Alternative titles; symbols
HGNC Approved Gene Symbol: NGFR
Cytogenetic location: 17q21.33 Genomic coordinates (GRCh38): 17:49,495,293-49,515,008 (from NCBI)
Bothwell (1996), Carter and Lewin (1997), and Bibel and Barde (2000) reviewed neurotrophins and their receptors. Nerve growth factor receptor (NGFR) is also referred to as p75(NTR) because of its molecular mass and its ability to bind at low affinity not only NGF (see 162030), but also other neurotrophins, including brain-derived neurotrophic factor (BDNF; 113505), neurotrophin-3 (NTF3; 162660), and neurotrophin-4 (NTF4; 162662). At the time of its discovery, NGFR was considered a unique type of protein. Subsequently, however, a large superfamily of tumor necrosis factor receptors were found to share the overall structure of NGFR (4 extracellular ligand-binding, cysteine-rich repeats, or CRs, and signaling through association with, or disassociation from, cytoplasmic interactors). The identification of this superfamily helped elucidate some of the biologic functions of NGFR, including its ultimate involvement in the nuclear factor kappa-B (NFKB; see 164011) and apoptosis pathways. As a monomer, NGFR binds NGF with low affinity. Higher affinity binding is achieved by association with higher molecular mass, low-affinity neurotrophin receptors, namely the tropomyosin receptor kinases, TRKA (NTRK1; 191315), TRKB (NTRK2; 600456), and TRKC (NTRK3; 191316). TRKA, TRKB, and TRKC are specific for or 'preferred by' NGF, NTF4 and BDNF, and NTF3, respectively (Ip et al., 1993). NTF3 also binds to TRKA and TRKB, but with significantly lower affinity.
Johnson et al. (1986) found that the 3.8-kb NGFR mRNA encodes a 427-amino acid protein containing a 28-amino acid signal peptide, an extracellular domain containing four 40-amino acid repeats, each with 6 cysteine residues at conserved positions, followed by a serine/threonine-rich region, a single transmembrane domain, and a 155-amino acid cytoplasmic domain.
Chao et al. (1986) isolated a cosmid clone containing NGFR and expressed it in mouse L cells and other cell lines.
Using a clone for the rat low-affinity Ngfr, Welcher et al. (1991) synthesized mutant Ngfr constructs and demonstrated that the cysteine-rich sequences of the Ngfr molecule contain the NGF-binding domain.
He and Garcia (2004) determined the 2.4-angstrom crystal structure of the prototypic neurotrophin, NGF (162030), complexed with the extracellular domain of p75. The complex is composed of an NGF homodimer asymmetrically bound to a single p75. The p75 protein binds along the homodimeric interface of NGF, which disables NGF's symmetry-related second p75 binding site through an allosteric conformational change. He and Garcia (2004) concluded that neurotrophin signaling through p75 may occur by disassembly of p75 dimers and assembly of asymmetric 2:1 neurotrophin/p75 complexes, which could potentially engage a Trk receptor to form a trimolecular signaling complex.
Using 3-dimensional structural analysis and a protein-protein interaction system, Wehrman et al. (2007) found no evidence of TRKA and p75 heterodimerization. Instead, TRKA formed a crab-shaped homodimer after interaction with NGF, and p75 existed on the cell surface as a preformed oligomer that was not dissociated by NGF. Wehrman et al. (2007) proposed that TRKA and NGFR do not interact directly, but that they likely communicate through convergence of downstream signaling pathways and/or shared adaptor molecules.
