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Gene Review

NTRK2  -  neurotrophic tyrosine kinase, receptor,...

Homo sapiens

Synonyms: BDNF/NT-3 growth factors receptor, GP145-TrkB, Neurotrophic tyrosine kinase receptor type 2, TRKB, Trk-B, ...
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Disease relevance of NTRK2


Psychiatry related information on NTRK2


High impact information on NTRK2

  • Here, by screening candidate genes with an antisense messenger RNA expression approach and by co-expressing the receptor tyrosine kinase TrkB and various sodium channels, we demonstrate that the tetrodotoxin-insensitive sodium channel Na(V)1.9 underlies the neurotrophin-evoked excitation [11].
  • Finally, neuronal activity promotes BDNF-induced TrkB endocytosis, a signaling event important for many long-term BDNF functions [12].
  • BDNF modulates synaptic transmission and plasticity primarily through the TrkB receptor, but the molecules involved in BDNF-mediated synaptic modulation are largely unknown [13].
  • A de novo mutation affecting human TrkB associated with severe obesity and developmental delay [14].
  • In addition, similar to MC4R mutants, mouse mutants that expresses the BDNF receptor TrkB at a quarter of the normal amount showed hyperphagia and excessive weight gain on higher-fat diets [15].

Chemical compound and disease context of NTRK2


Biological context of NTRK2

  • The analysis of ED-related phenotypes revealed a clear association between NTRK2, high scores of Harm avoidance measured by the temperament and character inventory (TCI-R; P=0.003) and minimum body mass index (minBMI; P<0.001) [6].
  • A population-based association study with six SNPs from the NTRK2 locus was performed in 164 ED patients and 121 controls [6].
  • Our data support a contribution of NTRK2 to the genetic susceptibility of ED, mainly ANP, and ED-related phenotypic traits, such as Harm avoidance and minBMI [6].
  • Mutation analysis of sporadic MTC did not reveal any sequence variants in NTRK2 but did reveal 3 variants in NTRK3, c.573C >T (N191N, exon 5), c.678T > C (N226N, exon 6) and c.1488C > G (A496A, exon 12) occurring among 19 chromosomes (31%), 1 chromosome (2%) and 24 chromosomes (39%), respectively [21].
  • We determined the genomic structure of NTRK2 and found that it consists of at least 17 exons varying in size from 36 to 306 bp [21].

Anatomical context of NTRK2


Associations of NTRK2 with chemical compounds

  • BDNF treatment of high TrkB-expressing TB8 (Tet-) and TB3 (Tet-) cells blocked drug-induced cell death in a dose-dependent manner [22].
  • BDNF also protected TrkB-expressing NGP and KCNR NB cells from chemotherapeutic agent-induced cell death, and LY294002 inhibited this protection [22].
  • RA treatment of SH-SY5Y cells induces the appearance of functional Trk B and Trk C receptors [26].
  • Specific neurotrophin binding to leucine-rich motif peptides of TrkA and TrkB [27].
  • We investigated the involvement of signaling mediated by brain-derived neurotrophic factor (BDNF) and its receptor tyrosine kinase TrkB in producing the altered GABA-related gene expression in schizophrenia [28].

Physical interactions of NTRK2

  • A discrete domain of the human TrkB receptor defines the binding sites for BDNF and NT-4 [29].
  • Furthermore, we screened an adult human brain cDNA library with the yeast two-and-a-half-hybrid system in order to identify other Shp2-binding proteins in TrkB-stimulated tyrosine phosphorylation signaling [30].
  • RESULTS: We have determined the 2.7 A crystal structure of neurotrophin-4/5 bound to the neurotrophin binding domain of its high-affinity receptor TrkB (TrkB-d5) [31].
  • More importantly, we show that E47 and NeuroD proteins bind the TrkB and p21(Cip1) promoter sequences in vivo [32].

Co-localisations of NTRK2


Regulatory relationships of NTRK2

  • However, the signaling properties of I98V, P660L and T821A were all indistinguishable from wild type.Conclusion:We provide further evidence for the impairment in signaling by Y722C and show that as well as a loss of signaling, this mutation affects the ability of TrkB to promote neurite outgrowth in response to BDNF [3].
  • Brain-derived neurotrophic factor activation of TrkB induces vascular endothelial growth factor expression via hypoxia-inducible factor-1alpha in neuroblastoma cells [34].
  • However, BDNF does not induce phosphorylation of FRS2 in cells expressing a deletion mutant of TrkB (TrkBDeltaPTB) missing the juxtamembrane NPXY motif [35].
  • NT-4 was active in promoting the survival of rat TrkB receptor-expressing fibroblasts, but was inactive on embryonic chicken sensory neurons, unlike the other members of the neurotrophin family and in contrast to the reported activities of partially purified NT-4 [36].
  • We conclude that TrkB expression in neuroblastoma cells results in an increase in their invasive capability via upregulated expression of HGF/c-Met and enhanced activity of proteolytic networks [37].

