Low-affinity nerve growth factor receptor
|, CD271, Gp80-LTNFRSF16, p75(NTR), p75NTR, nerve growth factor receptor|
The low-affinity nerve growth factor receptor (nerve growth factor receptor (TNFR superfamily, member 16), also called the LNGFR or p75 neurotrophin receptor) is one of the two receptor types for the neurotrophins, a family of protein growth factors that stimulate neuronal cells to survive and differentiate. LNGFR is a member of the tumor necrosis factor receptor (TNF receptor)superfamily – indeed, LNGFR was the first member of this large family of receptors to be characterized.
Nerve growth factor, the prototypical growth factor, is a protein secreted by a neuron's target. NGF is critical for the survival and maintenance of sympathetic and sensory neurons. NGF is released from the target cells, binds to and activates its high-affinity receptor tropomyosin receptor kinase A (TrkA), and is internalized into the responsive neuron. The NGF/TrkA complex is subsequently trafficked back to the cell body. This movement of NGF from axon tip to soma is thought to be involved in the long-distance signaling of neurons.
The activation of TrkA by NGF is critical in inducing the survival and differentiation caused by this growth factor.
However, NGF binds at least two receptors on the surface of cells that are capable of responding to this growth factor, TrkA (pronounced "Track A") and the LNGFR.
Trk family of receptor tyrosine kinases
TrkA is a receptor tyrosine kinase (meaning it mediates its actions by causing the addition of phosphate molecules on certain tyrosines in the cell, activating cellular signaling). There are other related Trk receptors, TrkB and TrkC. 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 binds and is activated by BDNF, NT-4, and NT-3, and TrkC binds and is activated only by NT-3.
Neurotrophins activating LNGFR may signal a cell to die via apoptosis, but this effect is counteracted by anti-apoptotic signaling by TrkA, TrkB, or TrkC signaling in cells that also express those receptors. LNGFR functions in a complex with Nogo receptor (NgR, Reticulon 4 receptor) to mediate RhoA-dependent inhibition of growth of regenerating axons exposed to inhibitory proteins of CNS myelin, such as Nogo, MAG or OMgP. LNGFR also activates a caspase- dependent signaling pathway that promotes developmental axon pruning, and axon degeneration in neurodegenerative disease.
Two distinct subpopulations of Olfactory ensheathing glia (being researched for nerve repair) have been identified with high or low cell surface expression of low-affinity nerve growth factor receptor (p75).
Role in cancer stem cells
LNGFR has been implicated as a marker for cancer stem cells in melanoma and other cancers. Melanoma cells transplanted into an immunodeficient mouse model were shown to require expression of CD271 in order to grow a melanoma. Gene knockdown of CD271 has also been shown to abolish neural crest stem cell properties of melanoma cells and decrease genomic stability leading to a reduced migration, tumorigenicity, proliferation and induction of apoptosis. 
Low-affinity nerve growth factor receptor has been shown to interact with:
- GRCh38: Ensembl release 89: ENSG00000064300 - Ensembl, May 2017
- GRCm38: Ensembl release 89: ENSMUSG00000000120 - Ensembl, May 2017
- "Human PubMed Reference:".
- "Mouse PubMed Reference:".
- Johnson D, Lanahan A, Buck CR, Sehgal A, Morgan C, Mercer E, Bothwell M, Chao M (1986). "Expression and structure of the human NGF receptor". Cell. 47 (4): 545–54. doi:10.1016/0092-8674(86)90619-7. PMID 3022937.
- Radeke MJ, Misko TP, Hsu C, Herzenberg LA, Shooter EM (1987). "Gene transfer and molecular cloning of the rat nerve growth factor receptor". Nature. 325 (6105): 593–7. doi:10.1038/325593a0. PMID 3027580.
