Oncogenic signaling of class IPI3K isoforms

The catalytic subunits of class I PI3Ks comprise four isoforms: p110 alpha, p110 beta, p110 delta and p110 gamma. Cancer-specific gain-of-function mutations in p110 alpha delta beta have been identified in various malignancies. Cancer-specific mutations in the non-alpha isoforms of class I PI3K have not yet been identified, however overexpression of either wild-type p110 beta, p110 gamma or p110 delta is sufficient to induce cellular transformation in chicken embryo fibroblasts. The mechanism whereby these non-a isoforms of class I mediate oncogenic signals is unknown. Here we show that potently transforming class I isoforms signal via Akt/mTOR, inhibit GSK3 beta and cause degradation of FoxO1. A functional Erk pathway is required for p110 gamma and p110 beta transformation but not for transformation by p110 delta or the H1047R mutant of p110 alpha. Transformation and signaling by p110 gamma and p110 beta are sensitive to loss of interaction with Ras, which acts as a membrane anchor. Mutations in the C2 domain of p110 delta reduce transformation, most likely by interfering with membrane association. Several small molecule inhibitors potently and specifically inhibit the oncogenic signaling and transformation of each of the class I PI3K, and, when used in combination with MEK inhibitors, can additively reduce the transformation induced by p110 beta and p110 gamma.