Female, Growth Factors, Hormones, LNGF (p75NTR), Male, Proteins
by
0

Nerve Growth Factor

Nerve growth factor (NGF) is a neurotrophic factor and neuropeptide primarily involved in the regulation of growth, maintenance, proliferation, and survival of certain target neurons. It is perhaps the prototypical growth factor, in that it was one of the first to be described. Since it was first isolated by Nobel Laureates Rita Levi-Montalcini and Stanley Cohen in 1956, numerous biological processes involving NGF have been identified, two of them being the survival of pancreatic beta cells and the regulation of the immune system.

Structure

NGF is initially in a 7S, 130-kDa complex of 3 proteins – Alpha-NGF, Beta-NGF, and Gamma-NGF (2:1:2 ratio) when expressed. This form of NGF is also referred to as proNGF (NGF precursor). The gamma subunit of this complex acts as a serine protease, and cleaves the N-terminal of the beta subunit, thereby activating the protein into functional NGF.

The term nerve growth factor usually refers to the 2.5S, 26-kDa beta subunit of the protein, the only component of the 7S NGF complex that is biologically active (i.e. acting as a signaling molecule).

Function

As its name suggests, NGF is involved primarily in the growth, as well as the maintenance, proliferation, and survival of nerve cells (neurons) and is critical for the survival and maintenance of sympathetic and sensory neurons as they undergo apoptosis in its absence. However, several recent studies suggest that NGF is also involved in pathways besides those regulating the life cycle of neurons.

  • 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. Progress in Brain Research. Vol. 146. pp. 111–26. doi:10.1016/S0079-6123(03)46008-1. ISBN 978-0-444-51472-1. PMID 14699960.

Neuronal proliferation

NGF can drive the expression of genes such as bcl-2 by binding to the Tropomyosin receptor kinase A, which stimulates the proliferation and survival of the target neuron.

High affinity binding between proNGF, sortilin, and p75NTR can result in either survival or programmed cell death. Study results indicate that superior cervical ganglia neurons that express both p75NTR and TrkA die when treated with proNGF, while 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. NF-κB regulates nuclear gene transcription to promote cell survival. Alternatively, programmed cell death 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 via AP-1 to increase pro-apoptotic gene transcription.

Proliferation of pancreatic beta cells

There is evidence that pancreatic beta cells express both the TrkA and p75NTR receptors of NGF. It has been shown that the withdrawal of NGF induces apoptosis in pancreatic beta cells, signifying that NGF may play a critical role in the maintenance and survival of pancreatic beta cells.

Regulation of the immune system

NGF plays a critical role in the regulation of both innate and acquired immunity. In the process of inflammation, NGF is released in high concentrations by mast cells, and induces axonal outgrowth in nearby nociceptive neurons. This leads to increased pain perception in areas under inflammation. In acquired immunity, NGF is produced by the Thymus as well as CD4+ T cell clones, inducing a cascade of maturation of T cells under infection.

Ovulation

NGF is abundant in seminal plasma. Recent studies have found that it induces ovulation in some mammals e.g. “induced” ovulators, such as llamas. Surprisingly, research showed that these induced animals will also ovulate when semen from on-schedule or “spontaneous” ovulators, such as cattle is used. Its significance in humans is unknown. It was previously dubbed ovulation-inducing factor (OIF) in semen before it was identified as beta-NGF in 2012.

Mechanism of action

NGF binds with at least two classes of receptors: the tropomyosin receptor kinase A (TrkA) and low-affinity NGF receptor (LNGFR/p75NTR). Both are associated with neurodegenerative disorders.

When NGF binds to the TrkA receptor, it drives the homodimerization of the receptor, which in turn causes the autophosphorylation of the tyrosine kinase segment. The tropomyosin receptor kinase A receptor has five extracellular domains, and the fifth domain is sufficient in binding NGF. Once bound, the complex undergoes endocytosis and activates the NGF transcriptional program, following two major pathways, the Ras/MAPK pathway and the PI3K/Akt pathway. The binding of NGF to TrkA also leads to the activation of PI 3-kinase, ras, and PLC signaling pathways. Alternatively, the p75NTR receptor can form a heterodimer with TrkA, which has higher affinity and specificity for NGF.