- Nicol GD (October 2008). "Nerve growth factor, sphingomyelins, and sensitization in sensory neurons". Sheng Li Xue Bao : [Acta Physiologica Sinica]. 60 (5): 603–4. PMID 18958367.
- Di Girolamo N, Sarris M, Chui J, Cheema H, Coroneo MT, Wakefield D (December 2008). "Localization of the low-affinity nerve growth factor receptor p75 in human limbal epithelial cells". Journal of Cellular and Molecular Medicine. 12 (6B): 2799–811. doi:10.1111/j.1582-4934.2008.00290.x. PMID 19210757.
- Chen LW, Yung KK, Chan YS, Shum DK, Bolam JP (December 2008). "The proNGF-p75NTR-sortilin signalling complex as new target for the therapeutic treatment of Parkinson's disease". CNS & Neurological Disorders Drug Targets. 7 (6): 512–23. doi:10.2174/187152708787122923. PMID 19128208.
- Kocsis JD, Lankford KL, Sasaki M, Radtke C (June 2009). "Unique in vivo properties of olfactory ensheathing cells that may contribute to neural repair and protection following spinal cord injury". Neuroscience Letters. 456 (3): 137–42. doi:10.1016/j.neulet.2008.08.093. PMC . PMID 19429149.
- Deponti D, Buono R, Catanzaro G, De Palma C, Longhi R, Meneveri R, Bresolin N, Bassi MT, Cossu G, Clementi E, Brunelli S (June 2009). "The Low Affinity Receptor for Neurotrophins p75NTR Plays a Key Role for Satellite Cell Function in Muscle Repair Acting via RhoA". Molecular Biology of the Cell. 20 (16): 3620–7. doi:10.1091/mbc.E09-01-0012. PMC . PMID 19553472.
- Honoré A, Le Corre S, Derambure C, Normand R, Duclos C, Boyer O, Marie JP, Guérout N (2011). "Isolation, characterization, and genetic profiling of subpopulations of olfactory ensheathing cells from the olfactory bulb". Glia. 60: 404–13. doi:10.1002/glia.22274. PMID 22161947.
- Boiko AD, Razorenova OV, van de Rijn M, Swetter SM, Johnson DL, Ly DP, Butler PD, Yang GP, Joshua B, Kaplan MJ, Longaker MT, Weissman IL (2010). "Human melanoma-initiating cells express neural crest nerve growth factor receptor CD271". Nature. 466 (7302): 133–7. doi:10.1038/nature09161. PMC . PMID 20596026.
- Redmer T, Welte Y, Behrens D, Fichtner I, Przybilla D, Wruck W, Yaspo ML, Lehrach H, Schäfer R, Regenbrecht CR (2014). "The nerve growth factor receptor CD271 is crucial to maintain tumorigenicity and stem-like properties of melanoma cells". PLOS ONE. 9 (5): e92596. doi:10.1371/journal.pone.0092596. PMC . PMID 24799129.
- Redmer T, Walz I, Klinger B, Khouja S, Welte Y, Schäfer R, Regenbrecht C (January 2017). "The role of the cancer stem cell marker CD271 in DNA damage response and drug resistance of melanoma cells". Oncogenesis. 6 (1): e291. doi:10.1038/oncsis.2016.88. PMC . PMID 28112719.
- Radke J, Roßner F, Redmer T (August 2017). "CD271 determines migratory properties of melanoma cells". Scientific Reports. 7 (1): 9834. doi:10.1038/s41598-017-10129-z. PMC . PMID 28852061.
- Shonukan O, Bagayogo I, McCrea P, Chao M, Hempstead B (Jun 2003). "Neurotrophin-induced melanoma cell migration is mediated through the actin-bundling protein fascin". Oncogene. 22 (23): 3616–23. doi:10.1038/sj.onc.1206561. PMID 12789270.
