Nerve growth factor (beta polypeptide)

NGF dimer (extracted from PDB 1SG1)
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols NGF; Beta-NGF; HSAN5; NGFB
External IDs OMIM: 162030 MGI: 97321 HomoloGene: 1876 ChEMBL: 1649058 GeneCards: NGF Gene
RNA expression pattern
PBB GE NGFB 206814 at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 4803 18049
Ensembl ENSG00000134259 ENSMUSG00000027859
UniProt P01138 P01139
RefSeq (mRNA) NM_002506.2 NM_001112698.1
RefSeq (protein) NP_002497.2 NP_001106168.1
Location (UCSC) Chr 1:
115.83 – 115.88 Mb		 Chr 3:
102.27 – 102.32 Mb
PubMed search [1] [2]
This box:

Nerve growth factor (NGF) is a small secreted protein that is important for the growth, maintenance, and survival of certain target neurons (nerve cells). It also functions as a signaling molecule.[1][2] It is perhaps the prototypical growth factor, in that it is one of the first to be described. While "nerve growth factor" refers to a single factor,[3] "nerve growth factors" refers to a family of factors also known as neurotrophins.[4] Other members of the neurotrophin family that are well recognized include Brain-Derived Neurotrophic Factor (BDNF), Neurotrophin-3 (NT-3), and Neurotrophin 4/5 (NT-4/5).

Contents

Function and mechanism of action [link]

NGF is critical for the survival and maintenance of sympathetic and sensory neurons. Without it, these neurons undergo apoptosis.[5] Nerve growth factor causes axonal growth. Studies have shown that it causes axonal branching and a bit of elongation.[6] NGF binds with at least two classes of receptors: the p75 LNGFR (for "low-affinity nerve growth factor receptor") neurotrophin receptor (p75(NTR)) and TrkA, a transmembrane tyrosine kinase. Both are associated with neurodegenerative disorders.

NGF binds to high-affinity tyrosine kinase receptor TrkA. This phosphorylates TrkA, which leads to the activation of PI 3 Kinase, ras, and PLC signaling pathways.

There is evidence that NGF circulates throughout the entire body and is important for maintaining homeostasis.[7]

Major neuron-survival pathways mediated by NGF signaling [link]

Binding interaction between NGF and the TrkA receptor facilitates receptor dimerization and tyrosine residue phosphorylation of the cytoplasmic tail by adjacent Trk receptors.[8] Trk receptor phosphorylation sites operate as Shc adaptor protein docking sites, which undergo phosphorylation by the TrkA receptor[9] Once the cytoplasmic adaptor protein (Shc) is phosphorylated by the receptor cytoplasmic tail, cell survival is initiated through several intracellular pathways.

One major pathway leads to the activation of the serine/threonine kinase, Akt. This pathway begins with the Trk receptor complex-recruitment of a second adaptor protein called growth factor-receptor bound protein-2 (Grb2) along with a docking protein called Grb2-associated Binder-1 (GAB1).[9] Subsequently, phosphatidylinositol-3 kinase (PI3K) is activated, resulting in Akt kinase activation.[9] Study results have shown that blocking PI3K or Akt activity results in death of sympathetic neurons in culture, regardless of NGF presence.[10] However if either kinase is constitutionally active, neurons survive even without NGF.[10]

A second pathway contributing to cell survival occurs through activation of the mitogen-activated protein kinase (MAPK) kinase. In this pathway, recruitment of a guanine nucleotide exchange factor by the adaptor and docking proteins leads to activation of a membrane-associated G-protein known as Ras.[9] The guanine nucleotide exchange factor mediates Ras activation through the GDP-GTP exchange process. The active Ras protein phosphorylates several proteins, along with the serine/ threonine kinase, Raf.[9] Raf, in turn activates the MAPK cascade to facilitate ribosomal s6 kinase(RSK) activation and transcriptional regulation.[9]

Both Akt and RSK, components of the PI3K-Akt and MAPK pathways respectively, act to phosphorylate the cyclic AMP response element binding protein (CREB) transcription factor.[9] Phosphorylated CREB translocates into the nucleus and mediates increased expression of anti-apoptotoc proteins,[9] thus promoting NGF-mediated cell survival. However, in the absence of NGF, the expression of pro-apoptotic proteins is increased when the activation of cell death-promoting transcription factors such as c-Jun are not suppressed by the aforementioned NGF-mediated cell survival pathways.[9]

Roles of ProNGF in the survival and death of neurons [link]

There is also evidence that shows that the precursor to NGF, pro-NGF, may also play important roles due to its abundance. These include apoptotic and neurotrophic properties.[11]

