The insulin-like growth factor I receptor is required for Akt activation and suppression of anoikis in cells transformed by the ETV6-NTRK3 chimeric tyrosine kinase

Mol Cell Biol. 2006 Mar;26(5):1754-69. doi: 10.1128/MCB.26.5.1754-1769.2006.

Abstract

Signaling through the insulin-like growth factor I receptor (IGF-IR) axis is essential for transformation by many dominantly acting oncoproteins. However, the mechanism by which IGF-IR contributes to oncogenesis remains unknown. To examine this, we compared transformation properties of the oncogenic ETV6-NTRK3 (EN) chimeric tyrosine kinase in IGF-IR-null R- mouse embryo fibroblasts with R- cells engineered to reexpress IGF-IR (R+ cells). We previously showed that R- cells expressing EN (R- EN cells) are resistant to transformation but that transformation is restored in R+ cells. We now show that while R- EN cells have intact Ras-extracellular signal-regulated kinase signaling and cell cycle progression, they are defective in phosphatidylinositol-3-kinase (PI3K)-Akt activation and undergo detachment-induced apoptosis (anoikis) under anchorage-independent conditions. In contrast, R+ cells expressing EN (R+ EN cells) suppress anoikis and are fully transformed. The requirement for IGF-IR in R- EN cells is overcome by ectopic expression of either activated Akt or a membrane-targeted form of EN. Moreover, compared to R- EN cells, R+ EN cells show a dramatic increase in membrane localization of insulin receptor substrate 1 (IRS-1) in association with EN. Since EN is known to bind IRS-1 as an adaptor protein, our findings suggest that IGF-IR may function to localize EN/IRS-1 complexes to cell membranes, in turn facilitating PI3K-Akt activation and suppression of anoikis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anoikis*
  • Cell Membrane / metabolism
  • Cell Proliferation / drug effects
  • Cell Transformation, Neoplastic / metabolism*
  • Cyclin D1 / genetics
  • Cyclin D1 / metabolism
  • Enzyme Activation
  • Enzyme Inhibitors / pharmacology
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism
  • Fibroblasts / pathology
  • Insulin Receptor Substrate Proteins
  • Male
  • Mice
  • Mice, Nude
  • Mutation
  • Oncogene Proteins, Fusion / genetics
  • Oncogene Proteins, Fusion / metabolism*
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphoinositide-3 Kinase Inhibitors
  • Phosphoproteins / metabolism
  • Proto-Oncogene Proteins c-akt / genetics
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Receptor, IGF Type 1 / genetics
  • Receptor, IGF Type 1 / metabolism*
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Tumor Stem Cell Assay

Substances

  • ETV6-NTRK3 fusion protein, human
  • Enzyme Inhibitors
  • Insulin Receptor Substrate Proteins
  • Irs1 protein, mouse
  • Oncogene Proteins, Fusion
  • Phosphoinositide-3 Kinase Inhibitors
  • Phosphoproteins
  • Recombinant Proteins
  • Cyclin D1
  • Receptor, IGF Type 1
  • Proto-Oncogene Proteins c-akt