title: Inactivation of the Class II PI3K-C2β Potentiates Insulin Signaling and Sensitivity.
abstract: 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.
authors.affiliation: UCL Cancer Institute, University College London, 72 Huntley Street, London WC1E 6DD, UK. Electronic address: s.alliouachene@ucl.ac.uk.
authors.forename: Samira
authors.initials: S
authors.lastname: Alliouachene
authors.affiliation: UCL Cancer Institute, University College London, 72 Huntley Street, London WC1E 6DD, UK.
authors.forename: Benoit
authors.initials: B
authors.lastname: Bilanges
authors.affiliation: Inserm/UPS UMR 1048, Institut des Maladies Métaboliques et Cardiovasculaires, 1 Avenue Jean Poulhès BP 84225, 31432 Toulouse Cedex 4, France.
authors.forename: Gaëtan
authors.initials: G
authors.lastname: Chicanne
authors.affiliation: Inositide Laboratory, The Babraham Institute, Cambridge CB22 3AT, UK.
authors.forename: Karen E
authors.initials: KE
authors.lastname: Anderson
authors.affiliation: UCL Cancer Institute, University College London, 72 Huntley Street, London WC1E 6DD, UK.
authors.forename: Wayne
authors.initials: W
authors.lastname: Pearce
authors.affiliation: UCL Cancer Institute, University College London, 72 Huntley Street, London WC1E 6DD, UK.
authors.forename: Khaled
authors.initials: K
authors.lastname: Ali
authors.affiliation: Inserm/UPS UMR 1048, Institut des Maladies Métaboliques et Cardiovasculaires, 1 Avenue Jean Poulhès BP 84225, 31432 Toulouse Cedex 4, France.
authors.forename: Colin
authors.initials: C
authors.lastname: Valet
authors.affiliation: UCL Cancer Institute, University College London, 72 Huntley Street, London WC1E 6DD, UK.
authors.forename: York
authors.initials: Y
authors.lastname: Posor
authors.affiliation: UCL Cancer Institute, University College London, 72 Huntley Street, London WC1E 6DD, UK.
authors.forename: Pei Ching
authors.initials: PC
authors.lastname: Low
authors.affiliation: UCL Cancer Institute, University College London, 72 Huntley Street, London WC1E 6DD, UK.
authors.forename: Claire
authors.initials: C
authors.lastname: Chaussade
authors.affiliation: Mary Lyon Centre, MRC Harwell, Harwell Science and Innovation Campus, Harwell OX11 0RD, UK.
authors.forename: Cheryl L
authors.initials: CL
authors.lastname: Scudamore
authors.affiliation: Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Rachel S
authors.initials: RS
authors.lastname: Salamon
authors.affiliation: Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Backer
authors.affiliation: Inositide Laboratory, The Babraham Institute, Cambridge CB22 3AT, UK.
authors.forename: Len
authors.initials: L
authors.lastname: Stephens
authors.affiliation: Inositide Laboratory, The Babraham Institute, Cambridge CB22 3AT, UK.
authors.forename: Phill T
authors.initials: PT
authors.lastname: Hawkins
authors.affiliation: Inserm/UPS UMR 1048, Institut des Maladies Métaboliques et Cardiovasculaires, 1 Avenue Jean Poulhès BP 84225, 31432 Toulouse Cedex 4, France.
authors.forename: Bernard
authors.initials: B
authors.lastname: Payrastre
authors.affiliation: UCL Cancer Institute, University College London, 72 Huntley Street, London WC1E 6DD, UK. Electronic address: bart.vanh@ucl.ac.uk.
authors.forename: Bart
authors.initials: B
authors.lastname: Vanhaesebroeck
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D001343:Autophagy; D001786:Blood Glucose / Q000032:analysis; D002478:Cells, Cultured; D058541:Class II Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D059305:Diet, High-Fat; D011992:Endosomes / Q000378:metabolism; D005234:Fatty Liver / Q000378:metabolism / Q000473:pathology; D055879:Gene Knock-In Techniques; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism; D007328:Insulin / Q000097:blood / Q000378:metabolism*; D008099:Liver / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C510733:Appl1 protein, mouse; D001786:Blood Glucose; D007328:Insulin; D058541:Class II Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases