Disease relevance of NTRK3

• A novel ETV6-NTRK3 gene fusion in congenital fibrosarcoma [1].
• Immunostaining has shown that only a subset of normal C cells expresses Trk family receptors, but in C-cell hyperplasia, they consistently express NTRK2, with variable expression of NTRK1 and NTRK3 [2].
• Secretory carcinomas (SCA) are distinguished from infiltrating ductal carcinomas (IDC) of the breast by their characteristic histomorphology and more favorable prognosis and by the expression of a chimeric tyrosine kinase that is encoded by the ETV6-NTRK3 fusion gene [3].
• Fusion of ETV6 to neurotrophin-3 receptor TRKC in acute myeloid leukemia with t(12;15)(p13;q25) [4].
• Finally, Trk-C is expressed in favorable neuroblastomas, essentially all of which also express TrkA [5].

Psychiatry related information on NTRK3

• 5' UTR-region SNP in the NTRK3 gene is associated with panic disorder [6].

High impact information on NTRK3

• Our studies indicate that a chimaeric PTK is expressed in CFS and this may contribute to oncogenesis by dysregulation of NTRK3 signal transduction pathways [1].
• Biochemical analysis indicates that phosphorylation at the Shc site positively regulates autophosphorylation of TrkB, but not of TrkC [7].
• Expressing TrkC from the TrkA locus causes a subset of dorsal root ganglia neurons to switch fate [8].
• RESULTS: Neither neurotrophins nor their receptors were identified in immature postmigrational ENS progenitors at 7 weeks' fetal developmental age; however, TrkC and TrkA were specifically localized to developing ENS cells after 19 developmental weeks [9].
• A kinase-deficient TrkC receptor isoform activates Arf6-Rac1 signaling through the scaffold protein tamalin [10].

Chemical compound and disease context of NTRK3

• We tested four histologically confirmed cases of SBC for the presence of the ETV6-NTRK3 gene fusion and then applied the FISH assay to tissue microarrays (TMAs) in order to screen 481 cases of formalin-fixed, paraffin-embedded invasive breast carcinomas of various histologic subtypes [11].
• Human melanoma TrkC: its association with a purine-analog-sensitive kinase activity [12].
• Here we demonstrate that, by using sensitive immune-complex kinase assays in human brain-metastatic (70W) melanoma cells, TrkC receptors associate with a kinase activity exhibiting a dose-dependent susceptibility to inhibition by the purine-analogs 6-thioguanine and 2-aminopurine [12].

Biological context of NTRK3

• Moreover, ETV6-NTRK3 gene fusions provide a potential diagnostic marker for CFS [1].
• We present here the construction of a BAC/PAC contig map that spans 2 Mb from the neurotrophin-3 receptor (NTRK3) gene region on 15q25.3 to the proximal end of the Bloom's syndrome region on 15q26.1, and the identification of a set of new chromosome 15 duplicons [13].
• We hypothesize that chimeric proteins mediate transformation by dysregulating NTRK3 signal transduction pathways via ligand-independent dimerization and PTK activation [14].
• We conclude that sequence variants in NTRK2 and NTRK3 are not likely to be responsible for large differences in expression at the protein level, but we cannot exclude very low penetrance effects [2].
• ETV6-NTRK3: a chimeric protein tyrosine kinase with transformation activity in multiple cell lineages [15].

Anatomical context of NTRK3

• Mutation analysis of NTRK2 and NTRK3, encoding 2 tyrosine kinase receptors, in sporadic human medullary thyroid carcinoma reveals novel sequence variants [2].
• Immunoreactivity for both catalytic and truncated TrkC receptor was observed in promyelocytes, myelocytes, some polymorphonuclear cells and megacaryocytes [16].
• Using reverse transcription-polymerase chain reaction, all transcripts encoding for catalytic and truncated human TrkB or TrkC receptors were detected together with trkAI transcripts, whereas trkAII transcripts were found only in control nerve tissues [16].
• Activation of the specific neurotrophin receptors TrkA, TrkB and TrkC influences the function of eosinophils [17].
• A 3.5% macrophages displayed immunoreactivity for TrkA-receptor protein, 10% for TrkB-receptor protein (full length isoform), and 2% for TrkC-receptor protein [18].

Associations of NTRK3 with chemical compounds

• Moreover, ETV6-NTRK3 has PTK activity and is autophosphorylated on tyrosine residues [14].
• We studied immunohistochemical expression of NTRK3, and conducted a reverse transcription-polymerase chain reaction (RT-PCR) assay to detect the ETV6-NTRK3 fusion transcripts using archival formalin-fixed paraffin-embedded tissues from 10 CIFSs [19].
• Compared with previous findings in IDCs, SCAs are characterized by a relatively low number of GAs, a low proliferative rate, infrequent HER2/neu protein overexpression, decreased steroid hormone receptor expression, and expression of ETV6-NTRK3 fusion gene [3].
• Neurotrophin-3/TrkC-induced apoptosis is inhibited by the mitogen-activated protein (MAP) kinase (MAPK) pharmacologic antagonists SB203580 and PD98059 [20].
• RA treatment of SH-SY5Y cells induces the appearance of functional Trk B and Trk C receptors [21].

Enzymatic interactions of NTRK3

• The neurotrophin-3 receptor TrkC directly phosphorylates and activates the nucleotide exchange factor Dbs to enhance Schwann cell migration [22].

Regulatory relationships of NTRK3

• TRKC is a receptor tyrosine kinase that is activated by neurotrophin-3 (NT-3) [4].
• Taken together, activation of TrkC triggers Schwann cell migration by regulating Dbs upon direct tyrosine phosphorylation, providing a mechanism whereby a membrane receptor tyrosine kinase can induce the activation of Rho GTPase-GEFs [22].

Other interactions of NTRK3

• Analysis of mRNA revealed the expression of ETV6-NTRK3 chimaeric transcripts in all three CFS tumours analysed [1].
• In later stages of MTC, NTRK2 expression was reduced while NTRK3 expression was increased [2].
• Mutants of the three NTRK3 PTK activation-loop tyrosines had variable PTK activity but had limited to absent transformation activity [14].
• Aganglionic HD intestine lacked intense and specific TrkC and BDNF enteric ganglionic immunoreactivity [23].
• RNA extraction was performed on formalin-fixed, paraffin-embedded tissue from 7 mixed epithelial and stromal tumors followed by reverse-transcription polymerase chain reaction to detect the ETV6-NTRK3 gene fusion [24].

Analytical, diagnostic and therapeutic context of NTRK3

• A fluorescence in situ hybridization study of ETV6-NTRK3 fusion gene in secretory breast carcinoma [11].
• To confirm the use of this assay in the differential diagnosis of CFS, they have screened a larger series of childhood pediatric spindle cell lesions for ETV6-NTRK3 gene fusions, including 11 cases of CFS, 13 malignant spindle cell tumors (including ATFS), and 38 benign spindle cell tumors (including IFB and MFB) [25].
• Non-resectable congenital tumors with the ETV6-NTRK3 gene fusion are highly responsive to chemotherapy [26].
• His tumor showed the ETV6-NTRK3 translocation as demonstrated by fluorescent in situ hybridization (FISH) [27].
• The combination of low MYC mRNA expression and high TrkC mRNA expression identified a good outcome group of PNET/MB patients (n = 7) with 100% progression-free survival after a median follow-up time of 55 months (range, 15-91 months) [28].

References