Inactivation of the Class II PI3K-C2β Potentiates Insulin Signaling and Sensitivity.

Autor:	Alliouachene S; UCL Cancer Institute, University College London, 72 Huntley Street, London WC1E 6DD, UK. Electronic address: s.alliouachene@ucl.ac.uk., Bilanges B; UCL Cancer Institute, University College London, 72 Huntley Street, London WC1E 6DD, UK., Chicanne G; Inserm/UPS UMR 1048, Institut des Maladies Métaboliques et Cardiovasculaires, 1 Avenue Jean Poulhès BP 84225, 31432 Toulouse Cedex 4, France., Anderson KE; Inositide Laboratory, The Babraham Institute, Cambridge CB22 3AT, UK., Pearce W; UCL Cancer Institute, University College London, 72 Huntley Street, London WC1E 6DD, UK., Ali K; UCL Cancer Institute, University College London, 72 Huntley Street, London WC1E 6DD, UK., Valet C; Inserm/UPS UMR 1048, Institut des Maladies Métaboliques et Cardiovasculaires, 1 Avenue Jean Poulhès BP 84225, 31432 Toulouse Cedex 4, France., Posor Y; UCL Cancer Institute, University College London, 72 Huntley Street, London WC1E 6DD, UK., Low PC; UCL Cancer Institute, University College London, 72 Huntley Street, London WC1E 6DD, UK., Chaussade C; UCL Cancer Institute, University College London, 72 Huntley Street, London WC1E 6DD, UK., Scudamore CL; Mary Lyon Centre, MRC Harwell, Harwell Science and Innovation Campus, Harwell OX11 0RD, UK., Salamon RS; Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY 10461, USA., Backer JM; Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY 10461, USA., Stephens L; Inositide Laboratory, The Babraham Institute, Cambridge CB22 3AT, UK., Hawkins PT; Inositide Laboratory, The Babraham Institute, Cambridge CB22 3AT, UK., Payrastre B; Inserm/UPS UMR 1048, Institut des Maladies Métaboliques et Cardiovasculaires, 1 Avenue Jean Poulhès BP 84225, 31432 Toulouse Cedex 4, France., Vanhaesebroeck B; UCL Cancer Institute, University College London, 72 Huntley Street, London WC1E 6DD, UK. Electronic address: bart.vanh@ucl.ac.uk.
Jazyk:	angličtina
Zdroj:	Cell reports [Cell Rep] 2015 Dec 01; Vol. 13 (9), pp. 1881-94. Date of Electronic Publication: 2015 Nov 19.
DOI:	10.1016/j.celrep.2015.10.052
Abstrakt:	In contrast to the class I phosphoinositide 3-kinases (PI3Ks), the organismal roles of the kinase activity of the class II PI3Ks are less clear. Here, we report that class II PI3K-C2β kinase-dead mice are viable and healthy but display an unanticipated enhanced insulin sensitivity and glucose tolerance, as well as protection against high-fat-diet-induced liver steatosis. Despite having a broad tissue distribution, systemic PI3K-C2β inhibition selectively enhances insulin signaling only in metabolic tissues. In a primary hepatocyte model, basal PI3P lipid levels are reduced by 60% upon PI3K-C2β inhibition. This results in an expansion of the very early APPL1-positive endosomal compartment and altered insulin receptor trafficking, correlating with an amplification of insulin-induced, class I PI3K-dependent Akt signaling, without impacting MAPK activity. These data reveal PI3K-C2β as a critical regulator of endosomal trafficking, specifically in insulin signaling, and identify PI3K-C2β as a potential drug target for insulin sensitization. (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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