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Gene Review

NGF  -  nerve growth factor (beta polypeptide)

Homo sapiens

Synonyms: Beta-NGF, Beta-nerve growth factor, HSAN5, NGFB
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Disease relevance of NGFB

  • This process, called sensitization or hyperalgesia, is mediated by a variety of proinflammatory factors, including bradykinin, ATP and NGF, which cause sensitization to noxious heat stimuli by enhancing the membrane current carried by the heat- and capsaicin-gated ion channel, TRPV1 [1].
  • To determine whether NGF has a direct effect on dorsal root ganglion neurons, we have begun to investigate the acute effects of NGF on capsaicin responses of small-diameter dorsal root ganglion cells in culture [2].
  • The developmental loss of neurons in sympathetic, sensory, and some parasympathetic ganglia in familial dysautonomia suggests an inherited defect in the action of beta-nerve growth factor (beta-NGF) [3].
  • The role of this growth factor in dysautonomia has been difficult to resolve as there is no known source of authentic human beta-NGF [3].
  • Notably, supernatants of eosinophils stimulated with IgA immune complex and interleukin 5 promote neurite extension of the PC-12 pheochromocytoma cell line; this effect is abolished by pretreatment of the supernatants with anti-NGF-neutralizing antibody [4].

Psychiatry related information on NGFB

  • In recent years, nerve growth factor (NGF) has gained attention as a potential therapeutic agent for Alzheimer's disease (AD) [5].
  • During a critical period of late prenatal development nerve growth factor (NGF) signalling through its cognate high affinity receptor trkA has been shown to be the main survival factor during a critical period of prenatal development [6].
  • Since trophic factors are increasingly recognized as playing a role in some decision-making steps during development, the influence of brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) on the commitment of pluripotent neural crest cells was investigated by in vitro clonal analysis [7].
  • This expression of cortical NGF receptors was compared with that seen in other neurological diseases and normal human development as well as in young and aged nonhuman primates [8].
  • These results show that naturally occurring age-related memory loss can be reversed by grafting cells engineered to secrete NGF directly to the NBM, and that either cholinergic hyper- or hypofunction may lead to cognitive impairments [9].

High impact information on NGFB

  • 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 [10].
  • Nerve growth factor (NGF) induces neurite outgrowth and promotes survival of embryonic sensory and sympathetic neurons [10].
  • Thus, NGF is an autocrine survival factor for memory B lymphocytes [11].
  • Production of nerve growth factor (NGF) was assessed in cultures of human T and B lymphocytes and macrophages [11].
  • Treatment of PC12 cells with nerve growth factor (NGF) induces a rapid increase in tyrosine phosphorylation of multiple cellular proteins [12].

Chemical compound and disease context of NGFB


Biological context of NGFB

  • Analysis of functional candidate genes in the disease critical region revealed a mutation in the coding region of the nerve growth-factor beta (NGFB) gene specific for the disease haplotype [16].
  • Two thyroid hormone regulated genes, the beta-subunits of nerve growth factor (NGFB) and thyroid stimulating hormone (TSHB), have been assigned to mouse chromosome 3 and human chromosome 1p22 [17].
  • CSFM maps to human chromosome 5q, while AMY2, NGFB, and NRAS map to human chromosome 1p [18].
  • Two thyroid hormone regulated genes, the beta-subunits of nerve growth factor (NGFB) and thyroid stimulating hormone (TSHB), are located less than 310 kb apart in both human and mouse genomes [17].
  • Multipoint linkage analysis showed that the amylase gene cluster is located distal to the nerve growth factor beta-subunit gene (NGFB) and is within 1 cM of the anonymous locus D1S10 [19].

Anatomical context of NGFB

  • Recombinant purified NT-6 has a spectrum of actions similar to NGF on chick sympathetic and sensory neurons, albeit with a lower potency [20].
  • NGF activity isolated from the male mouse submaxillary gland (MSG) consists of three types of subunits, alpha, beta and gamma, which specifically interact to form a 7S, approximately 130,000-molecular weight (Mr) complex [21].
  • Fragments of the recently cloned human gene for the beta subunit of nerve growth factor (beta-NGF) were used as hybridization probes in analyzing two sets of rodent-human somatic cell hybrids for the presence of human beta-NGF sequences [22].
  • The receptor p140trkA has many of the properties of the higher affinity class of NGF receptors, and is able to mediate survival and differentiation of the PC12 cell line, and cell growth and transformation in fibroblast cells [23].
  • The neurotrophins, of which nerve growth factor (NGF) is the best known example, support the survival and differentiation of chick embryo sensory neurons at extremely low concentrations, 10(-12) M or less [23].