Studies suggest that NGF circulates throughout the entire body via the blood plasma, and is important for the overall maintenance of homeostasis.

Neuron survival

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

  • Kaplan DR, Martin-Zanca D, Parada LF (Mar 1991). “Tyrosine phosphorylation and tyrosine kinase activity of the trk proto-oncogene product induced by NGF”. Nature. 350 (6314): 158–60. Bibcode:1991Natur.350..158K. doi:10.1038/350158a0. PMID 1706478. S2CID 4241996.
  • 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 978-0-12-374539-2.

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). Subsequently, phosphatidylinositol-3 kinase (PI3K) is activated, resulting in Akt kinase activation. Study results have shown that blocking PI3K or Akt activity results in death of sympathetic neurons in culture, regardless of NGF presence. However, if either kinase is constitutively active, neurons survive even without NGF.

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. 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. Raf in turn activates the MAPK cascade to facilitate ribosomal s6 kinase (RSK) activation and transcriptional regulation.

  • 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 978-0-12-374539-2.

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. Phosphorylated CREB translocates into the nucleus and mediates increased expression of anti-apoptotic proteins, 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.

  • 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 978-0-12-374539-2.

History

Rita Levi-Montalcini and Stanley Cohen discovered NGF in the 1950s while faculty members at Washington University in St Louis. The critical discover was done by Levi-Montalcini and Hertha Meyer at the Carlos Chagas Filho Biophysics Institute of the Federal University of Rio de Janeiro in 1952. Their publication in 1954 became the definitive proof for the existence of the protein. Meyer pioneered the methods of cell culture, specifically useful for protozoan parasites such as Toxoplasma, Plasmodium and Trypanosoma. She developed a method for electron microscopy that was used in the structural description of protozoans and discoveries of cell organelles. Her cell culture method led to the discovery of nerve growth factor, a protein that regulates development and survival of neurones.

Stanley Cohen was an American biochemist who, along with Rita Levi-Montalcini, was awarded the Nobel Prize in Physiology or Medicine in 1986 for the isolation of nerve growth factor and the discovery of epidermal growth factor.  His first academic employment was at the University of Colorado studying the metabolism of premature babies. In 1952 he moved to Washington University in St. Louis, working first in the department of radiology, learning isotope methodology, and then in the department of zoology. Working with Rita Levi-Montalcini, he isolated nerve growth factor. He later isolated a protein that could accelerate incisor eruption and eyelid opening in newborn mice, which was renamed epidermal growth factor. He continued research on cellular growth factors after joining the faculty of Vanderbilt University School of Medicine in 1959.

Franz Joseph Emil Fischer (1877 – 1947) was a German chemist. He was the founder and first director of the Kaiser Wilhelm Institute for Coal Research. He and Hans Tropsch discovered the Fischer–Tropsch process. He and Hans Schrader developed the Fischer assay, a standardized laboratory test for determining the oil yield from oil shale to be expected from a conventional shale oil extraction.[He also worked with Wilhelm Ostwald and Hermann Emil Fischer. 
He joined the NSDAP in 1933, and remained in office until his retirement in 1943.