Gong et al. (2008) reported the 2.6-angstrom resolution crystal structure of neurotrophin-3 (NT3; 162660) complexed to the ectodomain of glycosylated p75(NTR). In contrast with the previously reported asymmetric complex structure, which contains a dimer of NGF bound to a single ectodomain of deglycosylated p75(NTR), reported by He and Garcia (2004), Gong et al. (2008) showed that NT3 forms a central homodimer around which 2 glycosylated p75(NTR) molecules bind symmetrically. Symmetrical binding occurs along the NT3 interfaces, resulting in a 2:2 ligand-receptor cluster. A comparison of the symmetrical and asymmetric structures reveals significant differences in ligand-receptor interactions and p75(NTR) conformations. Biochemical experiments indicate that both NT3 and NGF bind to p75(NTR) with 2:2 stoichiometry in solution, whereas the 2:1 complexes are the result of artificial deglycosylation. Gong et al. (2008) therefore proposed that the symmetrical 2:2 complex reflects a native state of p75(NTR) activation at the cell surface. The authors concluded that their results provided a model for NTs/p75(NTR) recognition and signal generation, as well as insights into coordination between p75(NTR) and tyrosine kinase receptors.
Vilar et al. (2009) showed that NGFR formed disulfide-linked dimers independently of neurotrophin binding through the highly conserved cys257 in the transmembrane domain. Mutation of cys257 abolished neurotrophin-dependent receptor activity, but did not affect downstream signaling by the NGFR/NGR (RTN4R; 605566)/LINGO1 (LRRN6A; 609791) complex in response to MAG (159460), suggesting distinct, ligand-specific activation mechanisms for NGFR. Vilar et al. (2009) proposed that neurotrophins activate NGFR by a mechanism involving rearrangement of disulfide-linked receptor subunits.
Hempstead et al. (1991) showed by membrane fusion studies and gene transfer analysis that high-affinity binding of NGF requires TRKA and p75(NTR), each of which binds NGF with low affinity.
Dobrowsky et al. (1994) showed that neurotrophins activate p75(NTR) to induce apoptosis through the induction of the sphingomyelin (SM) cycle and increased production of ceramide. Overexpression of p75(NTR) was also found to activate the SM pathway. Dobrowsky et al. (1994) proposed that ceramide may regulate events during developmental cell death and participate in the maintenance of axonal structure and function.
Carter et al. (1996) showed that in the absence of TrkA, Ngf binds to p75(NTR) and activates Nfkb in rat Schwann cells. Nfkb activation did not occur in Schwann cells from mice lacking p75(NTR). Bdnf and Ntf3 bound to p75(NTR) without activating Nfkb.
Signaling pathways initiated by the binding of neurotrophins to p75(NTR) block TRK receptor signaling in certain contexts and synergize with TRK receptor signaling in other contexts. Using a Xenopus oocyte microinjection assay and calcium efflux analysis, Mischel et al. (2001) showed that the extracellular but not the cytoplasmic domain of rat p75(NTR) prevented the signaling of NTF3 through TRKA, but did not block NGF signaling through TRKA. NTF3 binding to p75(NTR) was not required for this inhibition. Coimmunoprecipitation analysis indicated that p75(NTR) and TRKA were associated when expressed in oocytes.
By screening a COS-7 cell line expressing a murine neuroblastoma/glioma cDNA library with soluble rabies virus glycoprotein, Tuffereau et al. (1998) obtained a cDNA encoding mouse p75(NTR). Cells expressing p75(NTR), even in the absence of Trk, became permissive for field isolates of rabies virus without prior adaptation in neuroblastoma cell cultures. Tuffereau et al. (1998) concluded that p75(NTR) is a receptor for rabies virus.
Using a yeast 2-hybrid screen with the intracellular domain of chick Ngfr as bait, Yamashita et al. (1999) identified chick Rhoa (165390) as an Ngfr-interacting protein. Transfection of Ngfr activated Rhoa, but neurotrophin binding blocked activation and allowed neurite elongation. Mice carrying mutant Ngfr showed retarded axonal outgrowth. Yamashita et al. (1999) concluded that NGFR modulates in a ligand-dependent manner the activity of intracellular proteins involved in regulating actin assembly.
