A tripartite complex composed of ETV6-NTRK3, IRS1 and IGF1R is required for ETV6-NTRK3-mediated membrane localization and transformation

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.

Case report of mammary analog secretory carcinoma of the parotid gland

“…Recently, Tognon et al . hypothesized that this chimeric gene transcript might activate phosphatidylinositol 3‐kinase (PI3K)‐Akt pathway, which was critical for transformation 8 . It is important to differentiate MASC form other types of salivary gland tumors because a new therapeutic strategy for tumors driven by ETV6‐NTRK3 oncoprotein might be provided in the future.…”

Individualized Systems Medicine Strategy to Tailor Treatments for Patients with Chemorefractory Acute Myeloid Leukemia

“…6C and D and Supplementary Table S6). The gained sensitivity to the dual IGF-IR/TrkC inhibitor BMS-754807 fi ts with the model of the TEL-TrkC fusion protein as a new driver, because the oncogenic potential of this fusion has been shown to be dependent on the activity of IGF-IR ( 18,19 ) and lead to hyperactivation of mTORC1 ( 20,21 ). Thus, we predict that in this patient, the mechanism of resistance involved Figure 5.…”

Genomic profiling of breast secretory carcinomas reveals distinct genetics from other breast cancers and similarity to mammary analog secretory carcinomas

“…1,2,5,9,10 ETV6-NTRK3 encodes a chimeric tyrosine kinase that signals through Rasmitogen activated protein kinase and phosphatidyl inositol-3 kinase pathways to transform cells of multiple lineages. [11][12][13][14][15][16] Morphologic features of breast secretory carcinomas are those of grade 1 or grade 2 tumors comprised of polygonal cells with eosinophilic or vacuolated cytoplasm and small, round to oval nuclei arranged in microcystic, solid, tubular, or papillary growth patterns and associated with periodic acid Schiff (PAS)-positive secretions. 1,2,5,6,17 High-grade tumors have only rarely been reported.…”