TY - JOUR
T1 - Inactivation of the Class II PI3K-C2β Potentiates Insulin Signaling and Sensitivity
AU - Alliouachene, Samira
AU - Bilanges, Benoit
AU - Chicanne, Gaëtan
AU - Anderson, Karen E.
AU - Pearce, Wayne
AU - Ali, Khaled
AU - Valet, Colin
AU - Posor, York
AU - Low, Pei Ching
AU - Chaussade, Claire
AU - Scudamore, Cheryl L.
AU - Salamon, Rachel S.
AU - Backer, Jonathan M.
AU - Stephens, Len
AU - Hawkins, Phill T.
AU - Payrastre, Bernard
AU - Vanhaesebroeck, Bart
N1 - Funding Information:
We thank M. Falasca (Curtin University, Australia) and G. Tibolla (University of Milan, Italy) for providing tissues from PI3K-C2β KO mice, D. Ciantar for help with microscopy (UCL, UK), C. Woelk (Southampton University, UK) and S. Castillo (UCL, UK) for help with statistics, Harald Stenmark (University of Oslo, Norway), S. Tooze (London Research Institute, UK), D. Withers (Imperial College London, UK), L. Foukas (UCL, UK), and R. Chin and A. Toker (Harvard, Boston) for advice and providing reagents, staff at TaconicArtemis (Cologne, Germany) for the mouse gene targeting, and M. Whitehead for critical input in interpretation of the data and writing of the manuscript. Fellowships were from EU Marie Curie (PIEF-GA-2009-252916) and EMBO (ALTF 753-2010) for S.A., from EMBO (ALTF 1227-2014) for Y.P., from EU Marie Curie (PIIF-GA-2009-252846) for C.C. and from EU Marie Curie (PIIF-GA-2013-330716) for P.C.L. Work in the laboratory of B.V. was supported by the UK BBSRC (BB/I007806/1), Cancer Research UK (C23338/A15965), the Ludwig Institute for Cancer Research and the National Institute for Health Research (NIHR) UCL Hospitals Biomedical Research Centre. Work in the laboratory of J.M.B. was supported by NIH DK 20541 and the Albert Einstein Diabetes Research and Training Center Animal Physiology Core. Work in the laboratory of B.P. was supported by Inserm and the Fondation pour la recherche médicale. Work in the laboratory of L.S. and P.T.H. was supported by the UK BBSRC (BB/J004456/1 and BB/I003916/1). B.V., L.S., and P.T.H. are consultants to Karus Therapeutics (Oxford, UK).
Publisher Copyright:
© 2015 The Authors.
PY - 2015/12/1
Y1 - 2015/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84947604001&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84947604001&partnerID=8YFLogxK
U2 - 10.1016/j.celrep.2015.10.052
DO - 10.1016/j.celrep.2015.10.052
M3 - Article
C2 - 26655903
AN - SCOPUS:84947604001
SN - 2211-1247
VL - 13
SP - 1881
EP - 1894
JO - Cell Reports
JF - Cell Reports
IS - 9
ER -