Schwann cells in developing and regenerating peripheral nerves express elevated levels of the neurotrophin receptor p75(NTR). Neurotrophins are key mediators of peripheral nervous system myelination. Cosgaya et al. (2002) demonstrated that myelin formation is inhibited in the absence of functional p75(NTR) and enhanced by blocking TRKC (191316) activity. Moreover, the enhancement of myelin formation by endogenous BDNF (113505) is mediated by the p75(NTR) receptor, whereas TRKC receptors are responsible for neurotrophin-3 (NT3; 162660) inhibition. Thus, Cosgaya et al. (2002) concluded that p75(NTR) and TRKC receptors have opposite effects on myelination. Cosgaya et al. (2002) developed a model for the actions of endogenous neurotrophins and their receptors throughout myelination. During glial proliferation, elongation, and ensheathment, NT3 levels decrease whereas TRKC and p57(NTR) remain constant. The activation of TRKC by NT3 during these phases prevents the myelination program from proceeding. When myelination is initiated, NT3 protein levels have already become undetectable, thereby removing its inhibitory action. At the same time, BDNF acts as a positive modulator of myelination through the activation of p75(NTR). Once active myelination is underway, extracellular BDNF is removed through its binding to the increased levels of TRKB-T1 (600456). After the myelination is complete, all the neurotrophins and their receptors are downregulated.
In inhibiting neurite outgrowth, several myelin components, including the extracellular domain of NOGOA (604475), oligodendrocyte myelin glycoprotein (OMGP; 164345), and myelin-associated glycoprotein (MAG; 159460), exert their effects through the same NOGO receptor. The glycosylphosphatidylinositol (GPI)-anchored nature of the NOGO receptor indicates the requirement for an additional transmembrane protein to transduce the inhibitory signals into the interior of responding neurons. Wang et al. (2002) demonstrated that p75, a transmembrane protein known to be a receptor for the neurotrophin family of growth factors, specifically interacts with the NOGO receptor. p75 is required for NOGO receptor-mediated signaling, as neurons from p75 knockout mice were no longer responsive to myelin or to any of the known NOGO receptor ligands. Blocking the p75-NOGO receptor interaction also reduced the activities of these inhibitors. Moreover, a truncated p75 protein lacking the intracellular domain, when overexpressed in primary neurons, attenuated the same set of inhibitory activities, suggesting that p75 is a signal transducer of the Nogo receptor-p75 receptor complex. Wang et al. (2002) suggested that interfering with p75 and its downstream signaling pathways may allow lesioned axons to overcome most of the inhibitory activities associated with central nervous system myelin.
Wong et al. (2002) reported that p75(NTR) is a coreceptor for the NOGO receptor (605566) for MAG signaling. In cultured human embryonic kidney (HEK) cells expressing the NOGO receptor, p75(NTR) was required for MAG-induced intracellular calcium elevation. Coimmunoprecipitation showed an association of the NOGO receptor with p75(NTR) that could be disrupted by an antibody against p75(NTR), and extensive coexpression was observed in the developing rat nervous system. Furthermore, a p75(NTR) antibody abolished MAG-induced repulsive turning of Xenopus axonal growth cones and calcium elevation, both in neurons and in the NOGO receptor/p75(NTR)-expressing HEK cells.
Tcherpakov et al. (2002) found that the intracellular domain of NGFR interacted with necdin (NDN; 602117) and Mageh1 (300548) in rodent neural tissue, and the interaction was enhanced by ligand stimulation. Rat neural precursor cells transfected with necdin or Mageh1 exhibited accelerated differentiation in response to NGF.
Rho is a small GTPase that regulates the state of actin polymerization (see 165390). In its active GTP-bound form, Rho inhibits axonal elongation. Yamashita and Tohyama (2003) showed that p75 interacts with the RhoGDP dissociation inhibitor-alpha (RhoGDI) (601925) to release RhoA and initiate its activation, and that the interaction is enhanced by MAG (159460) and NOGO (604475). The authors found that a peptide, referred to as Pep5, inhibited the interaction between RhoGDI and p75, thus potentially blocking inhibitory cues of central nervous system regeneration.
In cell cultures of rat sympathetic neurons innervating cardiac myocytes, Yang et al. (2002) showed that brain-derived neurotrophic factor (BDNF; 113505) rapidly (within 15 minutes) shifted the neurotransmitter release properties of the neurons from excitatory to inhibitory cholinergic transmission in response to neural stimulation via the presynaptic p75 neurotrophin receptor.
