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Nat Commun. 2015 Jun 23;6:7400. doi: 10.1038/ncomms8400.

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

Author information

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.

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.

PMID:
26100075
PMCID:
PMC4479417
DOI:
10.1038/ncomms8400
[Indexed for MEDLINE]
Free PMC Article

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