PIK3CA codes for the p110 alpha 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 p85 alpha and are also inhibited by a range of PI 3-kinase inhibitors (Wortmanin, LY294002, PI-103 and PIK-75) to a similar extent as WT p110 alpha. Both mutants display an increased V-max but while a PDGF derived diphosphotyrosylpeptide caused all increase in V-max for WT p85 alpha/p110 alpha 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. (C) 2009 Elsevier Inc. All rights reserved.