Critical role for the p110α phosphoinositide-3-OH kinase in growth and metabolic regulation (original) (raw)

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 p110a, a ubiquitously expressed PI(3)K involved in tyrosine kinase and Ras signalling, here we generated mice carrying a knockin mutation (D933A) that abrogates p110a kinase activity. Homozygosity for this kinase-dead p110a 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 p110a derives from its highly selective recruitment and activation to IRS signalling complexes compared to p110b, the other broadly expressed PI(3)K isoform, which did not contribute to IRS-associated PI(3)K activity. p110a was the principal IRS-associated PI(3)K in cancer cell lines. These findings demonstrate a critical role for p110a in growth factor and metabolic signalling and also suggest an explanation for selective mutation or overexpression of p110a in a variety of cancers 1,2 .