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Cellular Transformation and Activation of the Phosphoinositide-3-Kinase–Akt Cascade by the ETV6-NTRK3 Chimeric Tyrosine Kinase Requires c-Src

¹ Laboratory of Cancer Biology and Genetics, National Cancer Institute, Bethesda, Maryland; ² Department of Molecular Oncology, British Columbia Cancer Research Centre, Vancouver, British Columbia, Canada; and ³ Lee Gil Ya Cancer and Diabetes Institute, Gachon University of Medicine and Science, Incheon, Korea

Requests for reprints: Seong-Jin Kim, Laboratory of Cell Regulation and Carcinogenesis, National Cancer Institute, Building 41, Room B1106, 41 Library Drive, Bethesda, MD 20892-5055. Phone: 301-496-8350; Fax: 301-496-8395; E-mail: Kims{at}mail.nih.gov or jasonsjkim{at}gachon.ac.kr.

The ETV6-NTRK3 (EN) chimeric tyrosine kinase, a potent oncoprotein expressed in tumors derived from multiple cell lineages, functions as a constitutively active protein-tyrosine kinase. ETV6-NTRK expression leads to the constitutive activation of two major effector pathways of wild-type NTRK3, namely, the Ras–mitogen-activated protein kinase (MAPK) mitogenic pathway and the phosphoinositide-3-kinase (PI3K)-Akt pathway mediating cell survival, and both are required for EN transformation. However, it remains unclear how ETV6-NTRK3 activates Ras-Erk1/2 and/or PI3K-Akt cascades. Here, we define some aspects of the molecular mechanisms regulating ETV6-NTRK–dependent Ras-Erk1/2 and PI3K-Akt activation. We show that ETV6-NTRK3 associates with c-Src, and that treatment with SU6656, a c-Src inhibitor, completely blocks ETV6-NTRK-transforming activity. Treatment of NIH3T3 cells expressing ETV6-NTRK3 with SU6656 attenuated the activation of Ras-Erk1/2 and PI3K-Akt. Suppression of c-Src by RNA interference in NIH3T3-ETV6-NTRK3 cells resulted in markedly decreased expression of cyclin D1 and suppression of activation of Ras-Erk1/2 and PI3K-Akt. However, in Src-deficient cells, the ETV6-NTRK3 failed to activate the PI3K-Atk pathway, but not the Ras-Erk1/2 pathway. Therefore, these data indicate that ETV6-NTRK3 induces the PI3K-Akt cascade through the activation of c-Src. [Cancer Res 2007;67(7):3192–200]

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