Effects of oncogenic p110alpha subunit mutations on the lipid kinase activity of phosphoinositide 3-kinase.
The PIK3CA gene, encoding the p110alpha catalytic subunit of Class IA PI3Ks (phosphoinositide 3-kinases), is frequently mutated in many human tumours. The three most common tumour-derived alleles of p110alpha, H1047R, E542K and E545K, were shown to potently activate PI3K signalling in human epithelial cells. In the present study, we examine the biochemical activity of the recombinantly purified PI3K oncogenic mutants. The kinetic characterizations of the wt (wild-type) and the three 'hot spot' PI3K mutants show that the mutants all have approx. 2-fold increase in lipid kinase activities. Interestingly, the phosphorylated IRS-1 (insulin receptor substrate-1) protein shows activation of the lipid kinase activity for the wt and H1047R but not E542K and E545K PI3Kalpha, suggesting that these mutations represent different mechanisms of lipid kinase activation and hence transforming activity in cancer cells.
Carson
Jeffrey D
JD
Department of Enzymology and Mechanistic Pharmacology, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, PA 19426, USA.
Van Aller
Glenn
G
Lehr
Ruth
R
Sinnamon
Robert H
RH
Kirkpatrick
Robert B
RB
Auger
Kurt R
KR
Dhanak
Dashyant
D
Copeland
Robert A
RA
Gontarek
Richard R
RR
Tummino
Peter J
PJ
Luo
Lusong
L
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000483:Alleles; D020134:Catalytic Domain; D058534:Class I Phosphatidylinositol 3-Kinases; D004789:Enzyme Activation; D006801:Humans; D055504:Insulin Receptor Substrate Proteins; D007700:Kinetics; D009154:Mutation; D009857:Oncogenes; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics* / Q000378:metabolism; D010766:Phosphorylation; D011994:Recombinant Proteins / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism; D014407:Tumor Cells, Cultured
D048868:Adaptor Proteins, Signal Transducing; C526292:IRS1 protein, human; D055504:Insulin Receptor Substrate Proteins; D011994:Recombinant Proteins; D000255:Adenosine Triphosphate; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C497132:PIK3CB protein, human