Associations of NGFB with chemical compounds


Physical interactions of NGFB

  • The recent crystal structure of the complex between NGF and the ligand-binding domain of TrkA defines the orientation of NGF in the signaling complex, and eludicates the structural basis for binding and specificity in the family [27].
  • We conclude that monoamine-activated alpha 2M may block neurite outgrowth and neuronal survival by its specific binding to NGF receptors, thus inhibiting the NGF-promoted activation of intracellular second messenger pathways [28].
  • Here we show that the PTB domains of both the alpha and beta isoforms of FRS2 bind directly to the FGF or NGF receptors [29].
  • The number of high-affinity NGF binding sites was nearly the same for LAN5 and LAN5/NGFR, a finding suggesting that there is a limiting number of some separately coded factor or subunit that is required for high-affinity NGFRs [30].
  • When NGF binding to p75NTR was blocked by treating cells with either BDNF or PD90780, and where p75NTR expression was reduced by treating cells with antisense oligonucleotide to p75NTR, the protective effects of NGF were attenuated [31].

Enzymatic interactions of NGFB

  • 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 [32].
  • We have isolated a human cDNA for the signaling adapter molecule FRS-2/suc1-associated neurotrophic factor target and shown that it is tyrosine-phosphorylated in response to nerve growth factor (NGF) stimulation [33].
  • In addition, a chimeric TrkA-DDR1 receptor failed to become phosphorylated on stimulation with nerve growth factor (NGF), although it dimerized normally [34].
  • NGF/p75NTR-activated CK2 phosphorylates the phosphatase and tensin homologue deleted on chromosome 10 (PTEN), thus rendering this phosphatase inactive [35].

Regulatory relationships of NGFB


Other interactions of NGFB

  • Evidence indicates that co-expression of the two genes for the p75 receptor and the Trk NGF receptor can potentially lead to greater responsiveness to NGF, and suggests additional levels of regulation for the family of neurotrophin factors [41].
  • NGF rapidly increases membrane expression of TRPV1 heat-gated ion channels [1].
  • Sedimentation equilibrium showed that BDNF, NT-3, and NGF exist as strongly associated dimers in phosphate-buffered saline, pH 7 [42].
  • In this study, a minimum set of residues in the human TrkC second immunoglobulin-like domain, which does not bind nerve growth factor (NGF), were substituted with those from human TrkA [43].
  • The RET receptor signal pathway is functional in most NB, while loss of nerve growth factor (NGF) receptor (trkA) gene expression correlates with an aggressive phenotype [44].