Other interactions of NTRK2

  • Here, we provide evidence that the TrkB-BDNF pathway is associated with enhanced survival and resistance to chemotherapy in neuroblastoma [5].
  • Global gene regulation following external ligand stimulation was surprisingly similar in SY5Y-TrkA and SY5Y-TrkB cells except for the differential expression of distinct novel target genes [38].
  • We have evidence that coexpression of full-length TrkB and BDNF is associated with N-myc amplification and may represent an autocrine survival pathway [39].
  • Activation of PI3K/AKT survival pathway may contribute to the increased drug resistance in TrkB-expressing neuroblastomas [5].
  • In conclusion, the malignancy of PCa seems to be accompanied by increased TrkA and TrkB signaling (with a reduction of p75 NGFR expression) and CEP-701 could be used to reduce the metastasis formation in advanced PCa [40].

Analytical, diagnostic and therapeutic context of NTRK2


  1. Association of BDNF with restricting anorexia nervosa and minimum body mass index: a family-based association study of eight European populations. Ribasés, M., Gratacòs, M., Fernández-Aranda, F., Bellodi, L., Boni, C., Anderluh, M., Cristina Cavallini, M., Cellini, E., Di Bella, D., Erzegovesi, S., Foulon, C., Gabrovsek, M., Gorwood, P., Hebebrand, J., Hinney, A., Holliday, J., Hu, X., Karwautz, A., Kipman, A., Komel, R., Nacmias, B., Remschmidt, H., Ricca, V., Sorbi, S., Tomori, M., Wagner, G., Treasure, J., Collier, D.A., Estivill, X. Eur. J. Hum. Genet. (2005) [Pubmed]
  2. The human gene for neurotrophic tyrosine kinase receptor type 2 (NTRK2) is located on chromosome 9 but is not the familial dysautonomia gene. Slaugenhaupt, S.A., Blumenfeld, A., Liebert, C.B., Mull, J., Lucente, D.E., Monahan, M., Breakefield, X.O., Maayan, C., Parada, L., Axelrod, F.B. Genomics (1995) [Pubmed]
  3. Functional characterization of human NTRK2 mutations identified in patients with severe early-onset obesity. Gray, J., Yeo, G., Hung, C., Keogh, J., Clayton, P., Banerjee, K., McAulay, A., O'rahilly, S., Farooqi, I.S. International journal of obesity (2005) (2007) [Pubmed]
  4. Localization of neurotrophins and their high-affinity receptors during human enteric nervous system development. Hoehner, J.C., Wester, T., Påhlman, S., Olsen, L. Gastroenterology (1996) [Pubmed]
  5. Resistance to chemotherapy mediated by TrkB in neuroblastomas. Ho, R., Eggert, A., Hishiki, T., Minturn, J.E., Ikegaki, N., Foster, P., Camoratto, A.M., Evans, A.E., Brodeur, G.M. Cancer Res. (2002) [Pubmed]
  6. Contribution of NTRK2 to the genetic susceptibility to anorexia nervosa, harm avoidance and minimum body mass index. Ribases, M., Gratacos, M., Badia, A., Jimenez, L., Solano, R., Vallejo, J., Fernandez-Aranda, F., Estivill, X. Mol. Psychiatry (2005) [Pubmed]
  7. Association study of neurotrophic tyrosine kinase receptor type 2 (NTRK2) and childhood-onset mood disorders. Adams, J.H., Wigg, K.G., King, N., Burcescu, I., Vetró, A., Kiss, E., Baji, I., George, C.J., Kennedy, J.L., Kovacs, M., Barr, C.L. Am. J. Med. Genet. B Neuropsychiatr. Genet. (2005) [Pubmed]
  8. Reduced expression of the TrkB receptor in Huntington's disease mouse models and in human brain. Ginés, S., Bosch, M., Marco, S., Gavaldà, N., Díaz-Hernández, M., Lucas, J.J., Canals, J.M., Alberch, J. Eur. J. Neurosci. (2006) [Pubmed]
  9. Association of Specific Haplotypes of Neurotrophic Tyrosine Kinase Receptor 2 Gene (NTRK2) with Vulnerability to Nicotine Dependence in African-Americans and European-Americans. Beuten, J., Ma, J.Z., Payne, T.J., Dupont, R.T., Lou, X.Y., Crews, K.M., Elston, R.C., Li, M.D. Biol. Psychiatry (2007) [Pubmed]
