NGFR is a member of the Tumor Necrosis Factor receptor (TNFR) superfamily. It serves as a low-affinity common receptor subunit for multiple neurotrohins (NGF, BDNF, NTF3 (NT-3) and NTF4 (NT-4/5)) (Tomellini et al. et al., 2014). It lacks any enzymatic activity, and mediates signals through interacting protein partners.

The transcript encodes 427 amino acids, including a signal peptide sequence.

Nerve growth factor receptor (NGFR) is a low affinity cell surface receptor for NGF. It is a member of the Tumor Necrosis Factor receptor (TNFR) superfamily, and thus anonymously called TNFRSF16. NGFR not only serves as a common receptor subunit for neurotrophins (NGF, BDNF, NT-3 and NT-4/5), but also binds their precursors (pro-neurotrophins), pro-NGF, pro-BDNF, pro-NT-3 and pro-NT-4/5. It also works as a co-receptor with other receptor partners, such as SORT1 (Sortilin), LINGO1 and RTN4R (Nogo receptor/NOGO-R)(Wang et al. et al., 2002; Bronfman et al. et al., 2004; Mi et al. et al., 2004; Meabon et al. et al., 2015).
NGFR consists of 427-amino-acid in overall length, and possesses an extracellular region with four 40 amino acid repeats with 6 cysteins at conserved positions followed by a serine/threonine-rich region, a single transmembrane domain, and a 155 amino acid cytoplasmic domain. The extracellular receives N- and O- glycosylations, and the cysteine-rich region conserved among the TNFR superfamily is licensing it as a similar receptor. The intracellular region lacks any catalytic domain, instead it possesses a death domain implicated in protein-protein interaction. Therefore, its signaling potential is dependent on protein-protein interactions.
NGFR receives proteolytic processing. Extracellular cleavage is mediated by ADAM17/TACE, which modifies NGFR to a smaller 28-kDa membrane-bound C-terminal fragment (p75-CTF). Further processing of p75-CTF by γ-secretase releases the intracellular domain (p75-ICD), which is implicated in cell death (Underwood et al. et al., 2008). Recent report indicates that the most abundant homotypic arrangement for NGFR is a trimer, and both of the monomers and trimers coexist (Anastasia et al. et al., 2015). In neurons, the trimers are not required for NGFR activation irrespective of ligand stimulation, whereas monomers are capable of conferring acute responses. Activation of NGFR is context-dependent, where the oligomerization status and expression amount determine the biological effect, and the trimers seem to sequester NGFR from an active form.

NGFR is expressed in a wide variety of tissues, such as brain, peripheral neurons, schwann cells, liver, esophagus and oral epithelium and the mesenchyme. In development, it is expressed in neural crest stem cells, and is regarded as a neural crest stem (NCS) cell marker. NGFR is also expressed in adult tissue stem cells and cancer stem cells, derived from ectoderm, neural crest and mesoderm.

NGFR is localized on the cell surface, endosomes and caveolae (Bilderback et al. et al., 1999; Huang et al. et al., 1999). It also shows cytoplasmic and nuclear localization. Intracellular domain (ICD), a cleaved product of NGFR, is present in intracellular compartments (Parkhurst et al. et al., 2010).

