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A tripartite complex composed of ETV6-NTRK3, IRS1 and IGF1R is required for ETV6-NTRK3-mediated membrane localization

C E Tognon1, M J Martin, A Moradian

  • 1Department of Molecular Oncology, BC Cancer Research Centre, Vancouver, British Columbia, Canada.

Oncogene
|August 2, 2011
PubMed

Insights

The ETV6-NTRK3 (EN) oncoprotein requires insulin-like growth factor 1 receptor (IGF1R) and insulin receptor substrate 1 (IRS1) to localize to the cell membrane, driving cancer. Inhibiting IGF1R kinase activity may offer a new cancer therapy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Signaling

Background:

  • ETV6-NTRK3 (EN) is a potent oncoprotein driving various cancers.
  • Insulin-like growth factor 1 receptor (IGF1R) and insulin receptor substrate 1 (IRS1) are crucial for EN-mediated oncogenesis.

Purpose of the Study:

  • To investigate the mechanism by which IRS1 facilitates EN localization to IGF1R at the plasma membrane.
  • To elucidate the role of the EN/IRS1/IGF1R complex in activating phosphatidylinositol 3-kinase (PI3K)-Akt signaling for oncogenesis.

Main Methods:

  • Analysis of EN/IRS1/IGF1R complexes in transformed cells.
  • Assessment of EN transformation activity and cell survival using IGF1R/INSR inhibitor BMS-536924.
  • Co-localization studies of EN and IGF1R at the plasma membrane.

Main Results:

  • Both IRS1 and active IGF1R kinase are essential for EN-mediated cell transformation.
  • Tyrosine-phosphorylated IRS1 forms high molecular weight complexes with EN and IGF1R.
  • EN colocalizes with IGF1R at the plasma membrane, dependent on IGF1R kinase activity and Y950 residue.
  • BMS-536924 inhibits EN transformation, cell survival, and IRS protein interaction, causing a shift in EN complex size.

Conclusions:

  • A tripartite complex of EN, IRS1, and IGF1R is essential for localizing EN to the membrane and driving transformation.
  • This interaction explains the dependence of EN-driven tumors on IGF1R.
  • Targeting IGF1R kinase activity presents a potential therapeutic strategy for EN-driven cancers.

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