Functional differences between two classes of oncogenic mutation in the PIK3CA gene |
| |
| Authors: | Claire Chaussade Kitty Cho Claire Mawson Gordon W. Rewcastle Peter R. Shepherd |
| |
| Affiliation: | 1. Department of Molecular Medicine, University of Auckland, Private Bag 92019, Auckland, New Zealand;2. Auckland Cancer Society Research Centre, University of Auckland, Private Bag 92019, Auckland, New Zealand;3. Maurice Wilkins Centre for Molecular Biodiscovery, University of Auckland, Private Bag 92019, Auckland, New Zealand;1. Martin-Luther University Halle-Wittenberg, Institute of Biochemistry and Biotechnology, Kurt-Mothes Str. 3, 06120 Halle, Germany;2. Leibniz Institute of Plant Biochemistry, Department of Bioorganic Chemistry, Weinberg 3, 06120 Halle, Germany;1. Medical Oncology Unit, University Hospital of Parma, Parma, Italy;2. Department of Biomedical, Biotechnological and Translational, Section of Pathology, University Hospital of Parma, Parma, Italy;3. Pneumology Unit, University Hospital of Parma, Parma, Italy;4. Radiology Unit, University Hospital of Parma, Parma, Italy;1. Sustainable Energy Technologies Center, College of Engineering, P.O. Box 800, King Saud University, Riyadh 11421, Saudi Arabia;2. Department of Electrical Engineering, College of Engineering, P.O. Box 800, King Saud University, Riyadh 11421, Saudi Arabia |
| |
| Abstract: | 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 Vmax but while a PDGF derived diphosphotyrosylpeptide caused an increase in Vmax for WT p85α/p110α it did not for the E545K variant and actually decreased Vmax 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. |
| |
| Keywords: | |
| 本文献已被 ScienceDirect 等数据库收录！ |
|
