PIK3CA codes for the p110α 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 p85α 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 p110α. Both mutants display an increased V max but while a PDGF derived diphosphotyrosylpeptide caused an increase in V max for WT p85α/p110α 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.
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Functional differences between two classes of oncogenic mutation in the PIK3CA gene
Chaussade, Claire; Cho, Kitty; Mawson, Claire; Rewcastle, Gordon W.; Shepherd, Peter R.
Follow Biochemical and Biophysical Research Communications
, Volume 381 (4)
Elsevier – Apr 17, 2009
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