PI3K-C2γ is a Rab5 effector selectively controlling endosomal Akt2 activation downstream of insulin signalling

Laura Braccini, Elisa Ciraolo, Carlo C. Campa, Alessia Perino, Dario L. Longo, Gianpaolo Tibolla, Marco Pregnolato, Yanyan Cao, Beatrice Tassone, Federico Damilano, Muriel Laffargue, Enzo Calautti, Marco Falasca, Giuseppe D. Norata, Jonathan M. Backer and Emilio Hirsch ()
Additional contact information
Laura Braccini: Molecular Biotechnology Center, University of Torino
Elisa Ciraolo: Molecular Biotechnology Center, University of Torino
Carlo C. Campa: Molecular Biotechnology Center, University of Torino
Alessia Perino: Molecular Biotechnology Center, University of Torino
Dario L. Longo: Molecular Biotechnology Center, University of Torino
Gianpaolo Tibolla: University of Milan
Marco Pregnolato: Molecular Biotechnology Center, University of Torino
Yanyan Cao: Albert Einstein College of Medicine
Beatrice Tassone: Molecular Biotechnology Center, University of Torino
Federico Damilano: Molecular Biotechnology Center, University of Torino
Muriel Laffargue: INSERM UMR 1048, I2MC, Bât. L3, 1 av Jean-Poulhès, BP 84225
Enzo Calautti: Molecular Biotechnology Center, University of Torino
Marco Falasca: Metabolic Signalling Group, School of Biomedical Sciences, CHIRI Biosciences, Curtin University
Giuseppe D. Norata: University of Milan
Jonathan M. Backer: Albert Einstein College of Medicine
Emilio Hirsch: Molecular Biotechnology Center, University of Torino

Nature Communications, 2015, vol. 6, issue 1, 1-15

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms8400

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