Critical role for the p110α phosphoinositide-3-OH kinase in growth and metabolic regulation

Lazaros C. Foukas, Marc Claret, Wayne Pearce, Klaus Okkenhaug, Stephen Meek, Emma Peskett, Sara Sancho, Andrew J. H. Smith, Dominic J. Withers and Bart Vanhaesebroeck ()
Additional contact information
Lazaros C. Foukas: Ludwig Institute for Cancer Research
Marc Claret: Centre for Diabetes and Endocrinology, University College London, Rayne Institute
Wayne Pearce: Ludwig Institute for Cancer Research
Klaus Okkenhaug: Ludwig Institute for Cancer Research
Stephen Meek: Gene Targeting Laboratory, The Institute for Stem Cell Research, University of Edinburgh
Emma Peskett: Ludwig Institute for Cancer Research
Sara Sancho: University of Fribourg
Andrew J. H. Smith: Gene Targeting Laboratory, The Institute for Stem Cell Research, University of Edinburgh
Dominic J. Withers: Centre for Diabetes and Endocrinology, University College London, Rayne Institute
Bart Vanhaesebroeck: Ludwig Institute for Cancer Research

Nature, 2006, vol. 441, issue 7091, 366-370

Abstract: 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.

Date: 2006
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DOI: 10.1038/nature04694

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