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Molecular and Cellular Biology, March 2006, p. 1754-1769, Vol. 26, No. 5
0270-7306/06/$08.00+0     doi:10.1128/MCB.26.5.1754-1769.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

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

Department of Molecular Oncology, British Columbia Cancer Research Centre, Vancouver, British Columbia V5Z 1L3, Canada,¹ The Prostate Centre, Vancouver General Hospital, Vancouver, British Columbia, and Division of Urology, University of British Columbia, Vancouver, British Columbia V6H 3Z6, Canada,² The James Hogg iCAPTURE Centre for Cardiovascular and Pulmonary Research, Department of Pathology, University of British Columbia, Vancouver, British Columbia V6Z 1Y6, Canada,³ Department of Pathology, University of British Columbia, Vancouver, British Columbia V5Z 4H4, Canada⁴

Received 17 August 2005/ Returned for modification 21 September 2005/ Accepted 1 December 2005

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.

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