Hertha Meyer was born in Germany. In 1926, she moved to Kaiser Wilhelm Institute in Dalheim to work under Albert Fischer (or more likely Emil Fischer), who trained her in tissue culture. She made her first scientific publication with Fischer in 1928. Between 1930 and 1933, she worked at the clinical laboratory of the University of Berlin. Meyer moved to Italy in 1933. She managed to find a job of technician at the University of Turin. In Turin, Meyer was enrolled for a course in cytology of the nervous system and graduated under Giuseppe Levi, professor of human anatomy and pioneer of culturing cells. [It is also possible that she worked for Levi, and was not his student.] There she befriended Levi’s students like Renato Dulbecco, Salvador Luria, Rita Levi-Montalcini and Eugenia Sacerdote, all of who turned out to be notable scientists (the first three winning Nobel prizes). Antisemitic restrictions also became stronger in Italy so that Meyer was compelled to emigrate in Brazil in 1937 (or more likely 1939). In Rio de Janeiro, she got a job at the Manguinhos (or Manguinhos-Maré) campus of the Oswaldo Cruz Institute. She used her skills in tissue culture to develop vaccines, especially that of yellow fever from which she came to be noticed by the scientific community. In 1938, Carlos Chagas Filho, who had become chair of the biological physics at the Oswaldo Cruz Institute a year before, decided to established an independent biophysics laboratory as an “informal” extension of his own research. His focus was to set up a tissue culture laboratory, for which he was able to get financial support from Guilherme Guinle, a banker and a philanthropist, in 1940. He came to learn that Meyer’s works were exactly the kind he wanted. Accepting his invitation, Meyer became the official director of his laboratory in 1941. Her ability as a research scientist and head of the laboratory was reflected by a series of research reports by the very next year. However, Filho received a threat from Nazi supporters that his research fund would be suspended if he continued to employ Meyer (mentioned as “an Israeli woman”), which he completely ignored. Meyer’s salary was cut off for several months, but Filho fought to restore it. In 1945, the laboratory was recognised as an autonomous research centre, becoming the Biophysics Institute (officially Carlos Chagas Filho Institute of Biophysics) with major funding from the Rockefeller Foundation, and affiliated to the Federal University of Rio de Janeiro. Within a decade, the institute became the “most efficient tissue culture unit” in the world, as Levi-Montalcini put it.

Hermann Emil Louis Fischer FRS FRSE FCS (1852 –1919) was a German chemist and 1902 recipient of the Nobel Prize in Chemistry. He discovered the Fischer esterification. He also developed the Fischer projection, a symbolic way of drawing asymmetric carbon atoms. He also hypothesized lock and key mechanism of enzyme action. He never used his first given name, and was known throughout his life simply as Emil Fischer.

Her contributions include:

By transferring pieces of tumors to chick embryos, Montalcini established a mass of cells that was full of nerve fibers. The discovery of nerves growing everywhere like a halo around the tumor cells was surprising. When describing it, Montalcini said it is: “like rivulets of water flowing steadily over a bed of stones.”  The nerve growth produced by the tumor was unlike anything she had seen before – the nerves took over areas that would become other tissues and even entered veins in the embryo. But nerves did not grow into the arteries, which would flow from the embryo back to the tumor. This suggested to Montalcini that the tumor itself was releasing a substance that was stimulating the growth of nerves.

  • Yount, Lisa (2009). Rita Levi-Montalcini: Discoverer of Nerve Growth Factor. Chelsea House.
  • https://en.wikipedia.org/wiki/Rita_Levi-Montalcini

Levi-Montalcini later remarked:

The tumor had given a first hint of its existence in St. Louis but it was in Rio de Janeiro that it revealed itself, and it did so in a theatrical and grand way, as if spurred by the bright atmosphere of that explosive and exuberant manifestation of life that is the Carnival in Rio.

Levi-Montalcini R (1987-09-04). “The nerve growth factor 35 years later”. Science. 237 (4819): 1154–1162. doi:10.1126/science.3306916. ISSN 0036-8075. PMID 3306916.

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.

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

NGF is abundant in seminal plasma. Recent studies have found that it induces ovulation in some mammals. Nerve Growth Factors (NGF) were initially discovered due to their actions during development, but NGF are now known to be involved in the function throughout the life of the animal.

Interactions

Nerve growth factor has been shown to interact with Tropomyosin receptor kinase A.

Tropomyosin receptor kinase A (TrkA), also known as high affinity nerve growth factor receptor, neurotrophic tyrosine kinase receptor type 1, or TRK1-transforming tyrosine kinase protein is a protein that in humans is encoded by the NTRK1 gene.

