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Gene Review

NTRK1  -  neurotrophic tyrosine kinase, receptor,...

Homo sapiens

Synonyms: High affinity nerve growth factor receptor, MTC, Neurotrophic tyrosine kinase receptor type 1, TRK, TRK1, ...
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Disease relevance of NTRK1


Psychiatry related information on NTRK1


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


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


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


  1. A novel NTRK1 mutation associated with congenital insensitivity to pain with anhidrosis. Greco, A., Villa, R., Tubino, B., Romano, L., Penso, D., Pierotti, M.A. Am. J. Hum. Genet. (1999) [Pubmed]
  2. The DNA rearrangement that generates the TRK-T3 oncogene involves a novel gene on chromosome 3 whose product has a potential coiled-coil domain. Greco, A., Mariani, C., Miranda, C., Lupas, A., Pagliardini, S., Pomati, M., Pierotti, M.A. Mol. Cell. Biol. (1995) [Pubmed]
  3. Gain of function mutations of RTK conserved residues display differential effects on NTRK1 kinase activity. Miranda, C., Zanotti, G., Pagliardini, S., Ponzetto, C., Pierotti, M.A., Greco, A. Oncogene (2002) [Pubmed]
  4. RET/NTRK1 rearrangements in thyroid gland tumors of the papillary carcinoma family: correlation with clinicopathological features. Bongarzone, I., Vigneri, P., Mariani, L., Collini, P., Pilotti, S., Pierotti, M.A. Clin. Cancer Res. (1998) [Pubmed]
  5. Mutation analysis of NTRK2 and NTRK3, encoding 2 tyrosine kinase receptors, in sporadic human medullary thyroid carcinoma reveals novel sequence variants. Gimm, O., Dziema, H., Brown, J., de la Puente, A., Hoang-Vu, C., Dralle, H., Plass, C., Eng, C. Int. J. Cancer (2001) [Pubmed]
  6. A novel point mutation affecting the tyrosine kinase domain of the TRKA gene in a family with congenital insensitivity to pain with anhidrosis. Yotsumoto, S., Setoyama, M., Hozumi, H., Mizoguchi, S., Fukumaru, S., Kobayashi, K., Saheki, T., Kanzaki, T. J. Invest. Dermatol. (1999) [Pubmed]
  7. Reduction of cortical TrkA but not p75(NTR) protein in early-stage Alzheimer's disease. Counts, S.E., Nadeem, M., Wuu, J., Ginsberg, S.D., Saragovi, H.U., Mufson, E.J. Ann. Neurol. (2004) [Pubmed]
  8. Mutations in the TRKA/NGF receptor gene in patients with congenital insensitivity to pain with anhidrosis. Indo, Y., Tsuruta, M., Hayashida, Y., Karim, M.A., Ohta, K., Kawano, T., Mitsubuchi, H., Tonoki, H., Awaya, Y., Matsuda, I. Nat. Genet. (1996) [Pubmed]
  9. Association between high levels of expression of the TRK gene and favorable outcome in human neuroblastoma. Nakagawara, A., Arima-Nakagawara, M., Scavarda, N.J., Azar, C.G., Cantor, A.B., Brodeur, G.M. N. Engl. J. Med. (1993) [Pubmed]
  10. Congenital insensitivity to pain with anhidrosis (CIPA): effect of TRKA (NTRK1) missense mutations on autophosphorylation of the receptor tyrosine kinase for nerve growth factor. Mardy, S., Miura, Y., Endo, F., Matsuda, I., Indo, Y. Hum. Mol. Genet. (2001) [Pubmed]
  11. Thyroid carcinomas involving follicular and parafollicular C cells: seventeen cases with characterization of RET oncogenic activation. Vantyghem, M.C., Pigny, P., Leteurtre, E., Leclerc, L., Bauters, C., Douillard, C., D'Herbomez, M., Carnaille, B., Proye, C., Wemeau, J.L., Lecomte-Houcke, M. Thyroid (2004) [Pubmed]
  12. Effect of GnRH analogs on the expression of TrkA and p75 neurotrophin receptors in primary cell cultures from human prostate adenocarcinoma. Sánchez, C., Clementi, M., Benitez, D., Contreras, H., Huidobro, C., Castellón, E. Prostate (2005) [Pubmed]
  13. Glucose regulates expression of the nerve growth factor (NGF) receptors TrkA and p75NTR in rat islets and INS-1E beta-cells. Raile, K., Klammt, J., Garten, A., Laue, S., Blüher, M., Kralisch, S., Klöting, N., Kiess, W. Regul. Pept. (2006) [Pubmed]
  14. Analysis of SHP-1-mediated down-regulation of the TRK-T3 oncoprotein identifies Trk-fused gene (TFG) as a novel SHP-1-interacting protein. Roccato, E., Miranda, C., Raho, G., Pagliardini, S., Pierotti, M.A., Greco, A. J. Biol. Chem. (2005) [Pubmed]
  15. Genomic organization of the human NTRK1 gene. Greco, A., Villa, R., Pierotti, M.A. Oncogene (1996) [Pubmed]
  16. Search for NTRK1 proto-oncogene rearrangements in human thyroid tumours originated after therapeutic radiation. Bounacer, A., Schlumberger, M., Wicker, R., Du-Villard, J.A., Caillou, B., Sarasin, A., Suárez, H.G. Br. J. Cancer (2000) [Pubmed]
