1. ¹Department of Molecular and Experimental Medicine, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA, USA
2. ²In den Almen 15, Bad Dürkheim, Germany

Correspondence: Professor P Vogt, Department of Molecular and Experimental Medicine, The Scripps Research Institute, 10550 North Torrey Pines Road, BCC-239, La Jolla, CA 92037, USA. E-mail: pkvogt@scripps.edu

³Current address: Amgen, One Amgen Center Drive, Thousand Oaks, CA 91320, USA.

Received 2 July 2007; Revised 3 October 2007; Accepted 10 October 2007; Published online 12 November 2007.

Abstract

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