Pro-NGF is the uncleaved, precursor protein form of the active peptide form of NGF. The Pro-NGF precursor is biologically inactive, as it does not undergo post-transcriptional modification. Pro-NGF acts with a coreceptor, sortilin, to bind the 75kD neurotrophin receptor known as P75NTR (a tumor necrosis factor family member).[9] High affinity binding between Pro-NGF, sortilin, and p75NTR can result in either survival or programmed cell death (PCD). Study results indicate that superior cervical ganglia neurons that express both p75NTR and TrkA die when treated with proNGF,[12] where as NGF treatment of these same neurons results in survival and axonal growth. Survival and PCD mechanisms are mediated through adaptor protein binding to the death domain of the p75NTR cytoplasmic tail. Survival occurs when recruited cytoplasmic adaptor proteins facilitate signal transduction through tumor necrosis factor receptor members such as TRAF6, which results in the release of nuclear factor κB (NF-κB) transcription activator.[9] NF-κB regulates nuclear gene transcription to promote cell survival. Alternatively, PCD occurs when TRAF6 and neurotrophin receptor interacting factor (NRIF) are both recruited to activate c-Jun N-terminal kinase (JNK); which phosphorylates c-Jun. The activated transcription factor c-Jun regulates nuclear transcription to increase pro-apoptotic gene transcription.[9]

Structure [link]

The structure of NGF was first solved by X-ray crystallography and published in 1991 by McDonald et al. in Nature.[13][14] NGF forms a cystine knot structure made up of beta strands twisted around each other and linked by disulfide bonds. Most structures are dimeric. At the time this structure was solved, this fold had never been seen before. Hence NGF is the founding member of the nerve growth factor family of structurally conserved proteins.

History [link]

Rita Levi-Montalcini and Stanley Cohen discovered NGF in the 1950s while faculty members at Washington University in St Louis. However, its discovery, along with the discovery of other neurotrophins, was not widely recognized until 1986, when it won the Nobel Prize in Physiology or Medicine.[15][16][17]

Studies in 1971 determined the primary structure of NGF. This eventually led to the discovery of the NGF gene.

Medical significance [link]

NGF has the potential to help treat several diseases of the nervous system. It has shown this through numerous clinical trials. It has been shown to reduce neural degeneration.[18] It has also been shown to promote peripheral nerve regeneration in rats.[19]

There is strong evidence demonstrating more NGF is expressed in inflammatory [20] conditions. This may one day be used for the treatment of Multiple Sclerosis.[21] Also, it could possibly promote myelin repair.[22]

Also, NGF has been shown to play a role in number cardiovascular diseases, such as coronary atherosclerosis, obesity, type 2 diabetes, and metabolic syndrome.[23] Reduced plasma levels of NGF and BDNF have been associated with acute coronary syndromes and metabolic syndromes.[24][25] NGF could also be related to various psychiatric disorders, such as dementia, depression, schizophrenia, autism, Rett syndrome, anorexia nervosa, and bulimia nervosa.[26] NGF has also been shown to accelerate wound healing. There is evidence that it could be useful in the treatment of skin ulcers and cornea ulcers.[27]

NGF is known to have insulinotropic, angiogenic, and antioxidant properties. NGF suppresses food intake.

It has also been tied to Alzheimer's disease.[28][29][30]

Cultural significance [link]

In 2005, Enzo Emanuele and coworkers at University of Pavia found that nerve growth factor (NGF) has high levels when people first fall in love, but these levels return to as they were after one year. To be specific, four neurotrophin levels, i.e., NGF, BDNF, NT-3, and NT-4, of 58 subjects who had recently fallen in love were compared with levels in a control group who were either single or already engaged in a long-term relationship. The results showed that NGF levels were significantly higher in the subjects in love than as compared to either of the control groups.[31][32][33] Nerve growth factor may contribute to increased longevity and mental capacity.[34] Centenarian Rita Levi-Montalcini has been taking a daily solution in the form of eye drops, and has stated that her brain is more active now than it was four decades ago.[34]

Interactions [link]

Nerve growth factor has been shown to interact with TrkA[12][35][36] and Low affinity nerve growth factor receptor.[12][35]

See also [link]

References [link]