  • Malenka RC, Nestler EJ, Hyman SE (2009). “Chapter 8: Atypical neurotransmitters”. In Sydor A, Brown RY (eds.). Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. ISBN 9780071481274. Another common feature of neurotrophins is that they produce their physiologic effects by means of the tropomyosin receptor kinase (Trk) receptor family (also known as the tyrosine receptor kinase family). …Trk receptors All neurotrophins bind to a class of highly homologous receptor tyrosine kinases known as Trk receptors, of which three types are known: TrkA, TrkB, and TrkC. These transmembrane receptors are glycoproteins whose molecular masses range from 140 to 145 kDa. Each type of Trk receptor tends to bind specific neurotrophins: TrkA is the receptor for NGF, TrkB the receptor for BDNF and NT-4, and TrkC the receptor for NT-3.However, some overlap in the specificity of these receptors has been noted.
  • Martin-Zanca D, Hughes SH, Barbacid M (April 1986). “A human oncogene formed by the fusion of truncated tropomyosin and protein tyrosine kinase sequences”. Nature. 319 (6056): 743–8. Bibcode:1986Natur.319..743M. doi:10.1038/319743a0. PMID 2869410. S2CID 4316805.

This gene encodes a member of the neurotrophic tyrosine kinase receptor (NTKR) family. This kinase is a membrane-bound receptor that, upon neurotrophin binding, phosphorylates itself (autophosphorylation) and members of the MAPK pathway. The presence of this kinase leads to cell differentiation and may play a role in specifying sensory neuron subtypes. Mutations in this gene have been associated with congenital insensitivity to pain with anhidrosis, self-mutilating behaviors, intellectual disability and/or cognitive impairment and certain cancers. Alternate transcriptional splice variants of this gene have been found, but only three have been characterized to date.

Function and Interaction with NGF

TrkA is the high affinity catalytic receptor for the neurotrophin, Nerve Growth Factor, or “NGF”. As a kinase, TrkA mediates the multiple effects of NGF, which include neuronal differentiation, neural proliferation, nociceptor response, and avoidance of programmed cell death.

The binding of NGF to TrkA leads to a ligand-induced dimerization, and a proposed mechanism by which this receptor and ligand interact is that two TrkA receptors associate with a single NGF ligand. This interaction leads to a cross linking dimeric complex where parts of the ligand-binding domains on TrkA are associated with their respective ligands. TrkA has five binding domains on its extracellular portion, and the domain TrkA-d5 folds into an immunoglobulin-like domain which is critical and adequate for the binding of NGF. After being immediately bound by NGF, the NGF/TrkA complex is brought from the synapse to the cell body through endocytosis where it then activates the NGF-dependent transcriptional program. Upon activation, the tyrosine residues are phosphorylated within the cytoplasmic domain of TrkA, and these residues then recruit signaling molecules, following several pathways that lead to the differentiation and survival of neurons. Two pathways that this complex acts to promote growth is through the Ras/MAPK pathway and the PI3K/Akt pathway.

Family members

The three transmembrane receptors TrkA, TrkB, and TrkC (encoded by the genes NTRK1, NTRK2, and NTRK3 respectively) make up the Trk receptor family. This family of receptors are all activated by protein nerve growth factors, or neurotrophins. Also, there are other neurotrophic factors structurally related to NGF: BDNF (for Brain-Derived Neurotrophic Factor), NT-3 (for Neurotrophin-3) and NT-4 (for Neurotrophin-4). While TrkA mediates the effects of NGF, TrkB is bound and activated by BDNF, NT-4, and NT-3. Further, TrkC binds and is activated by NT-3. In one study, the Trk gene was removed from embryonic mice stem cells which led to severe neurological disease, causing most mice to die one month after birth. Thus, Trk is the mediator of developmental and growth processes of NGF, and plays a critical role in the development of the nervous system in many organisms.

