol-3,4-bisphosphate pool specifically required for delayed and sustained endosomal Akt2 stimulation. Accordingly, loss of PI3K-C2γ does not affect insulin-dependent Akt1 activation as well as S6K and FoxO1-3 phosphorylation, but selectively reduces Akt2 activation, which specifically inhibits glycogen synthase activity. As a consequence, PI3K-C2γ-deficient mice display severely reduced liver accumulation of glycogen and develop hyperlipidemia, adiposity as well as insulin resistance with age or after consumption of a high-fat diet. Our data indicate PI3K-C2γ supports an isoenzyme-specific forking of insulin-mediated signal transduction to an endosomal pool of Akt2, required for glucose homeostasis.
authors.affiliation: Molecular Biotechnology Center, Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino 10126, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Braccini
authors.affiliation: Molecular Biotechnology Center, Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino 10126, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Ciraolo
authors.affiliation: Molecular Biotechnology Center, Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino 10126, Italy.
authors.forename: Carlo C
authors.initials: CC
authors.lastname: Campa
authors.affiliation: Molecular Biotechnology Center, Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino 10126, Italy.
authors.forename: Alessia
authors.initials: A
authors.lastname: Perino
authors.affiliation: Molecular Biotechnology Center, Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino 10126, Italy.
authors.forename: Dario L
authors.initials: DL
authors.lastname: Longo
authors.affiliation: Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan 20133, Italy.
authors.forename: Gianpaolo
authors.initials: G
authors.lastname: Tibolla
authors.affiliation: Molecular Biotechnology Center, Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino 10126, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Pregnolato
authors.affiliation: Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York, New York 10461, USA.
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Cao
authors.affiliation: Molecular Biotechnology Center, Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino 10126, Italy.
authors.forename: Beatrice
authors.initials: B
authors.lastname: Tassone
authors.affiliation: Molecular Biotechnology Center, Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino 10126, Italy.
authors.forename: Federico
authors.initials: F
authors.lastname: Damilano
authors.affiliation: INSERM UMR 1048, I2MC, Bât. L3, 1 av Jean-Poulhès, BP 84225, Toulouse 4 31432, France.
authors.forename: Muriel
authors.initials: M
authors.lastname: Laffargue
authors.affiliation: Molecular Biotechnology Center, Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino 10126, Italy.
authors.forename: Enzo
authors.initials: E
authors.lastname: Calautti
authors.affiliation: Metabolic Signalling Group, School of Biomedical Sciences, CHIRI Biosciences, Curtin University, Perth, Western Australia 6102, Australia.
authors.forename: Marco
authors.initials: M
authors.lastname: Falasca
authors.affiliation: Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan 20133, Italy.
authors.forename: Giuseppe D
authors.initials: GD
authors.lastname: Norata
authors.affiliation: Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York, New York 10461, USA.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Backer
authors.affiliation: Molecular Biotechnology Center, Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino 10126, Italy.
authors.forename: Emilio
authors.identifier: 0000000290736024
authors.initials: E
authors.lastname: Hirsch
mesh_terms: D050154:Adiposity / Q000235:genetics; D000375:Aging / Q000235:genetics*; D000818:Animals; D059305:Diet, High-Fat; D011992:Endosomes / Q000378:metabolism; D051858:Forkhead Transcription Factors / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D006003:Glycogen / Q000378:metabolism*; D006006:Glycogen Synthase / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism*; D006706:Homeostasis; D006949:Hyperlipidemias / Q000235:genetics; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance / Q000235:genetics; D008099:Liver / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics* / Q000378:metabolism; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D015398:Signal Transduction; D020696:rab5 GTP-Binding Proteins / Q000378:metabolism*
chemical_list: D051858:Forkhead Transcription Factors; D007328:Insulin; D018129:Phosphatidylinositol Phosphates; C060980:phosphatidylinositol 3,4-diphosphate; D006003:Glycogen; D006006:Glycogen Synthase; D019869:Phosphatidylinositol 3-Kinases; C546638:Pik3c2g protein, mouse; C514862:Akt1 protein, mouse; C494922:Akt2 protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D019893:Ribosomal Protein S6 Kinases; D020696:rab5 GTP-Binding Proteins; D005947:Glucose