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Gene Review

Ntrk1  -  neurotrophic tyrosine kinase, receptor,...

Mus musculus

Synonyms: C80751, High affinity nerve growth factor receptor, Neurotrophic tyrosine kinase receptor type 1, Tkr, TrkA, ...
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Disease relevance of Ntrk1


Psychiatry related information on Ntrk1

  • Neurotrophin receptors (the receptor tyrosine kinases, Trks) mark the major classes of these sensory neurons: TrkA is expressed in neurons that sense temperature and noxious stimuli, and TrkC is expressed in proprioceptive neurons that sense body position [6].
  • Because the period of TrkA down-regulation corresponds with a critical period during which nociceptive phenotype can be altered by NGF (see Lewin and Mendell [1993] Trends Neurosci. 16:353-359), we examined whether NGF modulates the down-regulation of TrkA [7].

High impact information on Ntrk1

  • We report that the related neurotrophins NGF and NT-3, acting through a common receptor, TrkA, are required for sequential stages of sympathetic axon growth and, thus, innervation of target fields [8].
  • Mice lacking the gene for TrkA, a receptor tyrosine kinase for NGF, share dramatic phenotypic features of CIPA, including loss of responses to painful stimuli, although anhidrosis is not apparent in these animals [9].
  • Recent data have demonstrated that the product of the tyrosine kinase trk proto-oncogene binds NGF and is a component of the high affinity NGF receptor [10].
  • The trk proto-oncogene encodes a receptor for nerve growth factor [11].
  • We previously identified two tyrosine protein kinase genes, designated trk and trkB, that code for putative neurogenic cell surface receptors [12].

Chemical compound and disease context of Ntrk1

  • To discriminate these effects we used two p75NTR receptor-positive lines of cholinergic neuroblastoma cells, SN56 and T17 that are devoid of or express high affinity NGF (TrkA) receptors, respectively. cAMP and retinoic acid caused differentiation of both cell lines [13].
  • A K+ yptake protein, TrkA, is required for serum, protamine, and polymyxin B resistance in Vibrio vulnificus [14].

Biological context of Ntrk1

  • Genetic mapping of the high-affinity nerve growth factor receptor gene, Ntrk1, to mouse chromosome 3 [15].
  • Taken together, the data indicate that activated alpha2M is a pan-trk inhibitor, which by virtue of its binding to trk receptors may block trk-mediated signal transduction in dopaminergic neurons and lead to reduction of dopamine concentration in corpus striatum [16].
  • On the basis of the recent identification of a nerve growth factor (NGF) binding site within TrkA, the ability of the different structural entities within the extracellular domain of TrkB to bind the various neurotrophins was determined by using a recombinant receptor approach [17].
  • On the other hand, SK-N-BE cell proliferation was decreased after NGF treatment, even though these cells also express p75NTR but no TrkA receptors on their surface [18].
  • The reduction of TrkA expression in sensory neurons is a direct effect of Klf7 gene ablation, rather than a secondary effect of cell death [19].

Anatomical context of Ntrk1

  • In the absence of TrkA, NGF binding to p75NGR activated the transcription factor nuclear factor kappa B (NF-kappa B) in rat Schwann cells [20].
  • The Trk family of protein tyrosine kinases (TrkA/B/C) are receptors for neurotrophins, a family of closely related proteins that are important physiological regulators of the survival of specific neurons within the peripheral nervous system (PNS) of vertebrates [21].
  • Although studies in some, but not all, cell lines indicate that NT3 can also signal through TrkA and TrkB, it is not known if such signalling can occur in neurons [22].
  • TrkA high-affinity receptors are essential for the normal development of sympathetic paravertebral neurons and subpopulations of sensory neurons [23].
  • Synchronous onset of NGF and TrkA survival dependence in developing dorsal root ganglia [24].

Associations of Ntrk1 with chemical compounds

  • A mouse deficient in Nkx2.1 function does not form pallidal structures, lacks basal forebrain TrkA-positive neurons (probable cholinergic neurons) and has reduced numbers of cortical cells expressing GABA, DLX2 and calbindin that migrate from the pallidum through the striatum and into the cortex [25].
  • Our results are compatible with the idea that there are certain pathways which are under control of unliganded thyroid hormone receptor, and that one of these pathways results in regulation of trk expression [26].
  • In contrast, retinoic acid induces the expression of TrkA, the high-affinity receptor for nerve growth factor, and of a non-catalytic form of TrkB, in non-neural subsets of differentiated cells [27].
  • Aged 25-35 beta-amyloid (1 microM) caused no changes in choline acetyltransferase and pyruvate dehydrogenase activities in nondifferentiated and differentiated TrkA(-) cells [28].
  • Nerve growth factor and its functional receptor TrkA are up-regulated in murine decidual tissue of stress-triggered and substance P-mediated abortion [29].