Using rats and mice, Beattie et al. (2002) showed that p75 was required for death of oligodendrocytes following spinal cord injury and that this action was primarily mediated by the precursor of Ngf, proNgf. Lack of p75 resulted in fewer apoptotic oligodendrocytes and increased oligodendrocyte survival. ProNgf, obtained from injured mouse spinal cords, induced apoptosis in p75 +/+ cells, but not p75 -/- cells, and its activity was blocked by proNgf-specific antibody. Beattie et al. (2002) proposed that the role of proNGF is to eliminate damaged cells by activating p75 apoptotic machinery after injury.
Nykjaer et al. (2004) demonstrated that proNGF creates a signaling complex by simultaneously binding to p75(NTR) and sortilin (602458). Sortilin acts as a coreceptor and molecular switch governing the p75(NTR)-mediated proapoptotic signal induced by proNGF. Together with p75(NTR), sortilin facilitates the formation of a composite high-affinity binding site for proNGF. Thus, sortilin serves as a coreceptor and molecular switch, enabling neurons expressing TRK and p75(NTR) to respond to a proneurotrophin and to initiate proapoptotic rather than prosurvival actions. In the absence of sortilin, regulated activity of extracellular proteases may cleave proNGF to mature NGF, promoting TRK-mediated survival signals. Nykjaer et al. (2004) concluded that NGF-induced neuronal survival and death is far more complicated than previously appreciated, as it depends on an intricate balance between proNGF and mature NGF, as well as on the spatial and temporal expression of 3 distinct receptors: TRKA, p75(NTR), and sortilin.
Neurotrophins (NTFs) act as survival and differentiation factors in the nervous system and have been detected in the developing rodent testis. To determine whether neurotrophins could influence development and maturation of the human fetal testis, Robinson et al. (2003) examined the cell-specific expression and distribution of several members of the neurotrophin family and their receptors during the second trimester, with particular emphasis on NT4 and TRKB. They detected expression of mRNA for nerve growth factor (NGF; 162030), NTF3 and NTF4, BDNF, the high-affinity receptors TRKA (191315), TRKB, and TRKC, and NGFR in the human testis between 14 and 19 weeks' gestation. NT4 mRNA and protein were predominantly localized to the peritubular cells. These cells were also the site of expression of p75. By contrast, NGF and NT3 were mainly expressed in Sertoli and interstitial cells. The authors concluded that these data demonstrate the expression of neurotrophins and their receptors in the human fetal testis during the second trimester and indicate possible roles in the regulation of proliferation and survival of germ cells and peritubular cells.
Chan et al. (2006) showed that the polarity protein PAR3 (606745) localizes asymmetrically in Schwann cells at the axon-glial junction and that disruption of PAR3 localization, by overexpression and knockdown, inhibits myelination. Additionally, Chan et al. (2006) showed that PAR3 directly associates and recruits the p75 neurotrophin receptor to the axon-glial junction, forming a complex necessary for myelination. Chan et al. (2006) concluded that their results point to a critical role in the establishment of cell polarity for myelination.
Differentiation of hepatic stellate cells to extracellular matrix- and growth factor-producing cells supports liver regeneration through promotion of hepatocyte proliferation. Passino et al. (2007) showed that the neurotrophin receptor p75(NTR), a tumor necrosis factor receptor superfamily member expressed in hepatic stellate cells after fibrotic and cirrhotic liver injury in humans, is a regulator of liver repair. In mice, depletion of p75(NTR) exacerbated liver pathology and inhibited hepatocyte proliferation in vivo. p75(NTR)-null hepatic stellate cells failed to differentiate to myofibroblasts and did not support hepatocyte proliferation. Moreover, inhibition of p75(NTR) signaling to the small guanosine triphosphatase Rho resulted in impaired hepatic stellate cell differentiation. Passino et al. (2007) concluded that their results identified signaling from p75(NTR) to Rho as a mechanism for the regulation of hepatic stellate cell differentiation to regeneration-promoting cells that support hepatocyte proliferation in the diseased liver.
