ArticleOncogene2002
ETV6-NTRK3 transformation requires insulin-like growth factor 1 receptor signaling and is associated with constitutive IRS-1 tyrosine phosphorylation.
Article in Oncogene, 2002. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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Who cites it
28 citing papers in PubMed, 73 citations in OpenAlex.
- Delayed growth of SK-ES-1 Ewing sarcoma tumor xenografts is associated with reduced Trk and IGF1R pathway markers.Oncotarget · 2026Article
- Current management of neurotrophic receptor tyrosine kinase fusion-positive sarcoma: an updated review.Japanese journal of clinical oncology · 2025Review
- Article
- Functional Classification of Fusion Proteins in Sarcoma.Cancers · 2024Review
- The Impact of ETV6-NTRK3 Oncogenic Gene Fusions on Molecular and Signaling Pathway Alterations.Cancers · 2023Article
- Decoding Oncofusions: Unveiling Mechanisms, Clinical Impact, and Prospects for Personalized Cancer Therapies.Cancers · 2023Review
- The oncogenic fusion landscape in pediatric CNS neoplasms.Acta neuropathologica · 2022Review
- Methods for Identifying Patients with Tropomyosin Receptor Kinase (TRK) Fusion Cancer.Pathology oncology research : POR · 2020Review
- Targeting Insulin-Like Growth Factor 1 Receptor Delays M-Phase Progression and Synergizes with Aurora B Inhibition to Suppress Cell Proliferation.International journal of molecular sciences · 2020Article
- Insights into Current Tropomyosin Receptor Kinase (TRK) Inhibitors: Development and Clinical Application.Journal of medicinal chemistry · 2019Article
- Insulin-like growth factor 1 receptor stabilizes the ETV6-NTRK3 chimeric oncoprotein by blocking its KPC1/Rnf123-mediated proteasomal degradation.The Journal of biological chemistry · 2018Article
- The crucial role of multiomic approach in cancer research and clinically relevant outcomes.The EPMA journal · 2018Review
- Leptocarpin Suppresses Proliferation, Migration, and Invasion of Human Osteosarcoma by Targeting Type-1 Insulin-Like Growth Factor Receptor (IGF-1R).Medical science monitor : international medical journal of experimental and clinical research · 2017Article
- Genomic profiling of breast secretory carcinomas reveals distinct genetics from other breast cancers and similarity to mammary analog secretory carcinomas.Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc · 2017Article
- EGFR Mediates Responses to Small-Molecule Drugs Targeting Oncogenic Fusion Kinases.Cancer research · 2017Article
- Exploring Mouse Protein Function via Multiple Approaches.PloS one · 2016Article
- Transcription factor TIP27 regulates glucose homeostasis and insulin sensitivity in a PI3-kinase/Akt-dependent manner in mice.International journal of obesity (2005) · 2015Article
- TRKing down an old oncogene in a new era of targeted therapy.Cancer discovery · 2015Review
- Identification of kinase fusion oncogenes in post-Chernobyl radiation-induced thyroid cancers.The Journal of clinical investigation · 2013Article
- Mutation of the salt bridge-forming residues in the ETV6-SAM domain interface blocks ETV6-NTRK3-induced cellular transformation.The Journal of biological chemistry · 2013Article
Corrections and comments
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Authors and funding
5 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
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.
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