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PMID: 26100075 Published · epublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

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

Nature communications ·Vol. 6 ·2015-06-23 ·Pages 7400

Braccini L, Ciraolo E, Campa CC, Perino A, Longo DL, Tibolla G, Pregnolato M, Cao Y, Tassone B, Damilano F, Laffargue M, Calautti E, Falasca M, Norata GD, Backer JM, Hirsch E

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.

MeSH Terms
Adiposity/genetics Aging/genetics Animals Diet, High-Fat Endosomes/metabolism Forkhead Transcription Factors/metabolism Glucose/metabolism Glycogen/metabolism Glycogen Synthase/metabolism Hepatocytes/metabolism Homeostasis Hyperlipidemias/genetics Insulin/metabolism Insulin Resistance/genetics Liver/metabolism Mice Mice, Inbred C57BL Mice, Knockout Phosphatidylinositol 3-Kinases/genetics,metabolism Phosphatidylinositol Phosphates/metabolism Proto-Oncogene Proteins c-akt/metabolism Ribosomal Protein S6 Kinases/metabolism Signal Transduction rab5 GTP-Binding Proteins/metabolism
Chemicals
Forkhead Transcription Factors Insulin Phosphatidylinositol Phosphates phosphatidylinositol 3,4-diphosphate Glycogen Glycogen Synthase Phosphatidylinositol 3-Kinases Pik3c2g protein, mouse Akt1 protein, mouse Akt2 protein, mouse Proto-Oncogene Proteins c-akt Ribosomal Protein S6 Kinases rab5 GTP-Binding Proteins Glucose
Authors & Affiliations
16 authors, click to expand affiliations / ORCID
Braccini Laura
Molecular Biotechnology Center, Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino 10126, Italy.
Ciraolo Elisa
Molecular Biotechnology Center, Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino 10126, Italy.
Campa Carlo C
Molecular Biotechnology Center, Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino 10126, Italy.
Perino Alessia
Molecular Biotechnology Center, Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino 10126, Italy.
Longo Dario L
Molecular Biotechnology Center, Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino 10126, Italy.
Tibolla Gianpaolo
Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan 20133, Italy.
Pregnolato Marco
Molecular Biotechnology Center, Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino 10126, Italy.
Cao Yanyan
Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York, New York 10461, USA.
Tassone Beatrice
Molecular Biotechnology Center, Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino 10126, Italy.
Damilano Federico
Molecular Biotechnology Center, Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino 10126, Italy.
Laffargue Muriel
INSERM UMR 1048, I2MC, Bât. L3, 1 av Jean-Poulhès, BP 84225, Toulouse 4 31432, France.
Calautti Enzo
Molecular Biotechnology Center, Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino 10126, Italy.
Falasca Marco
Metabolic Signalling Group, School of Biomedical Sciences, CHIRI Biosciences, Curtin University, Perth, Western Australia 6102, Australia.
Norata Giuseppe D
Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan 20133, Italy.
Backer Jonathan M
Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York, New York 10461, USA.
Hirsch Emilio ORCID
Molecular Biotechnology Center, Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino 10126, Italy.
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Article Info
Journal
Nature communications
Abbr.
Nat Commun
ISSN
2041-1723
DOI
10.1038/ncomms8400
Published
2015-06-23
Epub
2015-00-23
Pages
7400
Language
English
Region
England
NLM ID
101528555
PMCID
PMC4479417
Subset
IM
Grants
NIA NIH HHS · R01 AG039632 · United States
NIGMS NIH HHS · GM112524 · United States
NIDDK NIH HHS · P30 DK041296 · United States
Telethon · GGP13002 · Italy
NIGMS NIH HHS · R01 GM112524 · United States
Telethon · TCP06001 · Italy
NIA NIH HHS · AG039632 · United States
NIDDK NIH HHS · P30 DK020541 · United States
NHLBI NIH HHS · T32 HL007374 · United States
NIDDK NIH HHS · P60 DK020541 · United States
External Links
PubMed source DOI: 10.1038/ncomms8400 PMC Full Text View journal details
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