  • McPhail, C. W. B. (1965). “Current Advances in Public Health Dentistry”. Canadian Journal of Public Health. 56 (12): 512–516. JSTOR 41983816. PMID 5857389.
  • Benito-Gutiérrez E, Garcia-Fernàndez J, Comella JX (February 2006). “Origin and evolution of the Trk family of neurotrophic receptors”. Molecular and Cellular Neurosciences. 31 (2): 179–92. doi:10.1016/j.mcn.2005.09.007. PMID 16253518. S2CID 25232377.
  • Smeyne RJ, Klein R, Schnapp A, Long LK, Bryant S, Lewin A, et al. (March 1994). “Severe sensory and sympathetic neuropathies in mice carrying a disrupted Trk/NGF receptor gene”. Nature. 368 (6468): 246–9. Bibcode:1994Natur.368..246S. doi:10.1038/368246a0. PMID 8145823. S2CID 4318721.

There is one other NGF receptor besides TrkA, called the “LNGFR” (for “Low-affinity nerve growth factor receptor “). As opposed to TrkA, the LNGFR plays a somewhat less clear role in NGF biology. Some researchers have shown the LNGFR binds and serves as a “sink” for neurotrophins. Cells which express both the LNGFR and the Trk receptors might therefore have a greater activity – since they have a higher “microconcentration” of the neurotrophin. It has also been shown, however, that in the absence of a co-expressed TrkA, the LNGFR may signal a cell to die via apoptosis – so therefore cells expressing the LNGFR in the absence of Trk receptors may die rather than live in the presence of a neurotrophin.

Role in disease

There are several studies that highlight TrkA’s role in various diseases. In one study conducted on two rat models, an inhibition of TrkA with AR786 led to a reduction in joint swelling, joint damage, and pain caused by inflammatory arthritis. Thus, blocking the binding of NGF allows for the alleviation of side effects from inherited arthritis, potentially highlighting a model to aid human inflammatory arthritis.

In one study done on patients with functional dyspepsia, scientists found a significant increase in TrkA and nerve growth factor in gastric mucosa. The increase of TrkA and nerve growth factor is linked to indigestion and gastric symptoms in patients, thus this increase may be linked with the development of functional dyspepsia.

In one study, a total absence of TrkA receptor was found in keratoconus-affected corneas, along with an increased level of repressor isoform of Sp3 transcription factor.

Gene fusions involving NTRK1 have been shown to be oncogenic, leading to the constitutive TrkA activation. In a research study by Vaishnavi A. et al., NTRK1 fusions are estimated to occur in 3.3% of lung cancer as assessed through next generation sequencing or fluorescence in situ hybridization.

While in some contexts, Trk A is oncogenic, in other contexts TrkA has the ability to induced terminal differentiation in cancer cells, halting cellular division. In some cancers, like neuroblastoma, TrkA is seen as a good prognostic marker as it is linked to spontaneous tumor regression.

Regulation

The levels of distinct proteins can be regulated by the “ubiquitin/proteasome” system. In this system, a small (7–8 kd)protein called “ubiquitin” is affixed to a target protein, and is thereby targeted for destruction by a structure called the “proteasome“. TrkA is targeted for proteasome-mediated destruction by an “E3 ubiquitin ligase” called NEDD4-2. This mechanism may be a distinct way to control the survival of a neuron. The extent and maybe type of TrkA ubiquitination can be regulated by the other, unrelated receptor for NGF, p75NTR.

Interactions

TrkA has been shown to interact with:

Ligands

Small molecules such as amitriptyline and gambogic acid derivatives have been claimed to activate TrkA. Amitriptyline activates TrkA and facilitates the heterodimerization of TrkA and TrkB in the absence of NGF. Binding of amitriptyline to TrkA occurs to the Leucine Rich Region (LRR) of the extracellular domain of the receptor, which is distinct from the NGF binding site. Amitryptiline possesses neurotrophic activity both in-vitro and in-vivo (mouse model). Gambogic amide, a derivative of gambogic acid, selectively activates TrkA (but not TrkB and TrkC) both in-vitro and in-vivo by interacting with the cytoplasmic juxtamembrane domain of TrkA.