  1. ^ Fiore M, Chaldakov GN, Aloe L (2009). "Nerve growth factor as a signaling molecule for nerve cells and also for the neuroendocrine-immune systems". Rev Neurosci 20 (2): 133–45. PMID 19774790. 
  2. ^ Purves D, Augustine G, Fitzpatrick D, Hall W, LaMantia A, McNamara J, White L (2004). Neuroscience. Sunderland, Mass: Sinauer. pp. 72–173, 600–606. ISBN 0-87893-725-0. 
  3. ^ Nerve+Growth+Factor at the US National Library of Medicine Medical Subject Headings (MeSH)
  4. ^ Nerve+Growth+Factors at the US National Library of Medicine Medical Subject Headings (MeSH)
  5. ^ Freeman RS, Burch RL, Crowder RJ, Lomb DJ, Schoell MC, Straub JA, Xie L (2004). NGF deprivation-induced gene expression: after ten years, where do we stand?. "NGF and Related Molecules in Health and Disease". Prog. Brain Res.. Progress in Brain Research 146: 111–26. DOI:10.1016/S0079-6123(03)46008-1. ISBN 978-0-444-51472-1. PMID 14699960. 
  6. ^ Madduri S, Papaloïzos M, Gander B (September 2009). "Synergistic effect of GDNF and NGF on axonal branching and elongation in vitro". Neurosci. Res. 65 (1): 88–97. DOI:10.1016/j.neures.2009.06.003. PMID 19523996. 
  7. ^ Levi-Montalcini R (2004). "The nerve growth factor and the neuroscience chess board". Prog. Brain Res. 146: 525–7. PMID 14699984. 
  8. ^ Kaplan DR, Martin-Zanca D, Parada LF (March 1991). "Tyrosine phosphorylation and tyrosine kinase activity of the trk proto-oncogene product induced by NGF". Nature 350 (6314): 158–60. DOI:10.1038/350158a0. PMID 1706478. 
  9. ^ a b c d e f g h i j k l Sanes DH, Thomas AR, Harris WA (2011). "Naturally-occurring neuron death". Development of the Nervous System, Third Edition. Boston: Academic Press. pp. 171-208}. ISBN 0-12-374539-X. 
  10. ^ a b Crowder RJ, Freeman RS (April 1998). "Phosphatidylinositol 3-kinase and Akt protein kinase are necessary and sufficient for the survival of nerve growth factor-dependent sympathetic neurons". J. Neurosci. 18 (8): 2933–43. PMID 9526010. 
  11. ^ Fahnestock M, Yu G, Coughlin MD (2004). ProNGF: a neurotrophic or an apoptotic molecule?. "NGF and Related Molecules in Health and Disease". Prog. Brain Res.. Progress in Brain Research 146: 101–10. DOI:10.1016/S0079-6123(03)46007-X. ISBN 978-0-444-51472-1. PMID 14699959. 
  12. ^ a b c Lee R, Kermani P, Teng KK, Hempstead BL (November 2001). "Regulation of cell survival by secreted proneurotrophins". Science 294 (5548): 1945–8. DOI:10.1126/science.1065057. PMID 11729324. 
  13. ^ PDB 1bet; McDonald NQ, Lapatto R, Murray-Rust J, Gunning J, Wlodawer A, Blundell TL (December 1991). "New protein fold revealed by a 2.3-A resolution crystal structure of nerve growth factor". Nature 354 (6352): 411–4. DOI:10.1038/354411a0. PMID 1956407. 
  14. ^ "NGF - twenty years a-growing". Quips. Protein Data Bank Europe. https://www.ebi.ac.uk/pdbe-apps/quips?story=NGFstory. 
  15. ^ The 1986 Nobel Prize in Physiology or Medicine for discoveries of growth factors
  16. ^ Presentation Speech by Professor Kerstin Hall The Nobel Prize in Physiology or Medicine 1986
  17. ^ Rita Levi-Montalcini – Nobel Lecture
  18. ^ Tuszynski M., Blesch A. (2004). Nerve growth factor: from animal models of cholinergic neuronal degeneration to gene therapy in Alzheimer’s disease. Progress in Brain Research, 146, 0079-6123
  19. ^ Sun W, Sun C, Lin H, Zhao H, Wang J, Ma H, Chen B, Xiao Z, Dai J (September 2009). "The effect of collagen-binding NGF-beta on the promotion of sciatic nerve regeneration in a rat sciatic nerve crush injury model". Biomaterials 30 (27): 4649–56. DOI:10.1016/j.biomaterials.2009.05.037. PMID 19573907. 
  20. ^ Freund V, Frossard N (2004). Expression of nerve growth factor in the airways and its possible role in asthma. "NGF and Related Molecules in Health and Disease". Prog. Brain Res.. Progress in Brain Research 146: 335–46. DOI:10.1016/S0079-6123(03)46021-4. ISBN 978-0-444-51472-1. PMID 14712791. 
  21. ^ Villoslada P, Genain CP (2004). Role of nerve growth factor and other trophic factors in brain inflammation. "NGF and Related Molecules in Health and Disease". Prog. Brain Res.. Progress in Brain Research 146: 403–14. DOI:10.1016/S0079-6123(03)46025-1. ISBN 978-0-444-51472-1. PMID 14699976. 
