Disease relevance of NTRK1

• A novel NTRK1 mutation associated with congenital insensitivity to pain with anhidrosis [1].
• Oncogenic rearrangements of the NTRK1 gene (also designated TRKA), encoding one of the receptors for the nerve growth factor, are frequently detected in thyroid carcinomas [2].
• We introduced the following mutations in NTRK1 tyrosine kinase domain: (i) D668N equivalent to Met D1246N associated to HPRC; (ii) D668V modelled on Kit D816V found in mastocytosis; (iii) M688T corresponding to Ret M918T associated to the cancer syndrome MEN2B [3].
• RET/NTRK1 rearrangements in thyroid gland tumors of the papillary carcinoma family: correlation with clinicopathological features [4].
• 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 [5].

Psychiatry related information on NTRK1

• Recently, three mutations in the tyrosine kinase domain of TRKA have been reported in patients with congenital insensitivity to pain with anhidrosis, which is an autosomal recessive disorder characterized by recurrent fever due to absence of sweating, no reaction to noxious stimuli, self-mutilating behavior, and mental retardation [6].
• Reduction of cortical TrkA but not p75(NTR) protein in early-stage Alzheimer's disease [7].

High impact information on NTRK1

• Our findings strongly suggest that defects in TRKA cause CIPA and that the NGF-TRKA system has a crucial role in the development and function of the nociceptive reception as well as establishment of thermoregulation via sweating in humans [8].
• Mutations in the TRKA/NGF receptor gene in patients with congenital insensitivity to pain with anhidrosis [8].
• N-myc amplification (indicated by a high copy number) correlated with advanced tumor stage, older age, an adrenal site of the primary tumor, low level of expression of TRK, and high level of expression of N-myc [9].
• In addition, we tested two primary neuroblastomas that expressed TRK for responsiveness to nerve growth factor [9].
• A high level of expression of the TRK proto-oncogene in a neuroblastoma is strongly predictive of a favorable outcome [9].

Chemical compound and disease context of NTRK1

• Congenital insensitivity to pain with anhidrosis (CIPA): effect of TRKA (NTRK1) missense mutations on autophosphorylation of the receptor tyrosine kinase for nerve growth factor [10].
• Seventeen cases of MTC or bilateral C-cell hyperplasia (CCH) and separate occult PTC were identified from 16 different families [11].
• In the present study we investigate the effects of GnRH analogs (leuprolide and cetrorelix) on the expression of TrkA and p75 neurotrophin receptors in primary cultures of human prostate cancer cells [12].
• In rat INS-1E insulinoma cells, expression of L-PK and p75NTR was suppressed by low glucose as in the islets, while expression of TrkA was strongly increased by low glucose levels and thus was regulated differently than in islets [13].

Biological context of NTRK1

• The TRK-T3 oncogene encodes a 68-kDa cytoplasmic protein reacting with NTRK1-specific antibodies [2].
• In previously reported studies we have demonstrated that NTRK1 oncogenic activation involves two genes, TPM3 and TPR, both localized similarly to the receptor tyrosine kinase, on the q arm of chromosome 1 [2].
• The breakpoint producing the TRK-T3 oncogene occurs within exons of both the TFG gene and the NTRK1 gene and produces a chimeric exon that undergoes alternative splicing [2].
• We provide evidence that SHP-1 SH2 and catalytic domains, respectively, associate with the TFG- and NTRK1-derived portions of TRK-T3 [14].
• Our results demonstrated that NTRK1 is contained within 25 Kb of DNA and is organized in 17 exons, one of which is alternatively spliced [15].

Anatomical context of NTRK1

• Here we report the characterization of a novel NTRK1-derived thyroid oncogene, named TRK-T3 [2].
• Molecular analysis of the NTRK1 rearranged fragments indicated that the chromosomal rearrangement is reciprocal and balanced and involves loss of a few nucleotides of germ line sequences [2].
• Our results concerning the radiation-associated tumours showed that only rearrangements between NTRK1 and TPM3 genes (TRK oncogene) were detected in 2/14 papillary carcinomas and in one lymph-node metastasis of one of these papillary thyroid carcinomas [16].
• These results suggest that Grit, a novel TrkA-interacting protein, regulates neurite outgrowth by modulating the Rho family of small GTPases [17].
• Expression of functional TrkA receptor tyrosine kinase in the HMC-1 human mast cell line and in human mast cells [18].