Deppmann et al. (2008) showed that brain-derived neurotrophic factor (BDNF; 113505) and neurotrophin-4 (NT4; 162662) can promote apoptosis of sympathetic neurons through the receptor p75, and their expression is regulated by NGF in sympathetic neurons. Strong NGF-TrkA signaling blocks p75-mediated killing of sympathetic neurons. Expression of p75 in sympathetic neurons commences in vivo 2 days after TrkA expression, and this expression is regulated by NGF. Thus, Deppmann et al. (2008) proposed that BDNF and NT4 are NGF-regulated apoptotic cues for developing sympathetic neurons, and that innervation-dependent expression of p75 regulates a neuron's susceptibility to these signals.
Using immunoprecipitation and confocal microscopy, Lim et al. (2008) demonstrated that Ngfr and ephrin-As (e.g., Efna2; 602756) colocalized within caveolae along mouse retinal axons and formed a complex required for Fyn (137025) phosphorylation upon binding EphAs (see 179610), activating a signaling pathway that led to cytoskeletal changes. Retinal axons repulsed EphAs by ephrin-A reverse signaling in an Ngfr-dependent manner. Mice lacking Ngfr constitutively or specifically in retina had aberrant anterior shifts in retinal axon terminations in the superior colliculus, consistent with diminished repellent activity mediated by graded collicular EphAs. Lim et al. (2008) concluded that NGFR is a signaling partner for EPHAs and that the EPHA/NGFR complex reverse signals to mediate axon repulsion required for guidance and mapping.
Boiko et al. (2010) demonstrated that in melanomas, tumor stem cells can be isolated prospectively as a highly enriched CD271-positive melanoma tumor stem cell population using a process that maximizes viable cell transplantation. The tumors sampled in this study were taken from a broad spectrum of sites and stages. High-viability cells isolated by fluorescence-activated cell sorting and resuspended in a matrigel vehicle were implanted into T-negative, B-negative, and NK-deficient Rag2 (179616)-null/gamma-c (308380)-null mice. The CD271-positive subset of cells was the tumor-initiating population in 90% (9 of 10) of melanomas tested. Transplantation of isolated CD271-positive melanoma cells into engrafted human skin or bone in Rag2-null/gamma-c-null mice resulted in melanoma; however, melanoma did not develop after transplantation of isolated CD271-negative cells. Boiko et al. (2010) also showed that in mice, tumors derived from transplanted human CD271-positive melanoma cells were capable of metastasis in vivo. CD271-positive melanoma cells lacked expression of TYR (606933), MART1 (605513), and MAGE (see 300016) in 86%, 69%, and 68% of melanoma patients, respectively, which helped to explain why T-cell therapies directed at these antigens usually result in only temporary tumor shrinkage.
Mycobacterium tuberculosis (Mtb; see 607948) can persist in unidentified niches in the host long before the onset of disease symptoms and even after effective treatment. Latent tuberculosis is a major risk factor for active disease. Das et al. (2013) hypothesized that bone marrow stem cells (BMSCs), comprising both hematopoietic stem cells (HSCs) and mesenchymal stem cells (MSCs), may provide an ideal protective niche since they are found in tuberculosis lung granulomas of infected humans and mice; renew themselves; possess drug efflux pumps, such as ABCG2 (603756); produce only low levels of reactive oxygen species; are quiescent; and are found in the immune-privileged niche in bone marrow. By screening BMSCs expressing the CD133 (604365) marker and several BMSC subpopulations, Das et al. (2013) found that undifferentiated CD271-positive/CD45 (151460)-negative MSCs, but not CD34 (142230)-positive/CD45-positive HSCs, were permissive for and tolerated Mtb. Experiments in mice showed that Mtb, even if in a nonreplicating state, resided in MSCs in both bone marrow and lungs, particularly in the ABCG2-positive side population of lung MSCs. Studies in patients who had successfully completed monitored tuberculosis treatment demonstrated that Mtb DNA and, in some patients, viable Mtb could be isolated from CD271-positive/CD45-negative bone marrow MSCs. Das et al. (2013) proposed that CD271-positive bone marrow MSCs can provide a long-term protective niche in which dormant Mtb resides.
