Functional differences between two classes of oncogenic mutation in the PIK3CA gene

Biochem Biophys Res Commun. 2009 Apr 17;381(4):577-81. doi: 10.1016/j.bbrc.2009.02.081. Epub 2009 Feb 20.

Abstract

PIK3CA codes for the p110alpha isoform of class-IA PI 3-kinase and oncogenic mutations in the helical domain and kinase domain are common in several cancers. We studied the biochemical properties of a common helical domain mutant (E545K) and a common kinase domain mutant (H1047R). Both retain the ability to autophosphorylate Ser608 of p85alpha and are also inhibited by a range of PI 3-kinase inhibitors (Wortmannin, LY294002, PI-103 and PIK-75) to a similar extent as WT p110alpha. Both mutants display an increased V(max) but while a PDGF derived diphosphotyrosylpeptide caused an increase in V(max) for WT p85alpha/p110alpha it did not for the E545K variant and actually decreased V(max) for the H1047R variant. Further, the E545K mutant was activated by H-Ras whereas the H1047R mutant was not. Together these results suggest helical domain mutants are in a state mimicking activation by growth factors whereas kinase domain mutants mimic the state activated by H-Ras.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Class I Phosphatidylinositol 3-Kinases
  • Humans
  • Mutation
  • Neoplasms / genetics*
  • Phosphatidylinositol 3-Kinases / genetics
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Phosphoinositide-3 Kinase Inhibitors
  • Protein Structure, Secondary / genetics
  • Protein Structure, Tertiary / genetics

Substances

  • Phosphoinositide-3 Kinase Inhibitors
  • Class I Phosphatidylinositol 3-Kinases
  • PIK3CA protein, human