ETV6-NTRK3 transformation requires insulin-like growth factor 1 receptor signaling and is associated with constitutive IRS-1 tyrosine phosphorylation.

Abstract	Congenital fibrosarcoma (CFS) and cellular mesoblastic nephroma (CMN) are pediatric spindle cell malignancies that share two specific cytogenetic abnormalities: trisomy of chromosome 11 and a t(12;15)(p13;q25) translocation. The t(12;15) rearrangement creates a transcriptionally active fusion gene that encodes a chimeric oncoprotein, ETV6-NTRK3 (EN). EN transforms NIH3T3 fibroblasts through constitutive activation of both the Ras-mitogen-activated protein kinase (MAPK) pathway and the phosphatidylinositol-3'kinase (PI3K)-Akt pathway. However, the role of trisomy 11 in CFS and CMN remains unknown. In this study we demonstrate elevated expression of the chromosome 11p15.5 insulin-like growth factor 2 gene (IGF2) in CFS and CMN tumors. Moreover, we present evidence that an intact IGF signaling axis is essential for in vitro EN-mediated transformation. EN only very weakly transformed so-called R-murine fibroblasts derived from mice with a targeted disruption of the IGF1 receptor gene (IGFRI), but transformation activity was fully restored in R- cells engineered to re-express IGFRI (R+ cells). We also observed that the major IGFRI substrate, insulin-receptor substrate-1 (IRS-1), was constitutively tyrosine phosphorylated and could be co-immunoprecipitated with EN in either R- or R+ cells expressing the EN oncoprotein. IRS-1 association with Grb2 and PI3K p85, which link IGFRI to the Ras-MAPK and PI3K-Akt pathways, respectively, was enhanced in both cell types in the presence of EN. However, activation of the Ras-MAPK and PI3K-Akt pathways was markedly attenuated in EN-expressing R- cells compared to EN-transformed R+ cells. This suggests that IRS-1 may be functioning as an adaptor in EN signal transduction, but that a link to EN transformation pathways requires the presence of IGFRI. Our findings indicate that an intact IGF signaling axis is essential for EN transformation, and are consistent with a role for trisomy 11 in augmenting this pathway in EN expressing tumors.
Authors	Kevin B Morrison, Cristina E Tognon, Mathew J Garnett, Cheri Deal, Poul H B Sorensen
Journal	Oncogene (Oncogene) Vol. 21 Issue 37 Pg. 5684-95 (Aug 22 2002) ISSN: 0950-9232 [Print] England
PMID	12173038 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	Adaptor Proteins, Signal Transducing DNA-Binding Proteins GRB2 Adaptor Protein Grb2 protein, mouse Insulin Receptor Substrate Proteins Irs1 protein, mouse Phosphoproteins Proteins Proto-Oncogene Proteins Proto-Oncogene Proteins c-ets Repressor Proteins Tyrosine Insulin-Like Growth Factor II Protein-Tyrosine Kinases Receptor, IGF Type 1 Receptor, trkC Protein Serine-Threonine Kinases Proto-Oncogene Proteins c-akt MAP Kinase Kinase 1 MAP Kinase Kinase 2 Map2k1 protein, mouse Mitogen-Activated Protein Kinase Kinases
Topics	Adaptor Proteins, Signal Transducing Animals Cell Transformation, Neoplastic DNA-Binding Proteins (physiology) GRB2 Adaptor Protein Insulin Receptor Substrate Proteins Insulin-Like Growth Factor II (genetics) MAP Kinase Kinase 1 MAP Kinase Kinase 2 Mice Mitogen-Activated Protein Kinase Kinases (metabolism) Phosphoproteins (metabolism) Phosphorylation Protein Serine-Threonine Kinases (metabolism) Protein-Tyrosine Kinases (metabolism) Proteins (physiology) Proto-Oncogene Proteins (metabolism) Proto-Oncogene Proteins c-akt Proto-Oncogene Proteins c-ets Receptor, IGF Type 1 (physiology) Receptor, trkC (physiology) Repressor Proteins (physiology) Signal Transduction Tyrosine (metabolism) ETS Translocation Variant 6 Protein

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