Oncogenic signaling of class I PI3K isoforms

Oncogene. 2008 Apr 17;27(18):2561-74. doi: 10.1038/sj.onc.1210918. Epub 2007 Nov 12.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Membrane / genetics
  • Cell Membrane / metabolism
  • Cell Transformation, Neoplastic / genetics
  • Cell Transformation, Neoplastic / metabolism*
  • Cells, Cultured
  • Chick Embryo
  • Chickens
  • Extracellular Signal-Regulated MAP Kinases / genetics
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Fibroblasts / enzymology*
  • Fibroblasts / pathology
  • Forkhead Transcription Factors / genetics
  • Forkhead Transcription Factors / metabolism
  • Glycogen Synthase Kinase 3 / genetics
  • Glycogen Synthase Kinase 3 / metabolism
  • Glycogen Synthase Kinase 3 beta
  • Isoenzymes / genetics
  • Isoenzymes / metabolism
  • Mutation*
  • Phosphatidylinositol 3-Kinases / genetics
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Protein Kinases / genetics
  • Protein Kinases / metabolism
  • Proto-Oncogene Proteins c-akt / genetics
  • Proto-Oncogene Proteins c-akt / metabolism
  • Signal Transduction* / genetics
  • TOR Serine-Threonine Kinases
  • ras Proteins / genetics
  • ras Proteins / metabolism

Substances

  • Forkhead Transcription Factors
  • Isoenzymes
  • Protein Kinases
  • Phosphatidylinositol 3-Kinases
  • TOR Serine-Threonine Kinases
  • Glycogen Synthase Kinase 3 beta
  • Proto-Oncogene Proteins c-akt
  • Extracellular Signal-Regulated MAP Kinases
  • Glycogen Synthase Kinase 3
  • ras Proteins