1. Ludwig Institute for Cancer Research, 91 Riding House Street, London W1W 7BS, UK
2. Centre for Diabetes and Endocrinology, University College London, Rayne Institute, 5 University Street, London WC1E 6JJ, UK
3. Gene Targeting Laboratory, The Institute for Stem Cell Research, University of Edinburgh, West Mains Road, Edinburgh EH9 3JQ, UK
4. Department of Medicine, University of Fribourg, 14 Chemin du Musée, CH-1700, Switzerland
5. Department of Biochemistry and Molecular Biology, University College London, Gower Street, London WC1E 6BT, UK
6. †Present address: Babraham Institute, Cambridge CB2 4AT, UK

Correspondence to: Bart Vanhaesebroeck^1,5 Correspondence and requests for materials should be addressed to B.V. (Email: bartvanh@ludwig.ucl.ac.uk).

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 p110, a ubiquitously expressed PI(3)K involved in tyrosine kinase and Ras signalling, here we generated mice carrying a knockin mutation (D933A) that abrogates p110 kinase activity. Homozygosity for this kinase-dead p110 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 p110 derives from its highly selective recruitment and activation to IRS signalling complexes compared to p110, the other broadly expressed PI(3)K isoform, which did not contribute to IRS-associated PI(3)K activity. p110 was the principal IRS-associated PI(3)K in cancer cell lines. These findings demonstrate a critical role for p110 in growth factor and metabolic signalling and also suggest an explanation for selective mutation or overexpression of p110 in a variety of cancers^{1, 2}.

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