Effects of oncogenic p110α subunit mutations on the lipid kinase activity of phosphoinositide 3-kinase

被引：104

作者：

Carson, Jeffrey D. ^{[1
]}

Van Aller, Glenn ^{[1
]}

Lehr, Ruth ^{[2
]}

Sinnamon, Robert H. ^{[2
]}

Kirkpatrick, Robert B. ^{[2
]}

Auger, Kurt R. ^{[3
]}

Dhanak, Dashyant ^{[4
]}

Copeland, Robert A. ^{[1
,3
]}

Gontarek, Richard R. ^{[1
]}

Tummino, Peter J. ^{[1
]}

Luo, Lusong ^{[1
]}

机构：

[1] GlaxoSmithKline Inc, Dept Enzymol & Mechanist Pharmacol, Collegeville, PA 19426 USA

[2] GlaxoSmithKline Inc, Mol Discovery Res, BRAD, Collegeville, PA 19426 USA

[3] GlaxoSmithKline Inc, CEDD, Dept Biol, Collegeville, PA 19426 USA

[4] GlaxoSmithKline Inc, Oncol CEDD, Dept Med Chem, Collegeville, PA 19426 USA

来源：

BIOCHEMICAL JOURNAL | 2008年 / 409卷 / 519-524期

关键词：

insulin receptor substrate-1 (IRS-1); lipid kinase activation; mutant activation; oncogenic mutant; phosphoinositide 3-kinase alpha (PI3K alpha);

D O I：

10.1042/BJ20070681

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

The PIK3CA gene, encoding the p110 alpha catalytic subunit of Class IA PI3Ks (phosphoinositide 3-kinases), is frequently mutated in many human tumours. The three most common tumour-derived alleles of p110 alpha, 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 PI3K alpha, suggesting that these mutations represent different mechanisms of lipid kinase activation and hence transforming activity in cancer cells.

引用

页码：519 / 524

页数：6