Role in cancer

TrkA has a dual role in cancer. TrkA was originally cloned from a colon tumor; the cancer occurred via a translocation, which resulted in the activation of the TrkA kinase domain. Although originally identified as an oncogenic fusion in 1982, only recently has there been a renewed interest in the Trk family as it relates to its role in human cancers because of the identification of NTRK1 (TrkA), NTRK2 (TrkB) and NTRK3 (TrkC) gene fusions and other oncogenic alterations in a number of tumor types. The mechanism of activation of the Human Trk oncogene is suspected to involve a folding of its kinase domain, leading the receptor to remain constitutively active. In contrast, Trk A also has the potential to induce differentiation and spontaneous regression of cancer in infants.

Inhibitors in development

There are several Trk inhibitors that have been FDA approved, and have been clinically seen to counteract the effects of Trk over-expression by acting as a Trk inhibitor.

  • Bailey JJ, Jaworski C, Tung D, Wängler C, Wängler B, Schirrmacher R (May 2020). “Tropomyosin receptor kinase inhibitors: an updated patent review for 2016-2019”. Expert Opinion on Therapeutic Patents. 30 (5): 325–339. doi:10.1080/13543776.2020.1737011. PMID 32129124. S2CID 212406547.

Entrectinib (formerly RXDX-101) is an investigational drug developed by Ignyta, Inc., which has potential antitumor activity. It is a selective pan-trk receptor tyrosine kinase inhibitor (TKI) targeting gene fusions in trkA, trkB, and trkC (coded by NTRK1, NTRK2, and NTRK3 genes) that is currently in phase 2 clinical testing.

“”Larotrectinib“” is an inhibitor to all of the Trk receptors (TrkA, TrkB, and TrkC) and the drug is used as a treatment for tumors with Trk fusions. A clinical study analyzing the efficiency of the drug found that Larotrectinib was an effective anti tumor treatment, and worked efficiently regardless of age of the patient or tumor type; additionally, the drug did not have long lasting side effects, highlighting the beneficial use of this drug in treating Trk fusions.

  • McPhail, C. W. B. (1965). “Current Advances in Public Health Dentistry”. Canadian Journal of Public Health. 56 (12): 512–516. JSTOR 41983816. PMID 5857389.