- Tcherpakov M, Bronfman FC, Conticello SG, Vaskovsky A, Levy Z, Niinobe M, Yoshikawa K, Arenas E, Fainzilber M (Dec 2002). "The p75 neurotrophin receptor interacts with multiple MAGE proteins". J. Biol. Chem. 277 (51): 49101–4. doi:10.1074/jbc.C200533200. PMID 12414813.
- Kuwako K, Taniura H, Yoshikawa K (Jan 2004). "Necdin-related MAGE proteins differentially interact with the E2F1 transcription factor and the p75 neurotrophin receptor". J. Biol. Chem. 279 (3): 1703–12. doi:10.1074/jbc.M308454200. PMID 14593116.
- Bronfman FC, Tcherpakov M, Jovin TM, Fainzilber M (Apr 2003). "Ligand-induced internalization of the p75 neurotrophin receptor: a slow route to the signaling endosome". J. Neurosci. 23 (8): 3209–20. PMID 12716928.
- Mukai J, Hachiya T, Shoji-Hoshino S, Kimura MT, Nadano D, Suvanto P, Hanaoka T, Li Y, Irie S, Greene LA, Sato TA (Jun 2000). "NADE, a p75NTR-associated cell death executor, is involved in signal transduction mediated by the common neurotrophin receptor p75NTR". J. Biol. Chem. 275 (23): 17566–70. doi:10.1074/jbc.C000140200. PMID 10764727.
- 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): 843–8. doi:10.1038/nature02319. PMID 14985763.
- Lee R, Kermani P, Teng KK, Hempstead BL (Nov 2001). "Regulation of cell survival by secreted proneurotrophins". Science. 294 (5548): 1945–8. doi:10.1126/science.1065057. PMID 11729324.
- Higuchi H, Yamashita T, Yoshikawa H, Tohyama M (Apr 2003). "PKA phosphorylates the p75 receptor and regulates its localization to lipid rafts". EMBO J. 22 (8): 1790–800. doi:10.1093/emboj/cdg177. PMC . PMID 12682012.
- Ye X, Mehlen P, Rabizadeh S, VanArsdale T, Zhang H, Shin H, Wang JJ, Leo E, Zapata J, Hauser CA, Reed JC, Bredesen DE (Oct 1999). "TRAF family proteins interact with the common neurotrophin receptor and modulate apoptosis induction". J. Biol. Chem. 274 (42): 30202–8. doi:10.1074/jbc.274.42.30202. PMID 10514511.
- Krajewska M, Krajewski S, Zapata JM, Van Arsdale T, Gascoyne RD, Berern K, McFadden D, Shabaik A, Hugh J, Reynolds A, Clevenger CV, Reed JC (Jun 1998). "TRAF-4 expression in epithelial progenitor cells. Analysis in normal adult, fetal, and tumor tissues". Am. J. Pathol. 152 (6): 1549–61. PMC . PMID 9626059.
- Buxser S, Puma P, Johnson GL (10 February 1985). "Properties of the nerve growth factor receptor. Relationship between receptor structure and affinity". Journal of Biological Chemistry. 260 (3): 1917–26. PMID 2981877.
- Glass DJ, Nye SH, Hantzopoulos P, Macchi MJ, Squinto SP, Goldfarb M, Yancopoulos GD (1991). "TrkB mediates BDNF/NT-3-dependent survival and proliferation in fibroblasts lacking the low affinity NGF receptor". Cell. 66 (2): 405–13. doi:10.1016/0092-8674(91)90629-D. PMID 1649703.
- Ibáñez CF (2002). "Jekyll-Hyde neurotrophins: the story of proNGF". Trends in Neurosciences. 25 (6): 284–6. doi:10.1016/S0166-2236(02)02169-0. PMID 12086739.
- Radeke MJ, Misko TP, Hsu C, Herzenberg LA, Shooter EM (1987). "Gene transfer and molecular cloning of the rat nerve growth factor receptor". Nature. 325 (6105): 593–597. doi:10.1038/325593a0. PMID 3027580.