Huebner et al. (1986) used genomic and cDNA clones for the NGFR gene to map the gene in somatic cell hybrids and by in situ hybridization. It was localized to 17q12-q22, a site that appears to be closely distal to the breakpoint (at 17q21) in acute promyelocytic leukemia. Thus, the location of NGFR is probably 17q21-q22. Rettig et al. (1986) used a monoclonal antibody to human NGFR to study cell surface expression of the receptor on a panel of mouse-human neuroblastoma hybrids. The serologic typing permitted assignment of the NGFR gene to 17q21-qter.
By analysis of Southern blots prepared from pulsed field gels, Bentley et al. (1989) showed that the NGFR gene is closely linked to the HOX2 gene cluster and is separated by a maximum of 500 kb from the HOX2 region (see 142960). Furthermore, studies of the physical linkage gave a gene order of HOX2.2--HOX2.1--NGFR.
By targeted disruption of exon 3 of the Ngfr gene, which encodes CR2, CR3, and CR4, Lee et al. (1992) generated mice lacking functional Ngfr. The Ngfr -/- mice were viable and fertile but developed skin defects in all extremities as well as ulcers that were prone to secondary infection with loss of epidermis. Immunohistochemistry revealed a lack of calcitonin gene-related peptide (CALCA; 114130)- and substance P (162320)-expressing peripheral sensory nerve fibers. Mutant mice had a loss of heat sensitivity but no defects in innervation of the iris or salivary gland. Mice carrying a single copy of a human NGFR transgene did not have neuropeptide and sensory loss or the peripheral ulcers.
Exposure to excessive levels of visible light, or phototoxicity, leads to apoptosis of photoreceptor cells. Using laser capture microdissection and RT-PCR analysis, Harada et al. (2000) demonstrated that retinal degeneration upregulates expression of p75(NTR) as well as NTRK3 in different parts of Muller glial cells but not in photoreceptors. Blockade of p75(NTR) with antiserum to its extracellular domain reversed decreased production of basic fibroblast growth factor (FGF2; 134920) mediated by Ngf and resulted in both structural and functional photoreceptor survival in vivo. In p75(NTR)-deficient mice, Harada et al. (2000) observed a significant reduction in retinal apoptosis compared with wildtype mice after light exposure. They proposed that blockade of p75(NTR) may potentiate the survival of photoreceptors in multiple forms of retinitis pigmentosa (e.g., RP1; 180100).
Rosch et al. (2005) found that hippocampal long-term depression (LTD) was impaired in Ngfr-knockout mice, and the expression of 2 AMPA receptor subunits, Glur2 (138247) and Glur3 (305915), but not Glur1 (138248) or Glur4 (138246), was significantly altered. The authors concluded that NGFR is involved in activity-dependent synaptic plasticity.
Fei et al. (2014) found that mice lacking p75 exhibited delayed axon outgrowth and reduced branching of gustatory axons at embryonic day 13.5 (E13.5). From E14.5 to E18.5, gustatory neurons innervated fewer papillae and failed to innervate the midregion of the tongue in p75 -/- mice. The effects of p75 loss on gustatory axons preceded the loss of geniculate ganglion neurons starting at E14.5 and contributed to a loss of taste buds at and after birth. Fei et al. (2014) noted that mice lacking Trkb do not lose as many taste buds as hybrid mice lacking both Trkb ligands, Bdnf and Nt4, suggesting that p75 may maintain those additional taste buds in the absence of Trkb. However, they found that mice lacking both Trkb and p75 had more taste buds than mice lacking only Trkb, but that these additional taste buds did not result from altered neuron numbers or increased innervation. Fei et al. (2014) concluded that p75 regulates gustatory neuron axon branching and tongue innervation patterns during taste system development, probably independently of BDNF, NT4, and TRKB, and that p75 does not support the remaining neurons or taste buds in the absence of TRKB.
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