PI3K-C2γ 3 is a Rab5 effector selectively controlling endosomal Akt2 activation downstream of insulin signalling(300 views) 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
Molecular Biotechnology Center, Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, 10126, Italy
Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, 20133, Italy
INSERM, 1 av Jean-Poulhes, Toulouse, 31432, France
Metabolic Signalling Group, School of Biomedical Sciences, Curtin University, Perth, WA 6102, Australia
Institute of Bioengineering, School of Life Sciences, Ecole Polytechnique Federale de Lausanne, Lausanne, CH-1015, Switzerland
Institute of Biostructure and Bioimaging, Molecular Biotechnology Center, University of Torino, Torino, 10126, Italy
Beth Israel Deaconess Medical Center, Harvard, Boston, MA 02215, United States
References: Not available.
PI3K-C2γ 3 is a Rab5 effector selectively controlling endosomal Akt2 activation downstream of insulin signalling
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.
PI3K-C2γ 3 is a Rab5 effector selectively controlling endosomal Akt2 activation downstream of insulin signalling
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PI3K-C2γ 3 is a Rab5 effector selectively controlling endosomal Akt2 activation downstream of insulin signalling