Analytical, diagnostic and therapeutic context of NGFB


  1. NGF rapidly increases membrane expression of TRPV1 heat-gated ion channels. Zhang, X., Huang, J., McNaughton, P.A. EMBO J. (2005) [Pubmed]
  2. Neurotrophins and hyperalgesia. Shu, X.Q., Mendell, L.M. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  3. Structural gene for beta-nerve growth factor not defective in familial dysautonomia. Breakefield, X.O., Orloff, G., Castiglione, C., Coussens, L., Axelrod, F.B., Ullrich, A. Proc. Natl. Acad. Sci. U.S.A. (1984) [Pubmed]
  4. Human eosinophils produce neurotrophins and secrete nerve growth factor on immunologic stimuli. Kobayashi, H., Gleich, G.J., Butterfield, J.H., Kita, H. Blood (2002) [Pubmed]
  5. BDNF mRNA is decreased in the hippocampus of individuals with Alzheimer's disease. Phillips, H.S., Hains, J.M., Armanini, M., Laramee, G.R., Johnson, S.A., Winslow, J.W. Neuron (1991) [Pubmed]
  6. The changing sensitivity in the life of the nociceptor. Koltzenburg, M. Pain (1999) [Pubmed]
  7. Role of the neurotrophic factors BDNF and NGF in the commitment of pluripotent neural crest cells. Sieber-Blum, M. Neuron (1991) [Pubmed]
  8. Cortical neurons express nerve growth factor receptors in advanced age and Alzheimer disease. Mufson, E.J., Kordower, J.H. Proc. Natl. Acad. Sci. U.S.A. (1992) [Pubmed]
  9. Somatic gene transfer of NGF to the aged brain: behavioral and morphological amelioration. Chen, K.S., Gage, F.H. J. Neurosci. (1995) [Pubmed]
  10. 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]
  11. Nerve growth factor is an autocrine survival factor for memory B lymphocytes. Torcia, M., Bracci-Laudiero, L., Lucibello, M., Nencioni, L., Labardi, D., Rubartelli, A., Cozzolino, F., Aloe, L., Garaci, E. Cell (1996) [Pubmed]
  12. Ras is essential for nerve growth factor- and phorbol ester-induced tyrosine phosphorylation of MAP kinases. Thomas, S.M., DeMarco, M., D'Arcangelo, G., Halegoua, S., Brugge, J.S. Cell (1992) [Pubmed]
  13. Coexpression of messenger RNA for TRK protooncogene and low affinity nerve growth factor receptor in neuroblastoma with favorable prognosis. Kogner, P., Barbany, G., Dominici, C., Castello, M.A., Raschellá, G., Persson, H. Cancer Res. (1993) [Pubmed]
  14. The neuropeptide pituitary adenylate cyclase activating protein stimulates human monocytes by transactivation of the Trk/NGF pathway. El Zein, N., Badran, B.M., Sariban, E. Cell. Signal. (2007) [Pubmed]
  15. The expression of neurotrophins and their receptors in the prenatal and adult human testis: evidence for functions in Leydig cells. Müller, D., Davidoff, M.S., Bargheer, O., Paust, H.J., Pusch, W., Koeva, Y., Jezek, D., Holstein, A.F., Middendorff, R. Histochem. Cell Biol. (2006) [Pubmed]
  16. A mutation in the nerve growth factor beta gene (NGFB) causes loss of pain perception. Einarsdottir, E., Carlsson, A., Minde, J., Toolanen, G., Svensson, O., Solders, G., Holmgren, G., Holmberg, D., Holmberg, M. Hum. Mol. Genet. (2004) [Pubmed]
  17. Two thyroid hormone regulated genes, the beta-subunits of nerve growth factor (NGFB) and thyroid stimulating hormone (TSHB), are located less than 310 kb apart in both human and mouse genomes. Dracopoli, N.C., Rose, E., Whitfield, G.K., Guidon, P.T., Bale, S.J., Chance, P.A., Kourides, I.A., Housman, D.E. Genomics (1988) [Pubmed]
  18. Localization of the murine macrophage colony-stimulating factor gene to chromosome 3 using interspecific backcross analysis. Buchberg, A.M., Jenkins, N.A., Copeland, N.G. Genomics (1989) [Pubmed]
  19. Mapping the human amylase gene cluster on the proximal short arm of chromosome 1 using a highly informative (CA)n repeat. Dracopoli, N.C., Meisler, M.H. Genomics (1990) [Pubmed]
  20. Neurotrophin-6 is a new member of the nerve growth factor family. Götz, R., Köster, R., Winkler, C., Raulf, F., Lottspeich, F., Schartl, M., Thoenen, H. Nature (1994) [Pubmed]
  21. Human beta-nerve growth factor gene sequence highly homologous to that of mouse. Ullrich, A., Gray, A., Berman, C., Dull, T.J. Nature (1983) [Pubmed]
  22. The human gene for the beta subunit of nerve growth factor is located on the proximal short arm of chromosome 1. Francke, U., de Martinville, B., Coussens, L., Ullrich, A. Science (1983) [Pubmed]
  23. The nerve growth factor family of receptors. Meakin, S.O., Shooter, E.M. Trends Neurosci. (1992) [Pubmed]
  24. Crystal structure of nerve growth factor in complex with the ligand-binding domain of the TrkA receptor. Wiesmann, C., Ultsch, M.H., Bass, S.H., de Vos, A.M. Nature (1999) [Pubmed]
