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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

Matthew J. Martin,1 Nataliya Melnyk,1 Michelle Pollard,1 Mary Bowden,2 Hon Leong,3 Thomas J. Podor,3 Martin Gleave,2 and Poul H. B. Sorensen1,4*

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.

* Corresponding author. Mailing address: Department of Molecular Oncology, British Columbia Cancer Research Centre, Room 4-112, Vancouver, British Columbia V5Z 1L4, Canada. Phone: (604) 675-8202. Fax: (604) 675-8218. E-mail: psor{at}interchange.ubc.ca.

Molecular and Cellular Biology, March 2006, p. 1754-1769, Vol. 26, No. 5
0022-538X/06/$08.00+0     doi:10.1128/MCB.26.5.1754-1769.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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