See also

References

  1. GRCh38: Ensembl release 89: ENSG00000134259 – Ensembl, May 2017
  2.  GRCm38: Ensembl release 89: ENSMUSG00000027859 – Ensembl, May 2017
  3. “Human PubMed Reference:”. National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. “Mouse PubMed Reference:”. National Center for Biotechnology Information, U.S. National Library of Medicine.
  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. Progress in Brain Research. Vol. 146. pp. 111–26. doi:10.1016/S0079-6123(03)46008-1. ISBN 978-0-444-51472-1. PMID 14699960.
  6. Lee R, Kermani P, Teng KK, Hempstead BL (Nov 2001). “Regulation of cell survival by secreted proneurotrophins”. Science. 294 (5548): 1945–48. Bibcode:2001Sci…294.1945L. doi:10.1126/science.1065057. PMID 11729324. S2CID 872149.
  7. 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 978-0-12-374539-2.
  8. Pierucci D, Cicconi S, Bonini P, Ferrelli F, Pastore D, Matteucci C, Marselli L, Marchetti P, Ris F, Halban P, Oberholzer J, Federici M, Cozzolino F, Lauro R, Borboni P, Marlier LN (Oct 2001). “NGF-withdrawal induces apoptosis in pancreatic beta cells in vitro”. Diabetologia. 44 (10): 1281–95. doi:10.1007/s001250100650. PMID 11692177.
  9. Lambiase A, Bracci-Laudiero L, Bonini S, Bonini S, Starace G, D’Elios MM, De Carli M, Aloe L (Sep 1997). “Human CD4+ T cell clones produce and release nerve growth factor and express high-affinity nerve growth factor receptors”. The Journal of Allergy and Clinical Immunology. 100 (3): 408–14. doi:10.1016/s0091-6749(97)70256-2. PMID 9314355.
  10. Ratto MH, Leduc YA, Valderrama XP, van Straaten KE, Delbaere LT, Pierson RA, Adams GP (Sep 2012). “The nerve of ovulation-inducing factor in semen”. Proceedings of the National Academy of Sciences of the United States of America. 109 (37): 15042–47. Bibcode:2012PNAS..10915042R. doi:10.1073/pnas.1206273109. PMC3443178. PMID22908303.
  11. Stoleru B, Popescu A, Tache D, Neamtu O, Emami G, Tataranu L, Buteica A, Dricu A, Purcaru S (2013). “Tropomyosin-Receptor-Kinases Signaling in the Nervous System”. Maedica. 8 (1): 43–48. PMC 3749761. PMID 24023598.
  12. 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): 184–88. Bibcode:1999Natur.401..184W. doi:10.1038/43705. PMID 10490030. S2CID 4337786.
  13. Marlin MC, Li G (2015). Biogenesis and Function of the NGF/TrkA Signaling Endosome. International Review of Cell and Molecular Biology. Vol. 314. pp. 239–57. doi:10.1016/bs.ircmb.2014.10.002. ISBN 9780128022832. PMC 4307610. PMID 25619719.
  14. Levi-Montalcini R (2004). “The nerve growth factor and the neuroscience chess board”. NGF and Related Molecules in Health and Disease. Progress in Brain Research. Vol. 146. pp. 525–27. doi:10.1016/s0079-6123(03)46033-0. ISBN 9780444514721. PMID 14699984.
  15. Kaplan DR, Martin-Zanca D, Parada LF (Mar 1991). “Tyrosine phosphorylation and tyrosine kinase activity of the trk proto-oncogene product induced by NGF”. Nature. 350 (6314): 158–60. Bibcode:1991Natur.350..158K. doi:10.1038/350158a0. PMID 1706478. S2CID 4241996.
  16. Crowder RJ, Freeman RS (Apr 1998). “Phosphatidylinositol 3-kinase and Akt protein kinase are necessary and sufficient for the survival of nerve growth factor-dependent sympathetic neurons”. The Journal of Neuroscience. 18 (8): 2933–43. doi:10.1523/JNEUROSCI.18-08-02933.1998. PMC 6792598. PMID 9526010.
  17. Levi-Montalcini R, Meyer H, Hamburger V (1954). “In vitro experiments on the effects of mouse sarcomas 180 and 37 on the spinal and sympathetic ganglia of the chick embryo”. Cancer Research. 14 (1): 49–57. ISSN 0008-5472. PMID 13126933.
  18. Levi-Montalcini R, Calissano P (1979). “The Nerve-Growth Factor”. Scientific American. 240 (6): 68–77. ISSN 0036-8733.
  19. Levi-Montalcini R (1998-11-16). “The saga of the nerve growth factor”. Neuroreport. 9 (16): R71–83. ISSN 0959-4965. PMID 9858356.
  20. Levi-Montalcini R (1987-09-04). “The nerve growth factor 35 years later”. Science. 237 (4819): 1154–1162. doi:10.1126/science.3306916. ISSN 0036-8075. PMID 3306916.
  21. The 1986 Nobel Prize in Physiology or Medicine for discoveries of growth factors
  22. Presentation Speech by Professor Kerstin Hall The Nobel Prize in Physiology or Medicine 1986
  23. Rita Levi-Montalcini – Nobel Lecture
  24. Ovulation spurred by newfound semen ingredient
  25. Adelman, George. Encyclopedia of Neuroscience . Boston: Birkhhaeuser, 1987. Print.[ISBN missing][page needed]
  26. Nykjaer A, Lee R, Teng KK, Jansen P, Madsen P, Nielsen MS, Jacobsen C, Kliemannel M, Schwarz E, Willnow TE, Hempstead BL, Petersen CM (Feb 2004). “Sortilin is essential for proNGF-induced neuronal cell death”. Nature. 427 (6977): 843–48. Bibcode:2004Natur.427..843N. doi:10.1038/nature02319. PMID 14985763. S2CID 4343450.

External links

Hormones
Cell signaling: Nervous tissue: Neurotrophic factors
Growth factors
Protein: nerve tissue protein
Growth factor receptor modulators

Categories: 

///////

Post a Comment

Your email address will not be published. Required fields are marked *