PI3K-C2γ 3 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, Emilio Hirsch

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64 Scopus citations

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.

Original languageEnglish (US)
Article number7400
JournalNature communications
Volume6
DOIs
StatePublished - Jun 23 2015

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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    Braccini, L., Ciraolo, E., Campa, C. C., Perino, A., Longo, D. L., Tibolla, G., Pregnolato, M., Cao, Y., Tassone, B., Damilano, F., Laffargue, M., Calautti, E., Falasca, M., Norata, G. D., Backer, J. M., & Hirsch, E. (2015). PI3K-C2γ 3 is a Rab5 effector selectively controlling endosomal Akt2 activation downstream of insulin signalling. Nature communications, 6, [7400]. https://doi.org/10.1038/ncomms8400