  22. ^ Althaus HH (2004). Remyelination in multiple sclerosis: a new role for neurotrophins?. "NGF and Related Molecules in Health and Disease". Prog. Brain Res.. Progress in Brain Research 146: 415–32. DOI:10.1016/S0079-6123(03)46026-3. ISBN 978-0-444-51472-1. PMID 14699977. 
  23. ^ Chaldakov GN, Fiore M, Stankulov IS, Manni L, Hristova MG, Antonelli A, Ghenev PI, Aloe L (2004). Neurotrophin presence in human coronary atherosclerosis and metabolic syndrome: a role for NGF and BDNF in cardiovascular disease?. "NGF and Related Molecules in Health and Disease". Prog. Brain Res.. Progress in Brain Research 146: 279–89. DOI:10.1016/S0079-6123(03)46018-4. ISBN 978-0-444-51472-1. PMID 14699970. 
  24. ^ Chaldakov GN, Fiore M, Tonchev AB, Dimitrov D, Pancheva R, Rancic G, Aloe L (2007). "Homo obesus: a metabotrophin-deficient species. Pharmacology and nutrition insight". Curr. Pharm. Des. 13 (21): 2176–9. DOI:10.2174/138161207781039616. PMID 17627549. 
  25. ^ Manni L, Nikolova V, Vyagova D, Chaldakov GN, Aloe L (June 2005). "Reduced plasma levels of NGF and BDNF in patients with acute coronary syndromes". Int. J. Cardiol. 102 (1): 169–71. DOI:10.1016/j.ijcard.2004.10.041. PMID 15939120. 
  26. ^ Chaldakov G., Tonchev A., Aloe L. (2009). NGF and BDNF: from nerves to adipose tissue, from neurokines to metabokines. Relevance to neuropsychiatric and cardiometabolic.
  27. ^ Kawamoto K, Matsuda H (2004). Nerve growth factor and wound healing. "NGF and Related Molecules in Health and Disease". Prog. Brain Res.. Progress in Brain Research 146: 369–84. DOI:10.1016/S0079-6123(03)46023-8. ISBN 978-0-444-51472-1. PMID 14699974. 
  28. ^ Counts S, Mufson E (2005). "The role of nerve growth factor receptors in cholinergic basal forebrain degeneration in prodromal Alzheimer disease". J Neuropathol Exp Neurol 64 (4): 263–72. PMID 15835262. 
  29. ^ Hempstead B (2006). "Dissecting the diverse actions of pro- and mature neurotrophins". Curr Alzheimer Res 3 (1): 19–24. DOI:10.2174/156720506775697061. PMID 16472198. 
  30. ^ Allen S, Dawbarn D (2006). "Clinical relevance of the neurotrophins and their receptors". Clin Sci (Lond) 110 (2): 175–91. DOI:10.1042/CS20050161. PMID 16411894. 
  31. ^ Emanuele E, Politi P, Bianchi M, Minoretti P, Bertona M, Geroldi D (April 2006). "Raised plasma nerve growth factor levels associated with early-stage romantic love". Psychoneuroendocrinology 31 (3): 288–94. DOI:10.1016/j.psyneuen.2005.09.002. PMID 16289361. 
  32. ^ "Molecule Gives Passionate Lovers Just One Year". Health News. redOrbit. 2005-11-25. https://www.redorbit.com/news/health/316141/molecule_gives_passionate_lovers_just_one_year/index.html. Retrieved 2012-03-02. 
  33. ^ Harris J (2005-11-29). "The question: Is love just a chemical?". Education. Guardian. https://education.guardian.co.uk/higher/research/story/0,9865,1653147,00.html. Retrieved 2012-03-02. 
  34. ^ a b Popham P (2009-04-25). "Is this the secret of eternal life? - Science - News - The Independent". The Independent. https://www.independent.co.uk/news/science/is-this-the-secret-of-eternal-life-1674005.htm. Retrieved 2012-03-02. 
  35. ^ a b Nykjaer A, Lee R, Teng KK, Jansen P, Madsen P, Nielsen MS, Jacobsen C, Kliemannel M, Schwarz E, Willnow TE, Hempstead BL, Petersen CM (February 2004). "Sortilin is essential for proNGF-induced neuronal cell death". Nature 427 (6977): 843–8. DOI:10.1038/nature02319. PMID 14985763. 
  36. ^ Wiesmann C, Ultsch MH, Bass SH, de Vos AM (September 1999). "Crystal structure of nerve growth factor in complex with the ligand-binding domain of the TrkA receptor". Nature 401 (6749): 184–8. DOI:10.1038/43705. PMID 10490030. 

External links [link]
Trk binding
NGF · BDNF · NT-3 · NT-4
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FGF homologous factors: FGF11 · FGF12 · FGF13 · FGF14

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NGF

NGF may refer to:

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