  17. Grit, a GTPase-activating protein for the Rho family, regulates neurite extension through association with the TrkA receptor and N-Shc and CrkL/Crk adapter molecules. Nakamura, T., Komiya, M., Sone, K., Hirose, E., Gotoh, N., Morii, H., Ohta, Y., Mori, N. Mol. Cell. Biol. (2002) [Pubmed]
  18. Expression of functional TrkA receptor tyrosine kinase in the HMC-1 human mast cell line and in human mast cells. Tam, S.Y., Tsai, M., Yamaguchi, M., Yano, K., Butterfield, J.H., Galli, S.J. Blood (1997) [Pubmed]
  19. Oncogenic AKAP9-BRAF fusion is a novel mechanism of MAPK pathway activation in thyroid cancer. Ciampi, R., Knauf, J.A., Kerler, R., Gandhi, M., Zhu, Z., Nikiforova, M.N., Rabes, H.M., Fagin, J.A., Nikiforov, Y.E. J. Clin. Invest. (2005) [Pubmed]
  20. Oncogenic rearrangements of the NTRK1/NGF receptor. Pierotti, M.A., Greco, A. Cancer Lett. (2006) [Pubmed]
  21. Specific neurotrophin binding to leucine-rich motif peptides of TrkA and TrkB. Windisch, J.M., Auer, B., Marksteiner, R., Lang, M.E., Schneider, R. FEBS Lett. (1995) [Pubmed]
  22. Diagnosis and management of medullary thyroid carcinoma. Massoll, N., Mazzaferri, E.L. Clin. Lab. Med. (2004) [Pubmed]
  23. Methylation adjacent to negatively regulating AP-1 site reactivates TrkA gene expression during cancer progression. Fujimoto, M., Kitazawa, R., Maeda, S., Kitazawa, S. Oncogene (2005) [Pubmed]
  24. The neurotrophin receptor, gp75, forms a complex with the receptor tyrosine kinase TrkA. Ross, A.H., Daou, M.C., McKinnon, C.A., Condon, P.J., Lachyankar, M.B., Stephens, R.M., Kaplan, D.R., Wolf, D.E. J. Cell Biol. (1996) [Pubmed]
  25. APPL1 Associates with TrkA and GIPC1 and Is Required for Nerve Growth Factor-Mediated Signal Transduction. Lin, D.C., Quevedo, C., Brewer, N.E., Bell, A., Testa, J.R., Grimes, M.L., Miller, F.D., Kaplan, D.R. Mol. Cell. Biol. (2006) [Pubmed]
  26. Direct binding of the signaling adapter protein Grb2 to the activation loop tyrosines on the nerve growth factor receptor tyrosine kinase, TrkA. MacDonald, J.I., Gryz, E.A., Kubu, C.J., Verdi, J.M., Meakin, S.O. J. Biol. Chem. (2000) [Pubmed]
  27. The Csk homologous kinase associates with TrkA receptors and is involved in neurite outgrowth of PC12 cells. Yamashita, H., Avraham, S., Jiang, S., Dikic, I., Avraham, H. J. Biol. Chem. (1999) [Pubmed]
  28. TrkA glycosylation regulates receptor localization and activity. Watson, F.L., Porcionatto, M.A., Bhattacharyya, A., Stiles, C.D., Segal, R.A. J. Neurobiol. (1999) [Pubmed]
  29. Effects of arsenic trioxide on the cellular proliferation, apoptosis and differentiation of human neuroblastoma cells. Cheung, W.M., Chu, P.W., Kwong, Y.L. Cancer Lett. (2007) [Pubmed]
  30. Two classes of astrocytes in the adult human and pig retina in terms of their expression of high affinity NGF receptor (TrkA). Ruiz-Ederra, J., Hitchcock, P.F., Vecino, E. Neurosci. Lett. (2003) [Pubmed]
  31. TrkA induces apoptosis of neuroblastoma cells and does so via a p53-dependent mechanism. Lavoie, J.F., Lesauteur, L., Kohn, J., Wong, J., Furtoss, O., Thiele, C.J., Miller, F.D., Kaplan, D.R. J. Biol. Chem. (2005) [Pubmed]
  32. Evidence for a role of the nerve growth factor receptor TrkA in tyrosine phosphorylation and processing of beta-APP. Tarr, P.E., Contursi, C., Roncarati, R., Noviello, C., Ghersi, E., Scheinfeld, M.H., Zambrano, N., Russo, T., D'Adamio, L. Biochem. Biophys. Res. Commun. (2002) [Pubmed]
  33. NGF activation of TrkA decreases N-myc expression via MAPK path leading to a decrease in neuroblastoma cell number. Woo, C.W., Lucarelli, E., Thiele, C.J. Oncogene (2004) [Pubmed]
  34. Increased expression of nerve growth factor (NGF) and high affinity NGF receptor (p140 TrkA) in human osteoarthritic chondrocytes. Iannone, F., De Bari, C., Dell'Accio, F., Covelli, M., Patella, V., Lo Bianco, G., Lapadula, G. Rheumatology (Oxford, England) (2002) [Pubmed]
  35. Bone marrow stroma in humans: anti-nerve growth factor receptor antibodies selectively stain reticular cells in vivo and in vitro. Cattoretti, G., Schiró, R., Orazi, A., Soligo, D., Colombo, M.P. Blood (1993) [Pubmed]
  36. Proximity of TPR and NTRK1 rearranging loci in human thyrocytes. Roccato, E., Bressan, P., Sabatella, G., Rumio, C., Vizzotto, L., Pierotti, M.A., Greco, A. Cancer Res. (2005) [Pubmed]
  37. Microarray analysis reveals differential gene expression patterns and regulation of single target genes contributing to the opposing phenotype of TrkA- and TrkB-expressing neuroblastomas. Schulte, J.H., Schramm, A., Klein-Hitpass, L., Klenk, M., Wessels, H., Hauffa, B.P., Eils, J., Eils, R., Brodeur, G.M., Schweigerer, L., Havers, W., Eggert, A. Oncogene (2005) [Pubmed]
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