ArticleThe Journal of biological chemistry2013
Mutation of the salt bridge-forming residues in the ETV6-SAM domain interface blocks ETV6-NTRK3-induced cellular transformation.
Article in The Journal of biological chemistry, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed, 20 citations in OpenAlex.
- From Classical to Emerging Biomarkers of Brain and Central Nervous System Tumors. An Evidence-Based Review with a Focus on Gliomas.Cellular and molecular neurobiology · 2026Review
- The oncogenic fusion protein EML4-NTRK3 requires three salt bridges for stability and biological activity.Heliyon · 2024Article
- 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
- Oncogenic fusion protein BCR-FGFR1 requires the breakpoint cluster region-mediated oligomerization and chaperonin Hsp90 for activation.Haematologica · 2020Article
- Article
- 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
- Novel identification of STAT1 as a crucial mediator of ETV6-NTRK3-induced tumorigenesis.Oncogene · 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
- Gene fusions in soft tissue tumors: Recurrent and overlapping pathogenetic themes.Genes, chromosomes & cancer · 2016Review
- The genomic landscape of diffuse intrinsic pontine glioma and pediatric non-brainstem high-grade glioma.Nature genetics · 2014Article
- Oncogenic rearrangements driving ionizing radiation-associated human cancer.The Journal of clinical investigation · 2013Article
- Biophysical characterization of the ETV6 PNT domain polymerization interfaces.The Journal of biological chemistryArticle
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Authors and funding
11 authors at 2 institutions in 1 country.
Funding
Abstract
The ETV6-NTRK3 (EN) chimeric oncogene is expressed in diverse tumor types. EN is generated by a t(12;15) translocation, which fuses the N-terminal SAM (sterile α-motif) domain of the ETV6 (or TEL) transcription factor to the C-terminal PTK (protein-tyrosine kinase) domain of the neurotrophin-3 receptor NTRK3. SAM domain-mediated polymerization of EN leads to constitutive activation of the PTK domain and constitutive signaling of the Ras-MAPK and PI3K-Akt pathways, which are essential for EN oncogenesis. Here we show through complementary biophysical and cellular biological techniques that mutation of Lys-99, which participates in a salt bridge at the SAM polymer interface, reduces self-association of the isolated SAM domain as well as high molecular mass complex formation of EN and abrogates the transformation activity of EN. We also show that mutation of Asp-101, the intermolecular salt bridge partner of Lys-99, similarly blocks transformation of NIH3T3 cells by EN, reduces EN tyrosine phosphorylation, inhibits Akt and Mek1/2 signaling downstream of EN, and abolishes tumor formation in nude mice. In contrast, mutations of Glu-100 and Arg-103, residues in the vicinity of the interdomain Lys-99-Asp-101 salt bridge, have little or no effect on these oncogenic characteristics of EN. Our results underscore the importance of specific electrostatic interactions for SAM polymerization and EN transformation.
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