Abstract
The eight catalytic subunits of the mammalian phosphoinositide-3-OH kinase (PI(3)K) family form the backbone of an evolutionarily conserved signalling pathway; however, the roles of most PI(3)K isoforms in organismal physiology and disease are unknown. To delineate the role of p110α, a ubiquitously expressed PI(3)K involved in tyrosine kinase and Ras signalling, here we generated mice carrying a knockin mutation (D933A) that abrogates p110α kinase activity. Homozygosity for this kinase-dead p110α led to embryonic lethality. Mice heterozygous for this mutation were viable and fertile, but displayed severely blunted signalling via insulin-receptor substrate (IRS) proteins, key mediators of insulin, insulin-like growth factor-1 and leptin action. Defective responsiveness to these hormones led to reduced somatic growth, hyperinsulinaemia, glucose intolerance, hyperphagia and increased adiposity in mice heterozygous for the D933A mutation. This signalling function of p110α derives from its highly selective recruitment and activation to IRS signalling complexes compared to p110β, the other broadly expressed PI(3)K isoform, which did not contribute to IRS-associated PI(3)K activity. p110α was the principal IRS-associated PI(3)K in cancer cell lines. These findings demonstrate a critical role for p110α in growth factor and metabolic signalling and also suggest an explanation for selective mutation or overexpression of p110α in a variety of cancers1,2.
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Acknowledgements
We thank M. Camps, T. Ruckle, C. Rommel (Serono Pharmaceutical Research Institute) and PIramed for pharmacological agents; W. Fantl for antibody reagents; and T. Arnett and I. Orriss for providing access and help with the DEXA scanner. Personal support for L.F., M.C. and K.O. was provided in part by a European Union FP5 Programme grant, and for W.P. by a European Union grant. The main grant support for this project was by Diabetes UK and the Ludwig Institute for Cancer Research (to B.V.) and by the Wellcome Trust and MRC (to D.J.W.), with additional support of the Biotechnology and Biological Science Research Council (to B.V.). The ISCR Gene Targeting Laboratory was supported by the Biotechnology and Biological Science Research Council.
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Supplementary Notes
This file contains Supplementary Figures and Legends 1–4, Supplementary Methods and Supplementary Table 1. These provide a detailed description of the gene targeting strategy, organ and cell size measurements, additional data from glucose and insulin tolerance tests and a list of the organs subjected to histological examination. (PDF 200 kb)
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Foukas, L., Claret, M., Pearce, W. et al. Critical role for the p110α phosphoinositide-3-OH kinase in growth and metabolic regulation. Nature 441, 366–370 (2006). https://doi.org/10.1038/nature04694
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DOI: https://doi.org/10.1038/nature04694
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