Requirement of Phosphatidylinositol(3,4,5)Trisphosphate in Phosphatidylinositol 3-Kinase-Induced Oncogenic Transformation

• Published in: Molecular cancer research 2009-07, Vol.7 (7), p.1132-1138
• Main Authors: Denley, Adam, Gymnopoulos, Marco, Kang, Sohye, Mitchell, Christina, Vogt, Peter K
• Format: Article
• Language: English
• Subjects: Animals; Catalytic Domain; Cell Line; Cell Transformation, Neoplastic - metabolism; Chick Embryo; Fibroblasts - metabolism; Inositol Polyphosphate 5-Phosphatases; oncogenicity; Phosphatidylinositol 3-Kinases - metabolism; Phosphatidylinositol Phosphates - metabolism; Phosphoric Monoester Hydrolases - metabolism; PIP3; PIPP phosphatase; Proto-Oncogene Proteins c-akt - metabolism; Signal Transduction
• ISSN: 1541-7786; 1557-3125
• DOI: 10.1158/1541-7786.MCR-09-0068

Phosphatidylinositol 3-kinases (PI3K) are divided into three classes, which differ in their substrates and products. Class I generates the inositol phospholipids PI(3)P, PI(3,4)P 2 , and PI(3,4,5)P 3 referred as PIP, PIP 2 , and PIP 3 , respectively. Class II produces PIP and PIP 2 , and class III generates only PIP. Substrate and product differences of the three classes are determined by the activation loops of their catalytic domains. Substitution of the class I activation loop with either class II or III activation loop results in a corresponding change of substrate preference and product restriction. We have evaluated such activation loop substitutions to show that oncogenic activity of class I PI3K is linked to the ability to produce PIP 3 . We further show that reduction of cellular PIP 3 levels by the 5′-phosphatase PIPP interferes with PI3K-induced oncogenic transformation. PIPP also attenuates signaling through Akt and target of rapamycin. Class III PI3K fails to induce oncogenic transformation. Likewise, a constitutively membrane-bound class I PI3K mutant retaining only the protein kinase is unable to induce transformation. We conclude that PIP 3 is an essential component of PI3K-mediated oncogenesis and that inability to generate PIP 3 abolishes oncogenic potential. (Mol Cancer Res 2009;7(7):1132–8)