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J. Biol. Chem., Vol. 279, Issue 8, 6225-6234, February 20, 2004
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From the
Departments of Pathology and Pediatrics, British Columbia Research Institute for Children's and Women's Health and the University of British Columbia, Vancouver, British Columbia V5Z4H4, Canada, and the **Laboratory of Cell Regulation and Carcinogenesis, NCI, National Institutes of Health, Bethesda, Maryland 20892
Receptor tyrosine kinases are integral components of cellular signaling pathways and are frequently deregulated in malignancies. The NTRK family of neurotrophin receptors mediate neuronal cell survival and differentiation, but altered NTRK signaling has also been implicated in oncogenesis. The ETV6-NTRK3 (EN) gene fusion occurs in human pediatric spindle cell sarcomas and secretory breast carcinoma, and encodes the oligomerization domain of the ETV6 transcription factor fused to the protein-tyrosine kinase domain of NTRK3. The EN protein functions as a constitutively active protein-tyrosine kinase with potent transforming activity in multiple cell lineages, and EN constitutively activates both the Ras-MAPK and phosphatidylinositol 3-kinase-Akt pathways. EN transformation is associated with constitutive tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1). Further, IRS-1 functions as the adaptor protein linking EN to downstream signaling pathways. However, the exact nature of the EN-IRS-1 interaction remains unknown. We now demonstrate that EN specifically binds the phosphotyrosine binding domain of IRS-1 via an interaction at the C terminus of EN. An EN mutant lacking the C-terminal 19 amino acids does not bind IRS-1 and lacks transforming ability. Moreover, expression of an IRS-1 polypeptide containing the phosphotyrosine binding domain acts in a dominant negative manner to inhibit EN transformation, and overexpression of IRS-1 potentiates EN transforming activity. These findings indicate that EN·IRS-1 complex formation through the NTRK3 C terminus is essential for EN transformation.
Received for publication, July 10, 2003 , and in revised form, October 28, 2003.
* This work was supported in part by the Canadian Institutes for Health Research (to P. H. B. S.) and by the Johal Program in Pediatric Oncology Basic and Translational Research at the British Columbia Research Institute for Children's and Women's Health. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Recipient of a doctoral trainee award from the Michael Smith Foundation for Health Research.
¶ Recipient of a doctoral research award from the Canadian Institutes for Health Research.
|| Recipient of a postdoctoral fellowship from the Candlelighter's Childhood Cancer Foundation/Canadian Institutes for Health Research.
To whom correspondence should be addressed: British Columbia Research Institute for Children's and Women's Health, Rm. 3082, 950 West 28th Ave., Vancouver, BC V5Z4H4, Canada. Tel.: 604-875-2936; Fax: 604-875-3417; E-mail: psor{at}interchange.ubc.ca.
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