  25. Promotion of central cholinergic and dopaminergic neuron differentiation by brain-derived neurotrophic factor but not neurotrophin 3. Knüsel, B., Winslow, J.W., Rosenthal, A., Burton, L.E., Seid, D.P., Nikolics, K., Hefti, F. Proc. Natl. Acad. Sci. U.S.A. (1991) [Pubmed]
  26. Efficient processing and expression of human nerve growth factor receptors in Xenopus laevis oocytes: effects on maturation. Sehgal, A., Wall, D.A., Chao, M.V. Mol. Cell. Biol. (1988) [Pubmed]
  27. Nerve growth factor: structure and function. Wiesmann, C., de Vos, A.M. Cell. Mol. Life Sci. (2001) [Pubmed]
  28. Monoamine-activated alpha 2-macroglobulin binds trk receptor and inhibits nerve growth factor-stimulated trk phosphorylation and signal transduction. Koo, P.H., Qiu, W.S. J. Biol. Chem. (1994) [Pubmed]
  29. FRS2 proteins recruit intracellular signaling pathways by binding to diverse targets on fibroblast growth factor and nerve growth factor receptors. Ong, S.H., Guy, G.R., Hadari, Y.R., Laks, S., Gotoh, N., Schlessinger, J., Lax, I. Mol. Cell. Biol. (2000) [Pubmed]
  30. Characterization of two neuroblastoma cell lines expressing recombinant nerve growth factor receptors. Reddy, U.R., Venkatakrishnan, G., Roy, A.K., Chen, J., Hardy, M., Mavilio, F., Rovera, G., Pleasure, D., Ross, A.H. J. Neurochem. (1991) [Pubmed]
  31. The common neurotrophin receptor p75NTR enhances the ability of PC12 cells to resist oxidative stress by a trkA-dependent mechanism. Wang, W., Dow, K.E., Riopelle, R.J., Ross, G.M. Neurotoxicity research. (2001) [Pubmed]
  32. 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]
  33. The signaling adapter FRS-2 competes with Shc for binding to the nerve growth factor receptor TrkA. A model for discriminating proliferation and differentiation. Meakin, S.O., MacDonald, J.I., Gryz, E.A., Kubu, C.J., Verdi, J.M. J. Biol. Chem. (1999) [Pubmed]
  34. Functional analysis of discoidin domain receptor 1: effect of adhesion on DDR1 phosphorylation. L'hôte, C.G., Thomas, P.H., Ganesan, T.S. FASEB J. (2002) [Pubmed]
  35. Activation of casein kinase II and inhibition of phosphatase and tensin homologue deleted on chromosome 10 phosphatase by nerve growth factor/p75NTR inhibit glycogen synthase kinase-3beta and stimulate axonal growth. Arevalo, M.A., Rodríguez-Tébar, A. Mol. Biol. Cell (2006) [Pubmed]
  36. 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]
  37. 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]
  38. FKHRL1 and its homologs are new targets of nerve growth factor Trk receptor signaling. Zheng, W.H., Kar, S., Quirion, R. J. Neurochem. (2002) [Pubmed]
  39. Neurotrophic factors in relapsing remitting and secondary progressive multiple sclerosis patients during interferon beta therapy. Caggiula, M., Batocchi, A.P., Frisullo, G., Angelucci, F., Patanella, A.K., Sancricca, C., Nociti, V., Tonali, P.A., Mirabella, M. Clin. Immunol. (2006) [Pubmed]
  40. 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]
  41. p75 and Trk: a two-receptor system. Chao, M.V., Hempstead, B.L. Trends Neurosci. (1995) [Pubmed]
  42. Comparison of the biophysical characteristics of human brain-derived neurotrophic factor, neurotrophin-3, and nerve growth factor. Narhi, L.O., Rosenfeld, R., Talvenheimo, J., Prestrelski, S.J., Arakawa, T., Lary, J.W., Kolvenbach, C.G., Hecht, R., Boone, T., Miller, J.A. J. Biol. Chem. (1993) [Pubmed]
  43. TrkA amino acids controlling specificity for nerve growth factor. O'Connell, L., Hongo, J.A., Presta, L.G., Tsoulfas, P. J. Biol. Chem. (2000) [Pubmed]
  44. The RET and TRKA pathways collaborate to regulate neuroblastoma differentiation. Peterson, S., Bogenmann, E. Oncogene (2004) [Pubmed]
  45. Comparative analysis of mouse-human hybrids with rearranged chromosomes 1 by in situ hybridization and Southern blotting: high-resolution mapping of NRAS, NGFB, and AMY on human chromosome 1. Münke, M., Lindgren, V., de Martinville, B., Francke, U. Somat. Cell Mol. Genet. (1984) [Pubmed]
  46. Evolutionary studies of the nerve growth factor family reveal a novel member abundantly expressed in Xenopus ovary. Hallböök, F., Ibáñez, C.F., Persson, H. Neuron (1991) [Pubmed]
  47. Chromosomal locations of the human and mouse genes for precursors of epidermal growth factor and the beta subunit of nerve growth factor. Zabel, B.U., Eddy, R.L., Lalley, P.A., Scott, J., Bell, G.I., Shows, T.B. Proc. Natl. Acad. Sci. U.S.A. (1985) [Pubmed]
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