Physical interactions of Ntrk1

  • We show that Klf7 binds to the endogenous TrkA minimal enhancer and can activate transcription from the TrkA minimal enhancer in a sequence-dependent manner [19].

Regulatory relationships of Ntrk1

  • Thus, Klf7 specifically regulates TrkA gene expression and is required for the development of a subset of nociceptive sensory neurons [19].
  • Thus, p75NTR induces death regardless of the presence or absence of TrkA expression [30].
  • p53 is essential for developmental neuron death as regulated by the TrkA and p75 neurotrophin receptors [31].
  • Furthermore, activation of trkB receptors in the postsynaptic neuron was required, as BDNF-induced potentiation was blocked by postsynaptic injection of a trk tyrosine kinase inhibitor [32].
  • We now report that nerve growth factor (NGF)-induced activation of the TrkA receptor tyrosine kinase induces MMP-9 expression in both primary cultured rat aortic smooth muscle cells and in a smooth muscle cell line genetically manipulated to express TrkA [33].

Other interactions of Ntrk1

  • In the present paper, we use antibodies to TrkA, TrkB, and TrkC to characterize their expression patterns and to determine which subpopulations of cells are lost in mice lacking individual neurotrophins or Trk receptors [34].
  • Biochemical and functional interactions between the neurotrophin receptors trk and p75NTR [35].
  • Sympathetic neuron survival and TrkA expression in NT3-deficient mouse embryos [36].
  • The expression of transcripts encoding catalytic TrkC is negligible at this stage, suggesting that NT3 acts mainly via TrkA [36].
  • Unlike nerve growth factor and brain-derived neurotrophic factor, NT-3 can to some extent also bind and activate non-cognate TrkA and B receptors, although the physiological relevance of these interactions is unclear [37].
  • TrkA is recruited and retained within lipid rafts through its association with flotillin, an intrinsic constituent of these membrane microdomains, via the adapter protein, c-Cbl associated protein (CAP) [38].

Analytical, diagnostic and therapeutic context of Ntrk1

  • Thus, the trk family of receptors are likely to be important signal transducers of NGF-related trophic signals in the formation and maintenance of neuronal circuits [10].
  • To assess the possibility of ligand-receptor cross-talk as a developmental mechanism, we have compared the onset of survival dependence of lumbar DRG neurons on NT-3, TrkC, NGF, and TrkA signaling in mice deficient in these molecules as a result of gene targeting [24].
  • Immunoprecipitation using three distinct anti-pan-Trk antibodies suggests that pp38 is not a fragment of TrkA [39].
  • Immunofluorescence examinations were made in the rostral back skin for nerve fibres, NGF and TrkA receptor [2].
  • In situ hybridization analysis in the mouse embryo reveals a striking temporal and spatial regulation of trk transcription, with expression confined to the sensory cranial (trigeminal, superior, jugular) and dorsal root ganglia (DRG) of neural crest origin [40].


