ArticleOncogene2012
A tripartite complex composed of ETV6-NTRK3, IRS1 and IGF1R is required for ETV6-NTRK3-mediated membrane localization and transformation.
Article in Oncogene, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 36 citations in OpenAlex.
- SOX11 is frequently expressed in ETV6::NTRK3-rearranged infantile fibrosarcoma and congenital mesoblastic nephroma.Virchows Archiv : an international journal of pathology · 2025Article
- The Impact of ETV6-NTRK3 Oncogenic Gene Fusions on Molecular and Signaling Pathway Alterations.Cancers · 2023Article
- CircVAPA promotes small cell lung cancer progression by modulating the miR-377-3p and miR-494-3p/IGF1R/AKT axis.Molecular cancer · 2022Article
- Fusion partners of NTRK3 affect subcellular localization of the fusion kinase and cytomorphology of melanocytes.Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc · 2021Article
- Brain Metastases in Lung Cancers with Emerging Targetable Fusion Drivers.International journal of molecular sciences · 2020Review
- Review
- Cystine/glutamate antiporter xCT (SLC7A11) facilitates oncogenic RAS transformation by preserving intracellular redox balance.Proceedings of the National Academy of Sciences of the United States of America · 2019Article
- NTRK fusion-positive cancers and TRK inhibitor therapy.Nature reviews. Clinical oncology · 2018Review
- 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
- Oncogenic fusion proteins adopt the insulin-like growth factor signaling pathway.Molecular cancer · 2018Review
- 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
- IGF-1R promotes the expression of cyclin D1 protein and accelerates the G1/S transition by activating Ras/Raf/MEK/ERK signaling pathway.International journal of clinical and experimental pathology · 2017Article
- Detecting and targetting oncogenic fusion proteins in the genomic era.Biology of the cell · 2015Review
Corrections and comments
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Authors and funding
14 authors at 4 institutions in 3 countries.
Funding
Abstract
ETV6-NTRK3 (EN), a chimeric tyrosine kinase generated by t(12;15) translocations, is a dominantly acting oncoprotein in diverse tumor types. We previously showed that insulin-like growth factor 1 receptor (IGF1R) is essential for EN-mediated oncogenesis and that insulin receptor substrate 1 (IRS1) is constitutively tyrosine phosphorylated and bound by EN in transformed cells. Given that IRS1 is also an adapter for IGF1R, we hypothesized that IRS1 might localize EN to IGF1R at the membrane to activate phosphatidylinositol 3-kinase (PI3K)-Akt, which is critical for EN oncogenesis. In this study, we examined EN/IRS1/IGF1R complexes in detail. We find that both IRS1 and kinase active IGF1R are required for EN transformation, that tyrosine phosphorylated IRS1 is present in high molecular weight complexes with EN and IGF1R, and that EN colocalizes with IGF1R at the plasma membrane. Both IGF1R kinase activity and an intact cytoplasmic Y950 residue, the IRS1-docking site of IGF1R, are required, confirming the importance of the IGF1R/IRS1 interaction for EN oncogenesis. The dual specificity IGF1R and insulin receptor (INSR) inhibitor, BMS-536924, blocks EN transformation activity, cell survival and its interaction with IRS proteins, and induces a striking shift of EN proteins to smaller sized molecular complexes. We conclude that a tripartite complex of EN, IRS1 and IGF1R localizes EN to the membrane and that this is essential for EN-mediated transformation. These findings provide an explanation for the observed IGF1R dependency of EN transformation. Blocking IGF1R kinase activity may, therefore, provide a tractable therapeutic strategy for the many tumor types driven by the EN oncoprotein.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.