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

被引：64

作者：

Alliouachene, Samira ^{[1
]}

Bilanges, Benoit ^{[1
]}

Chicanne, Gaetan ^{[2
]}

Anderson, Karen E. ^{[3
]}

Pearce, Wayne ^{[1
]}

Ali, Khaled ^{[1
]}

Valet, Colin ^{[2
]}

Posor, York ^{[1
]}

Low, Pei Ching ^{[1
]}

Chaussade, Claire ^{[1
]}

Scudamore, Cheryl L. ^{[4
]}

Salamon, Rachel S. ^{[5
]}

Backer, Jonathan M. ^{[5
]}

Stephens, Len ^{[3
]}

Hawkins, Phill T. ^{[3
]}

Payrastre, Bernard ^{[2
]}

Vanhaesebroeck, Bart ^{[1
]}

机构：

[1] UCL, UCL Canc Inst, London WC1E 6DD, England

[2] Inst Malad Metabol & Cardiovasc, Inserm UPS UMR 1048, F-31432 Toulouse 4, France

[3] Babraham Inst, Inositide Lab, Cambridge CB22 3AT, England

[4] MRC Harwell, Mary Lyon Ctr, Harwell OX11 0RD, Berks, England

[5] Albert Einstein Coll Med, Dept Mol Pharmacol, Bronx, NY 10461 USA

来源：

CELL REPORTS | 2015年 / 13卷 / 09期

基金：

英国生物技术与生命科学研究理事会;

关键词：

PHOSPHOINOSITIDE; 3-KINASE; METABOLIC-REGULATION; P110-ALPHA ISOFORM; P110-BETA ISOFORM; CELL-MIGRATION; AKT ACTIVATION; ALPHA-ISOFORM; PI3K; RECEPTOR; APPL1;

D O I：

10.1016/j.celrep.2015.10.052

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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-C2b 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-C2b inhibition selectively enhances insulin signaling only in metabolic tissues. In a primary hepatocyte model, basal PI3P lipid levels are reduced by 60% upon PI3K-C2b 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-C2b as a critical regulator of endosomal trafficking, specifically in insulin signaling, and identify PI3K-C2b as a potential drug target for insulin sensitization.

引用

页码：1881 / 1894

页数：14

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