  10. Brain-derived neurotrophic factor in the ventral midbrain-nucleus accumbens pathway: a role in depression. Eisch, A.J., Bolaños, C.A., de Wit, J., Simonak, R.D., Pudiak, C.M., Barrot, M., Verhaagen, J., Nestler, E.J. Biol. Psychiatry (2003) [Pubmed]
  11. Neurotrophin-evoked depolarization requires the sodium channel Na(V)1.9. Blum, R., Kafitz, K.W., Konnerth, A. Nature (2002) [Pubmed]
  12. Activity-dependent modulation of the BDNF receptor TrkB: mechanisms and implications. Nagappan, G., Lu, B. Trends Neurosci. (2005) [Pubmed]
  13. BDNF-mediated neurotransmission relies upon a myosin VI motor complex. Yano, H., Ninan, I., Zhang, H., Milner, T.A., Arancio, O., Chao, M.V. Nat. Neurosci. (2006) [Pubmed]
  14. A de novo mutation affecting human TrkB associated with severe obesity and developmental delay. Yeo, G.S., Connie Hung, C.C., Rochford, J., Keogh, J., Gray, J., Sivaramakrishnan, S., O'Rahilly, S., Farooqi, I.S. Nat. Neurosci. (2004) [Pubmed]
  15. Brain-derived neurotrophic factor regulates energy balance downstream of melanocortin-4 receptor. Xu, B., Goulding, E.H., Zang, K., Cepoi, D., Cone, R.D., Jones, K.R., Tecott, L.H., Reichardt, L.F. Nat. Neurosci. (2003) [Pubmed]
  16. Nicotine regulates SH-SY5Y neuroblastoma cell proliferation through the release of brain-derived neurotrophic factor. Serres, F., Carney, S.L. Brain Res. (2006) [Pubmed]
  17. Regulation by nicotine of gpr51 and ntrk2 expression in various rat brain regions. Sun, D., Huang, W., Hwang, Y.Y., Zhang, Y., Zhang, Q., Li, M.D. Neuropsychopharmacology (2007) [Pubmed]
  18. Identification of differentially methylated CpG islands in prostate cancer. Yamada, Y., Toyota, M., Hirokawa, Y., Suzuki, H., Takagi, A., Matsuzaki, T., Sugimura, Y., Yatani, R., Shiraishi, T., Watanabe, M. Int. J. Cancer (2004) [Pubmed]
  19. Induction of TrkB by retinoic acid mediates biologic responsiveness to BDNF and differentiation of human neuroblastoma cells. Eukaryotic Signal Transduction Group. Kaplan, D.R., Matsumoto, K., Lucarelli, E., Thiele, C.J. Neuron (1993) [Pubmed]
  20. Downregulation of Bim by brain-derived neurotrophic factor activation of TrkB protects neuroblastoma cells from paclitaxel but not etoposide or cisplatin-induced cell death. Li, Z., Zhang, J., Liu, Z., Woo, C.W., Thiele, C.J. Cell Death Differ. (2007) [Pubmed]
  21. 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]
  22. Brain-derived neurotrophic factor activation of TrkB protects neuroblastoma cells from chemotherapy-induced apoptosis via phosphatidylinositol 3'-kinase pathway. Jaboin, J., Kim, C.J., Kaplan, D.R., Thiele, C.J. Cancer Res. (2002) [Pubmed]
  23. Human and rat hepatic stellate cells express neurotrophins and neurotrophin receptors. Cassiman, D., Denef, C., Desmet, V.J., Roskams, T. Hepatology (2001) [Pubmed]
  24. Cloning and expression of a novel neurotrophin, NT-7, from carp. Lai, K.O., Fu, W.Y., Ip, F.C., Ip, N.Y. Mol. Cell. Neurosci. (1998) [Pubmed]
  25. Neurotrophin-4/5 and neurotrophin-3 are present within the human ovarian follicle but appear to have different paracrine/autocrine functions. Seifer, D.B., Feng, B., Shelden, R.M., Chen, S., Dreyfus, C.F. J. Clin. Endocrinol. Metab. (2002) [Pubmed]
  26. Extracellular-regulated kinases and phosphatidylinositol 3-kinase are involved in brain-derived neurotrophic factor-mediated survival and neuritogenesis of the neuroblastoma cell line SH-SY5Y. Encinas, M., Iglesias, M., Llecha, N., Comella, J.X. J. Neurochem. (1999) [Pubmed]
  27. 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]
