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

  • Nat Commun. 2015 Jun 23:6:7400. doi: 10.1038/ncomms8400.
Laura Braccini  1 ,  Elisa Ciraolo  1 ,  Carlo C Campa  1 ,  Alessia Perino  1 ,  Dario L Longo  1 ,  Gianpaolo Tibolla  2 ,  Marco Pregnolato  1 ,  Yanyan Cao  3 ,  Beatrice Tassone  1 ,  Federico Damilano  1 ,  Muriel Laffargue  4 ,  Enzo Calautti  1 ,  Marco Falasca  5 ,  Giuseppe D Norata  2 ,  Jonathan M Backer  3 ,  Emilio Hirsch  1
Affiliations
  • 1. Molecular Biotechnology Center, Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino 10126, Italy.
  • 2. Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan 20133, Italy.
  • 3. Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York, New York 10461, USA.
  • 4. INSERM UMR 1048, I2MC, Bât. L3, 1 av Jean-Poulhès, BP 84225, Toulouse 4 31432, France.
  • 5. Metabolic Signalling Group, School of Biomedical Sciences, CHIRI Biosciences, Curtin University, Perth, Western Australia 6102, Australia.
PMID: 26100075 DOI: 10.1038/ncomms8400
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.