ArticleMolecular and cellular biology2004
Mutations in the SAM domain of the ETV6-NTRK3 chimeric tyrosine kinase block polymerization and transformation activity.
Article in Molecular and cellular biology, 2004. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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Who cites it
26 citing papers in PubMed, 47 citations in OpenAlex.
- Secretory carcinoma of the breast: a report of six cases with different immunophenotypes and molecular subtypes.Histopathology · 2026Article
- Filament formation and NAD processing by noncanonical human FAM118 sirtuins.Nature structural & molecular biology · 2025Article
- ERK signaling promotes resistance to TRK kinase inhibition in NTRK fusion-driven glioma mouse models.Cell reports · 2024Article
- Novel insight into mechanisms of ROS1 catalytic activation via loss of the extracellular domain.Scientific reports · 2024Article
- Functional Classification of Fusion Proteins in Sarcoma.Cancers · 2024Review
- Phase separation underlies signaling activation of oncogenic NTRK fusions.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- Sticky, Adaptable, and Many-sided: SAM protein versatility in normal and pathological hematopoietic states.BioEssays : news and reviews in molecular, cellular and developmental biology · 2023Review
- Methods for Identifying Patients with Tropomyosin Receptor Kinase (TRK) Fusion Cancer.Pathology oncology research : POR · 2020Review
- Review
- ALK Fusion Partners Impact Response to ALK Inhibition: Differential Effects on Sensitivity, Cellular Phenotypes, and Biochemical Properties.Molecular cancer research : MCR · 2018Article
- 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
- 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
- DNA Occupancy of Polymerizing Transcription Factors: A Chemical Model of the ETS Family Factor Yan.Biophysical journal · 2017Article
- NTRK3 kinase fusions in Spitz tumours.The Journal of pathology · 2016Article
- 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
- Article
- Tyrosine kinase gene fusions in cancer: translating mechanisms into targeted therapies.Journal of cellular and molecular medicine · 2012Review
- Article
- Characterization of a newly identified ETV6-NTRK3 fusion transcript in acute myeloid leukemia.Diagnostic pathology · 2011Article
- SAM domain-dependent activity of PfTKL3, an essential tyrosine kinase-like kinase of the human malaria parasite Plasmodium falciparum.Cellular and molecular life sciences : CMLS · 2010Article
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The 12p13 ETV6 (TEL) gene is frequently targeted by chromosomal translocations in human malignancies, resulting in the formation of oncogenic ETV6 gene fusions. Many of the known partner genes encode protein tyrosine kinases (PTKs), generating fusion proteins that function as chimeric PTKs. ETV6-NTRK3 (EN), comprised of the ETV6 SAM domain fused to the NTRK3 PTK, is unique among ETV6 chimeric oncoproteins, as it is expressed in cancers of multiple lineages. We initially hypothesized that, similar to other ETV6-PTK chimeras, SAM-mediated dimerization of EN leads to constitutive activation of the PTK and downstream signaling cascades. However, when the EN SAM domain was replaced with an inducible FK506 binding protein (FKBP) dimerization system, resulting FKBP-NTRK3 chimeras failed to transform NIH 3T3 cells even though PTK activation was preserved. It was recently shown that the ETV6 SAM domain has two potential interacting surfaces, raising the possibility that this domain can mediate protein polymerization. We therefore mutated each EN SAM binding interface in a manner shown previously to abolish self-association of wild-type ETV6. Each mutation completely blocked the ability of EN to polymerize, to activate its PTK, and to transform NIH 3T3 cells. Furthermore, EN itself formed large polymeric structures within cells while mutant EN proteins were present only as monomers. Finally, we observed a dominant negative effect on the transformation of isolated SAM domains coexpressed in EN-transformed cells. Taken together, our results suggest that higher-order polymerization may be a critical requirement for the transformation activity of EN and possibly other ETV6-PTK fusion proteins.
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