NGFR forms disulfide-linked dimers independently of ligand binding (Vilar et al. et al., 2009). Variety of functions mediated by NGFR owes to co-receptors. NGFR cooperates with tyrosine kinase receptors of neurophilins; NTRK1 (TrkA) for NGF binding, NTRK2 (TrkB) for BDNF and NT-4/5 and NTRK3 (TrkC) for NT-3. NGFR also cooperates with non-tyrosine kinase receptors, sortilin, Lingo-1 and NOGO-R. A trimetric receptor complex with Lingo-1 and NOGO-R binds RTN4 (Nogo-66), MAG (myelin associated glycoprotein) and OMG (oligodendrocyte myelin glycoprotein).
NGFR confers diverse functions to cells, which is totally dependent on cell types, differentiation status, binding to neurotrophins, neurotrophin maturation status, availability of co-receptors, accessibility to intracytoplasmic effectors, post-translation modification and cleavages. A variety of NGFR-mediated signals mediate cell proliferation and survival (Gentry et al. et al., 2000), differentiation, cell cycle progression (Chittka et al. et al., 2004), apoptosis (Rabizadeh et al. et al., 1993) (Nykjaer et al. et al., 2004), neurite outgrowth and retraction (Rabizadeh et al. et al., 1999), myelination (Notterpek et al., 2003), cell migration and invasion.
Signaling:
NGFR lacks its own enzymatic activity. Instead, it associates with a variety of intracellular proteins to mediate signals. TRAF2 , TRAF4 and TRAF6 mediate NF-κB activation (Khursigara et al. et al., 1999; Ye et al. et al., 1999). NGFR, through its death domain (DD), binds RIPK2 (RIP2) by a neurotrophin-dependent manner, activates NF-κB and supports Schwann cell survival (Khursigara et al. et al., 2001). Similarly, PTPN13 (Fas-associated phosphatase-1/FAP-1) and FAIM (Fas apoptosis inhibitory molecule) associate NGFR, and activates NF-κB and mediate neurite outgrowth (Irie et al. et al., 1999) (Sole et al. et al., 2004). NGFR activates RAC1, which leads to JNK activation and cell death (Harrington et al. et al., 2002). Pro-neurotrophin such as pro-BDNF activates CASP3 (Caspase-3) and JNK, leading to neuronal cell death (Charalampopoulos et al. et al., 2012). JNK is necessary but not sufficient for NGFR-mediated cell death. NGFR constitutively associates with ARHGDIA (RhoGDI), preventing its inhibition towards RHOA. RIP2 recruitment to DD and RhoGDI release from it, is mechanistically linked, and RhoGDI prevents RhoA activity upon release from NGFR. RIP2 has another competitor BEX1 for NGFR binding; BEX1 inhibits NF-κB activation and cell cycle progression. Association of MAGED1 (Neurotrophin receptor-interacting MAGE homolog/NRAGE), NGFRAP1 (p75NTR-associated cell death executor/NADE) and neurotrophin receptor interacting factor (NRIF) is related with pro-apoptotic signaling (Sasaki et al. et al., 2005; Bertrand et al. et al., 2008) (Mukai et al. et al., 2000) (Linggi et al. et al., 2005). Other binding partners include Schwann cell factor 1 (SC1) (Chittka et al. et al., 2004) and SALL2 (Pincheira et al. et al., 2009) both inducing cell cycle arrest, PARD3 (Par-3) which is involved in polarized myelination, and PDE4A4/5 implicated in enhanced cAMP degradation (Sachs et al. et al., 2007). NGFR also binds MAGI1 , which induces neurite outgrowth (Ito et al. et al., 2013). SHC1 is constitutively bound with NGFR, which may play a role in activation of phosphoinositide 3-kinase (PI3K) and Akt (protein kinase B) (Epa et al. et al., 2004). PI3K-Akt pathway supports survival of many types of cells (So et al. et al., 2013). Rab5 Family GTPases RAB5A and RAB31 directly associate with the DD of NGFR, and NGFR regulates glucose homeostasis and insulin sensitivity.
Stem cell Marker:
A variety of stem/progenitor cells express NGFR (Tomellini et al. et al., 2014). Inner cell mass of blastocysts is NGFR-positive, indicating that embryonic stem cells express NGFR. Later in the development, neural crest stem cells (NCSC) express NGFR (Schuldiner et al. et al., 2000), where three neutrophins, BDNF, NT-3 and NT-4, mediate their survival (Pyle et al. et al., 2006). NGFR also marks adult stem cells. Tissue stem cells originating from NCSCs express NGFR, and NGFR seemingly maintains their undifferentiated phenotypes and survival via NT-3(Kruger et al. et al., 2002) (Chalazonitis et al., 2004). Mesenchymal stem cells (MSCs) also express NGFR, where NGFR inhibits the differentiation of MSCs into osteogenic, adipogenic, chondrogenic and myogenic lineages (Mikami et al. et al., 2011). NGFR is a marker for precursors of hepatic stellate cells and portal fibloblast in the liver (Suzuki et al. et al., 2008). Likewise, keratinocyte of the basal layer of epidermis, and esophageal and oropharyngeal mucosas basal layer cells possessing tissue stem cell properties, are NGFR-positive.