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

  • Foukas, Lazaros C. Ludwig Institute for Cancer Research, London, UK
  • Claret, Marc Centre for Diabetes and Endocrinology, University College London, UK
  • Pearce, Wayne Ludwig Institute for Cancer Research, London, UK
  • Okkenhaug, Klaus Ludwig Institute for Cancer Research, London, UK - Babraham Institute, Cambridge, UK
  • Meek, Stephen Gene Targeting Laboratory, The Institute for Stem Cell Research, University of Edinburgh, UK
  • Peskett, Emma Ludwig Institute for Cancer Research, London, UK
  • Sancho, Sara Department of Medicine, University of Fribourg, Switzerland
  • Smith, Andrew J. H. Gene Targeting Laboratory, The Institute for Stem Cell Research, University of Edinburgh, UK
  • Withers, Dominic J. Centre for Diabetes and Endocrinology, University College London, UK
  • Vanhaesebroeck, Bart Ludwig Institute for Cancer Research, London, UK - Department of Biochemistry and Molecular Biology, University College London, UK
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    12.04.2006
Published in:
  • Nature. - 2006, vol. 441, p. 366-370
English 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 p110alpha, a ubiquitously expressed PI(3)K involved in tyrosine kinase and Ras signalling, here we generated mice carrying a knockin mutation (D933A) that abrogates p110alpha kinase activity. Homozygosity for this kinase-dead p110alpha 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 p110alpha derives from its highly selective recruitment and activation to IRS signalling complexes compared to p110beta, the other broadly expressed PI(3)K isoform, which did not contribute to IRS-associated PI(3)K activity. p110alpha was the principal IRS-associated PI(3)K in cancer cell lines. These findings demonstrate a critical role for p110alpha in growth factor and metabolic signalling and also suggest an explanation for selective mutation or overexpression of p110alpha in a variety of cancers1, 2.
Faculty
Faculté des sciences et de médecine
Department
Département de Médecine
Language
  • English
Classification
Biology
License
License undefined
Identifiers
Persistent URL
https://folia.unifr.ch/unifr/documents/300126
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