Oncogenic signaling of class I PI3K isoforms

The catalytic subunits of class I PI3Ks comprise four isoforms: p110alpha, p110beta, p110delta and p110gamma. Cancer-specific gain-of-function mutations in p110alpha 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 p110beta, p110gamma or p110delta is sufficient to induce cellular transformation in chicken embryo fibroblasts. The mechanism whereby these non-alpha isoforms of class I mediate oncogenic signals is unknown. Here we show that potently transforming class I isoforms signal via Akt/mTOR, inhibit GSK3beta and cause degradation of FoxO1. A functional Erk pathway is required for p110gamma and p110beta transformation but not for transformation by p110delta or the H1047R mutant of p110alpha. Transformation and signaling by p110gamma and p110beta are sensitive to loss of interaction with Ras, which acts as a membrane anchor. Mutations in the C2 domain of p110delta 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 p110beta and p110gamma.