Associations of NTRK1 with chemical compounds

• By contrast, radiation-induced tumors are associated with paracentric inversions activating the receptor tyrosine kinases RET and NTRK1 [19].
• The NTRK1 gene encodes the high affinity receptor for Nerve Growth Factor, and its action regulates neural development and differentiation [20].
• Specific neurotrophin binding to leucine-rich motif peptides of TrkA and TrkB [21].
• Pentagastrin- or calcium-stimulated plasma CT testing is useful in identifying CCH or early MTC in carriers of RET mutations that are associated with late onset MTC [22].
• Preoperative measurement of plasma free metanephrine and neck ultrasonography always should be done if the diagnosis of MTC is known preoperatively [22].

Physical interactions of NTRK1

• A peptide corresponding to this region effectively bound NGF and blocked binding of NGF to the recombinant extracellular domain of TrkA [21].
• Consequently, activation of TrkA gene expression by methylation was considered to be caused by the direct interference of c-Jun binding to the negatively regulating AP-1-like site [23].
• The high-affinity NGF receptor is thought to be a complex of two receptors , gp75 and the tyrosine kinase TrkA, but direct biochemical evidence for such an association had been lacking [24].
• APPL1 was isolated as a binding partner for the TrkA-interacting protein GIPC1 from rat brain lysate by mass spectrometry [25].
• Grb2 binding to TrkA is mediated by the central SH2 domain, requires a kinase-active TrkA, and is phosphotyrosine-dependent [26].

Enzymatic interactions of NTRK1

• We find that wild-type TRKA precursor proteins in a neuronal and a non-neuronal cell line were differentially processed and phosphorylated in an NGF-dependent and -independent manner, respectively [10].
• Binding assays and far Western blotting analysis, using glutathione S-transferase fusion proteins containing the Src homology 2 (SH2) and SH3 domains of CHK, demonstrate that the SH2 domain of CHK binds directly to the tyrosine-phosphorylated TrkA receptors [27].
• Unglycosylated TrkA core protein is phosphorylated even in the absence of ligand stimulation and displays constitutive kinase activity as well as constitutive interaction with the signaling molecules Shc and PLC-gamma [28].

Regulatory relationships of NTRK1

• NGF stimulation of HMC-1 cells induced tyrosine phosphorylation of TrkA protein, increased expression of the early response genes c-fos and NGF1-A, and activation of ERK-mitogen-activated protein (MAP) kinase, results which indicate that TrkA receptors in HMC-1 cells are fully functional [18].
• Concomitantly, TrkA was down-regulated and TrkB up-regulated [29].
• Our study revealed that most of the GFAP-positive cells express TrkA, whereas a rare, novel subpopulation of astrocytes was found to be devoid of TrkA [30].
• TrkA induces apoptosis of neuroblastoma cells and does so via a p53-dependent mechanism [31].
• Here we present evidence that the nerve growth factor receptor TrkA may also promote phosphorylation of APP [32].

Other interactions of NTRK1

• Taken together, our findings show that human mast cells express a functional TrkA receptor tyrosine kinase and indicate that NGF may be able to promote certain aspects of mast cell development and/or maturation in humans [18].
• By flow cytometry, HMC-1 cells exhibited expression of TrkA, TrkB, and TrkC receptor proteins containing full-length tyrosine kinase domains [18].
• Rearrangements of NTRK1 are frequently detected in human papillary thyroid carcinoma and lead to the formation of chimeric oncogenes, similarly to what observed for the other neurotrophin receptor RET [15].
• In neuroblastoma (NB), expression of the TrkA receptor is correlated with good prognosis while N-myc amplification is correlated with poor prognosis [33].
• CONCLUSIONS: This is the first study showing that human chondrocytes synthesize NFG-beta and express on their surface the high affinity NGFR (p140 TrkA) [34].

Analytical, diagnostic and therapeutic context of NTRK1

• We document the presence of RNA message for the low- (LNGFR) and the high-affinity NGF receptor (NTRK1) by using RT-PCR on fresh BM aspirate and on LTBMC [35].
• Sequence analysis revealed that TRK-T3 contains 1,412 nucleotides of NTRK1 preceded by 598 nucleotides belonging to a novel gene that we have named TFG (TRK-fused gene) [2].
• The distance between NTRK1 and its oncogenic partner TPR was determined by two-color fluorescence in situ hybridization and two-dimensional microscopy [36].
• Microarray analysis reveals differential gene expression patterns and regulation of single target genes contributing to the opposing phenotype of TrkA- and TrkB-expressing neuroblastomas [37].
• NGF-beta and TrkA expression was evaluated by immunofluorescence and flow cytometry analysis [34].

References