  1. Differential effects of combined trk receptor mutations on dorsal root ganglion and inner ear sensory neurons. Minichiello, L., Piehl, F., Vazquez, E., Schimmang, T., Hökfelt, T., Represa, J., Klein, R. Development (1995) [Pubmed]
  2. Effects of high-affinity nerve growth factor receptor inhibitors on symptoms in the NC/Nga mouse atopic dermatitis model. Takano, N., Sakurai, T., Ohashi, Y., Kurachi, M. Br. J. Dermatol. (2007) [Pubmed]
  3. Rational basis for Trk inhibition therapy for prostate cancer. Weeraratna, A.T., Arnold, J.T., George, D.J., DeMarzo, A., Isaacs, J.T. Prostate (2000) [Pubmed]
  4. Production of nerve growth factor by mouse hepatocellular carcinoma cells and expression of TrkA in tumor-associated arteries in mice. Kishibe, K., Yamada, Y., Ogawa, K. Gastroenterology (2002) [Pubmed]
  5. Human trk oncogenes activated by point mutation, in-frame deletion, and duplication of the tyrosine kinase domain. Coulier, F., Kumar, R., Ernst, M., Klein, R., Martin-Zanca, D., Barbacid, M. Mol. Cell. Biol. (1990) [Pubmed]
  6. Expressing TrkC from the TrkA locus causes a subset of dorsal root ganglia neurons to switch fate. Moqrich, A., Earley, T.J., Watson, J., Andahazy, M., Backus, C., Martin-Zanca, D., Wright, D.E., Reichardt, L.F., Patapoutian, A. Nat. Neurosci. (2004) [Pubmed]
  7. Nerve growth factor receptor TrkA is down-regulated during postnatal development by a subset of dorsal root ganglion neurons. Molliver, D.C., Snider, W.D. J. Comp. Neurol. (1997) [Pubmed]
  8. A neurotrophin signaling cascade coordinates sympathetic neuron development through differential control of TrkA trafficking and retrograde signaling. Kuruvilla, R., Zweifel, L.S., Glebova, N.O., Lonze, B.E., Valdez, G., Ye, H., Ginty, D.D. Cell (2004) [Pubmed]
  9. 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]
  10. The neurotrophic factors brain-derived neurotrophic factor and neurotrophin-3 are ligands for the trkB tyrosine kinase receptor. Soppet, D., Escandon, E., Maragos, J., Middlemas, D.S., Reid, S.W., Blair, J., Burton, L.E., Stanton, B.R., Kaplan, D.R., Hunter, T. Cell (1991) [Pubmed]
  11. The trk proto-oncogene encodes a receptor for nerve growth factor. Klein, R., Jing, S.Q., Nanduri, V., O'Rourke, E., Barbacid, M. Cell (1991) [Pubmed]
  12. The trkB tyrosine protein kinase gene codes for a second neurogenic receptor that lacks the catalytic kinase domain. Klein, R., Conway, D., Parada, L.F., Barbacid, M. Cell (1990) [Pubmed]
  13. Effects of NGF on acetylcholine, acetyl-CoA metabolism, and viability of differentiated and non-differentiated cholinergic neuroblastoma cells. Szutowicz, A., Madziar, B., Pawełczyk, T., Tomaszewicz, M., Bielarczyk, H. J. Neurochem. (2004) [Pubmed]
  14. A K+ yptake protein, TrkA, is required for serum, protamine, and polymyxin B resistance in Vibrio vulnificus. Chen, Y.C., Chuang, Y.C., Chang, C.C., Jeang, C.L., Chang, M.C. Infect. Immun. (2004) [Pubmed]
  15. Genetic mapping of the high-affinity nerve growth factor receptor gene, Ntrk1, to mouse chromosome 3. Kingsmore, S.F., Watson, M.L., Seldin, M.F. Genomics (1993) [Pubmed]
  16. Inhibition of phosphorylation of TrkB and TrkC and their signal transduction by alpha2-macroglobulin. Hu, Y.Q., Koo, P.H. J. Neurochem. (1998) [Pubmed]
  17. Brain-derived neurotrophic factor, neurotrophin-3, and neurotrophin-4 bind to a single leucine-rich motif of TrkB. Windisch, J.M., Marksteiner, R., Lang, M.E., Auer, B., Schneider, R. Biochemistry (1995) [Pubmed]
  18. Neurotrophin effects on neuroblastoma cells: correlation with trk and p75NTR expression and influence of Trk receptor bodies. Evangelopoulos, M.E., Weis, J., Kruttgen, A. J. Neurooncol. (2004) [Pubmed]
  19. The zinc finger transcription factor Klf7 is required for TrkA gene expression and development of nociceptive sensory neurons. Lei, L., Laub, F., Lush, M., Romero, M., Zhou, J., Luikart, B., Klesse, L., Ramirez, F., Parada, L.F. Genes Dev. (2005) [Pubmed]
  20. Selective activation of NF-kappa B by nerve growth factor through the neurotrophin receptor p75. Carter, B.D., Kaltschmidt, C., Kaltschmidt, B., Offenhäuser, N., Böhm-Matthaei, R., Baeuerle, P.A., Barde, Y.A. Science (1996) [Pubmed]
