Phosphatidylinositol 3-Kinase Mutations Identified in Human Cancer Are Oncogenic

• Published in: Proceedings of the National Academy of Sciences - PNAS 2005-01, Vol.102 (3), p.802-807
• Main Authors: Kang, Sohye, Bader, Andreas G., Vogt, Peter K.
• Format: Article
• Language: English
• Subjects: Animals; Antibodies; Biological Sciences; Cancer; Carrier Proteins - metabolism; Cell Proliferation; Cell Transformation, Neoplastic - genetics; Chick Embryo; Chickens; Enzymes; Exons; Fibroblasts - enzymology; Fibroblasts - pathology; Genetic mutation; Humans; Lipids; Medical research; Mutant proteins; Mutation; Mutation, Missense; Neoplasms - enzymology; Neoplasms - genetics; Phosphatidylinositol 3-Kinases - genetics; Phosphatidylinositols; Phosphorylation; Protein Serine-Threonine Kinases - metabolism; Protein synthesis; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-akt; Ribosomal Protein S6 Kinases - metabolism; Signal Transduction - genetics; Tumors
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0408864102

Mutations in genes that encode components of the phosphatidylinositol 3-kinase (PI3-kinase) signaling pathway are common in human cancer. The recent discovery of nonrandom somatic mutations in the PIK3CA gene of many human tumors suggests an oncogenic role for the mutated enzyme. We have determined the growth-regulatory and signaling properties of the three most frequently observed PI3-kinase mutations: E542K, E545K, and H1047R. Expressed in chicken embryo fibroblasts, all three mutants induce oncogenic transformation with high efficiency. This transforming ability is correlated with elevated catalytic activity in in vitro kinase assays. The mutant-transformed cells show constitutive phosphorylation of Akt, of p70 S6 kinase, and of the 4E-binding protein 1. Phosphorylation of S6 kinase and of 4E-binding protein 1 is regulated by the target of rapamycin (TOR) kinase and affects rates of protein synthesis. The inhibitor of TOR, rapamycin, strongly interferes with cellular transformation induced by the PI3-kinase mutants, suggesting that the TOR and its downstream targets are essential components of the transformation process. The oncogenic transforming activity makes the mutated PI3-kinase proteins promising targets for small molecule inhibitors that could be developed into effective and highly specific anticancer drugs.