title: Functional differences between two classes of oncogenic mutation in the PIK3CA gene.
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.
authors.affiliation: Department of Molecular Medicine, University of Auckland, New Zealand.
authors.forename: Claire
authors.initials: C
authors.lastname: Chaussade
authors.forename: Kitty
authors.initials: K
authors.lastname: Cho
authors.forename: Claire
authors.initials: C
authors.lastname: Mawson
authors.forename: Gordon W
authors.initials: GW
authors.lastname: Rewcastle
authors.forename: Peter R
authors.initials: PR
authors.lastname: Shepherd
mesh_terms: D058534:Class I Phosphatidylinositol 3-Kinases; D006801:Humans; D009154:Mutation; D009369:Neoplasms / Q000235:genetics*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017433:Protein Structure, Secondary / Q000235:genetics; D017434:Protein Structure, Tertiary / Q000235:genetics
chemical_list: D058534:Class I Phosphatidylinositol 3-Kinases; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; C484760:PIK3CA protein, human