title: Critical role for the p110alpha phosphoinositide-3-OH kinase in growth and metabolic regulation.
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 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 cancers.
authors.affiliation: Ludwig Institute for Cancer Research, 91 Riding House Street, London W1W 7BS, UK.
authors.forename: Lazaros C
authors.initials: LC
authors.lastname: Foukas
authors.forename: Marc
authors.initials: M
authors.lastname: Claret
authors.forename: Wayne
authors.initials: W
authors.lastname: Pearce
authors.forename: Klaus
authors.initials: K
authors.lastname: Okkenhaug
authors.forename: Stephen
authors.initials: S
authors.lastname: Meek
authors.forename: Emma
authors.initials: E
authors.lastname: Peskett
authors.forename: Sara
authors.initials: S
authors.lastname: Sancho
authors.forename: Andrew J H
authors.initials: AJ
authors.lastname: Smith
authors.forename: Dominic J
authors.initials: DJ
authors.lastname: Withers
authors.forename: Bart
authors.initials: B
authors.lastname: Vanhaesebroeck
mesh_terms: D050154:Adiposity; D000818:Animals; D001835:Body Weight; D020134:Catalytic Domain; D045744:Cell Line, Tumor; D058534:Class I Phosphatidylinositol 3-Kinases; D004435:Eating; D020964:Embryo Loss / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D004789:Enzyme Activation; D005947:Glucose / Q000378:metabolism; D006128:Growth / Q000502:physiology*; D006579:Heterozygote; D006720:Homozygote; D006946:Hyperinsulinism / Q000378:metabolism; D007328:Insulin / Q000378:metabolism*; D055504:Insulin Receptor Substrate Proteins; D020738:Leptin / Q000378:metabolism; D051379:Mice; D009154:Mutation / Q000235:genetics; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism; D011972:Receptor, Insulin / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; D020738:Leptin; D010750:Phosphoproteins; D019869:Phosphatidylinositol 3-Kinases; C509622:1-phosphatidylinositol 3-kinase p110 subunit, mouse; D058534:Class I Phosphatidylinositol 3-Kinases; D011972:Receptor, Insulin; D005947:Glucose