  21. TrkB and TrkC neurotrophin receptors cooperate in promoting survival of hippocampal and cerebellar granule neurons. Minichiello, L., Klein, R. Genes Dev. (1996) [Pubmed]
  22. Developmental changes in NT3 signalling via TrkA and TrkB in embryonic neurons. Davies, A.M., Minichiello, L., Klein, R. EMBO J. (1995) [Pubmed]
  23. Reduced acetylcholinesterase (AChE) activity in adrenal medulla and loss of sympathetic preganglionic neurons in TrkA-deficient, but not TrkB-deficient, mice. Schober, A., Minichiello, L., Keller, M., Huber, K., Layer, P.G., Roig-López, J.L., García-Arrarás, J.E., Klein, R., Unsicker, K. J. Neurosci. (1997) [Pubmed]
  24. Synchronous onset of NGF and TrkA survival dependence in developing dorsal root ganglia. White, F.A., Silos-Santiago, I., Molliver, D.C., Nishimura, M., Phillips, H., Barbacid, M., Snider, W.D. J. Neurosci. (1996) [Pubmed]
  25. Loss of Nkx2.1 homeobox gene function results in a ventral to dorsal molecular respecification within the basal telencephalon: evidence for a transformation of the pallidum into the striatum. Sussel, L., Marin, O., Kimura, S., Rubenstein, J.L. Development (1999) [Pubmed]
  26. Unliganded c-erbA/thyroid hormone receptor induces trkB expression in neuroblastoma cells. Pastor, R., Bernal, J., Rodríguez-Peña, A. Oncogene (1994) [Pubmed]
  27. Neuronal differentiation of P19 embryonal cells exhibits cell-specific regulation of neurotrophin receptors. Salvatore, A.M., Cozzolino, M., Gargano, N., Galanti, S., Levi, A., Alemà, S. Neuroreport (1995) [Pubmed]
  28. Interactions between p75 and TrkA receptors in differentiation and vulnerability of SN56 cholinergic cells to beta-amyloid. Madziar, B., Tomaszewicz, M., Matecki, A., Bielarczyk, H., Szutowicz, A. Neurochem. Res. (2003) [Pubmed]
  29. Nerve growth factor and its functional receptor TrkA are up-regulated in murine decidual tissue of stress-triggered and substance P-mediated abortion. Tometten, M., Klapp, B.F., Joachim, R., Fest, S., Zenclussen, A.C., Peters, E.M., Hertwig, K., Arck, P.C. Am. J. Reprod. Immunol. (2004) [Pubmed]
  30. TrkA mediates developmental sympathetic neuron survival in vivo by silencing an ongoing p75NTR-mediated death signal. Majdan, M., Walsh, G.S., Aloyz, R., Miller, F.D. J. Cell Biol. (2001) [Pubmed]
  31. p53 is essential for developmental neuron death as regulated by the TrkA and p75 neurotrophin receptors. Aloyz, R.S., Bamji, S.X., Pozniak, C.D., Toma, J.G., Atwal, J., Kaplan, D.R., Miller, F.D. J. Cell Biol. (1998) [Pubmed]
  32. BDNF enhancement of postsynaptic NMDA receptors is blocked by ethanol. Kolb, J.E., Trettel, J., Levine, E.S. Synapse (2005) [Pubmed]
  33. Nerve growth factor activation of Erk-1 and Erk-2 induces matrix metalloproteinase-9 expression in vascular smooth muscle cells. Khan, K.M., Falcone, D.J., Kraemer, R. J. Biol. Chem. (2002) [Pubmed]
  34. Characterization of neurotrophin and Trk receptor functions in developing sensory ganglia: direct NT-3 activation of TrkB neurons in vivo. Fariñas, I., Wilkinson, G.A., Backus, C., Reichardt, L.F., Patapoutian, A. Neuron (1998) [Pubmed]
  35. Biochemical and functional interactions between the neurotrophin receptors trk and p75NTR. Bibel, M., Hoppe, E., Barde, Y.A. EMBO J. (1999) [Pubmed]
  36. Sympathetic neuron survival and TrkA expression in NT3-deficient mouse embryos. Wyatt, S., Piñon, L.G., Ernfors, P., Davies, A.M. EMBO J. (1997) [Pubmed]
  37. Binding of neurotrophin-3 to p75LNGFR, TrkA, and TrkB mediated by a single functional epitope distinct from that recognized by trkC. Rydén, M., Ibáñez, C.F. J. Biol. Chem. (1996) [Pubmed]
  38. Nerve growth factor stimulates the concentration of TrkA within lipid rafts and extracellular signal-regulated kinase activation through c-Cbl-associated protein. Limpert, A.S., Karlo, J.C., Landreth, G.E. Mol. Cell. Biol. (2007) [Pubmed]
  39. Induction of a distinct morphology and signal transduction in TrkB/PC12 cells by nerve growth factor and brain-derived neurotrophic factor. Iwasaki, Y., Ishikawa, M., Okada, N., Koizumi, S. J. Neurochem. (1997) [Pubmed]
  40. Expression of the trk proto-oncogene is restricted to the sensory cranial and spinal ganglia of neural crest origin in mouse development. Martin-Zanca, D., Barbacid, M., Parada, L.F. Genes Dev. (1990) [Pubmed]
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