  28. Relationship of brain-derived neurotrophic factor and its receptor TrkB to altered inhibitory prefrontal circuitry in schizophrenia. Hashimoto, T., Bergen, S.E., Nguyen, Q.L., Xu, B., Monteggia, L.M., Pierri, J.N., Sun, Z., Sampson, A.R., Lewis, D.A. J. Neurosci. (2005) [Pubmed]
  29. A discrete domain of the human TrkB receptor defines the binding sites for BDNF and NT-4. Naylor, R.L., Robertson, A.G., Allen, S.J., Sessions, R.B., Clarke, A.R., Mason, G.G., Burston, J.J., Tyler, S.J., Wilcock, G.K., Dawbarn, D. Biochem. Biophys. Res. Commun. (2002) [Pubmed]
  30. Analysis of tyrosine phosphorylation-dependent protein-protein interactions in TrkB-mediated intracellular signaling using modified yeast two-hybrid system. Yamada, M., Suzuki, K., Mizutani, M., Asada, A., Matozaki, T., Ikeuchi, T., Koizumi, S., Hatanaka, H. J. Biochem. (2001) [Pubmed]
  31. Specificity in Trk receptor:neurotrophin interactions: the crystal structure of TrkB-d5 in complex with neurotrophin-4/5. Banfield, M.J., Naylor, R.L., Robertson, A.G., Allen, S.J., Dawbarn, D., Brady, R.L. Structure (Camb.) (2001) [Pubmed]
  32. Basic helix-loop-helix proteins bind to TrkB and p21(Cip1) promoters linking differentiation and cell cycle arrest in neuroblastoma cells. Liu, Y., Encinas, M., Comella, J.X., Aldea, M., Gallego, C. Mol. Cell. Biol. (2004) [Pubmed]
  33. BDNF and TrkB co-localize in CA1 neurons resistant to transient forebrain ischemia in the adult gerbil. Ferrer, I., Ballabriga, J., Martí, E., Pozas, E., Planas, A.M., Blasi, J. J. Neuropathol. Exp. Neurol. (1997) [Pubmed]
  34. Brain-derived neurotrophic factor activation of TrkB induces vascular endothelial growth factor expression via hypoxia-inducible factor-1alpha in neuroblastoma cells. Nakamura, K., Martin, K.C., Jackson, J.K., Beppu, K., Woo, C.W., Thiele, C.J. Cancer Res. (2006) [Pubmed]
  35. The protein tyrosine phosphatase, Shp2, is required for the complete activation of the RAS/MAPK pathway by brain-derived neurotrophic factor. Easton, J.B., Royer, A.R., Middlemas, D.S. J. Neurochem. (2006) [Pubmed]
  36. Characterization and crystallization of recombinant human neurotrophin-4. Fandl, J.P., Tobkes, N.J., McDonald, N.Q., Hendrickson, W.A., Ryan, T.E., Nigam, S., Acheson, A., Cudny, H., Panayotatos, N. J. Biol. Chem. (1994) [Pubmed]
  37. The neurotrophin receptor TrkB cooperates with c-Met in enhancing neuroblastoma invasiveness. Hecht, M., Schulte, J.H., Eggert, A., Wilting, J., Schweigerer, L. Carcinogenesis (2005) [Pubmed]
  38. 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]
  39. Expression of TrkA, TrkB and TrkC in human neuroblastomas. Brodeur, G.M., Nakagawara, A., Yamashiro, D.J., Ikegaki, N., Liu, X.G., Azar, C.G., Lee, C.P., Evans, A.E. J. Neurooncol. (1997) [Pubmed]
  40. Tyrosine kinase inhibitor CEP-701 blocks the NTRK1/NGF receptor and limits the invasive capability of prostate cancer cells in vitro. Festuccia, C., Muzi, P., Gravina, G.L., Millimaggi, D., Speca, S., Dolo, V., Ricevuto, E., Vicentini, C., Bologna, M. Int. J. Oncol. (2007) [Pubmed]
  41. Mapping of the tyrosine kinase receptors trkA (NTRK1), trkB (NTRK2) and trkC(NTRK3) to human chromosomes 1q22, 9q22 and 15q25 by fluorescence in situ hybridization. Valent, A., Danglot, G., Bernheim, A. Eur. J. Hum. Genet. (1997) [Pubmed]
  42. 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]
  43. Neurotrophin modulation of voltage-gated potassium channels in rat through TrkB receptors is time and sensory experience dependent. Tucker, K., Fadool, D.A. J. Physiol. (Lond.) (2002) [Pubmed]
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