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FUNCTION Low affinity neurotrophin receptor which can bind to mature NGF, BDNF, NTF3, and NTF4 (PubMed:11559852, PubMed:1317267). Forms a heterodimeric receptor with SORCS2 that binds the precursor forms of NGF (proNGF), BDNF (proBDNF) and NTF3 (proNT3) with high affinity, and has much lower affinity for mature NGF and BDNF (PubMed:22155786, PubMed:24908487, PubMed:27457814). Plays an important role in differentiation and survival of specific neuronal populations during development (PubMed:11559852, PubMed:1317267). Can mediate cell survival as well as cell death of neural cells (PubMed:11559852, PubMed:1317267, PubMed:24908487). The heterodimeric receptor formed with SORCS2 plays a role in proBDNF-dependent synaptic plasticity, in hippocampal long term depression (LTD) and long term potentiation (LTP) (PubMed:27457814). Plays a role in the inactivation of RHOA (By similarity). Plays a role in the regulation of the translocation of GLUT4 to the cell surface in adipocytes and skeletal muscle cells in response to insulin, probably by regulating RAB31 activity, and thereby contributes to the regulation of insulin-dependent glucose uptake (PubMed:22460790). Necessary for the circadian oscillation of the clock genes BMAL1, PER1, PER2 and NR1D1 in the suprachiasmatic nucleus (SCN) of the brain and in liver and of the genes involved in glucose and lipid metabolism in the liver (PubMed:23785138).FUNCTION (Microbial infection) Cell surface receptor for rabies virus glycoprotein Gs.FUNCTION Does not bind NGF, BDNF, NTF3, and NTF4.SUBUNIT Homodimer; disulfide-linked. Heterodimer with SORCS2 (PubMed:22155786, PubMed:24908487, PubMed:27457814). The extracellular domains of the heterodimer bind NGF. The cytoplasmic region of the heterodimer binds TRIO. NGF binding mediates dissociation of TRIO from the receptor complex (PubMed:22155786). Interacts with TRAF2, TRAF4, TRAF6, PTPN13 and RANBP9. Interacts through TRAF6 with SQSTM1 which bridges NGFR to NTRK1. Interacts with BEX1 (By similarity). Interacts with BEX3 (PubMed:11830582). Interacts with KIDINS220 and NTRK1. Can form a ternary complex with NTRK1 and KIDINS220 and this complex is affected by the expression levels of KIDINS220. An increase in KIDINS220 expression leads to a decreased association of NGFR and NTRK1. Interacts (via death domain) with RAB31 (PubMed:22460790). Interacts with NTRK2; may regulate the ligand specificity of the NTRK2 receptor (PubMed:11559852). Interacts with LINGO1. Interacts with NRADD. Interacts with MAGED1; the interaction antagonizes the association NGFR:NTRK1 (By similarity). Interacts with RTN4R (PubMed:22923615). Interacts (via death domain) with ARHGDIA and RIPK2 (By similarity). Interacts with BFAR (By similarity).SUBUNIT (Microbial infection) Binds to rabies virus glycoprotein Gs.SUBCELLULAR LOCATION Detected in Schwann cells (PubMed:11559852). Detected in embryonic brain, in hippocampus neurons (at protein level) (PubMed:22155786, PubMed:27457814). Detected in brain and spinal cord (PubMed:11559852).DEVELOPMENTAL STAGE Detected in embryonic large blood vessels at 11.5 dpc.INDUCTION Expression oscillates in a circadian manner in the suprachiasmatic nucleus (SCN) of the brain and in liver. Expression seen at higher levels during the light period and lower during the dark period.DOMAIN The death domain mediates interaction with RANBP9 (By similarity). It also mediates interaction with ARHGDIA and RIPK2 (By similarity).DOMAIN The extracellular domain is responsible for interaction with NTRK1.PTM N-glycosylated (PubMed:11559852). O-glycosylated.PTM Phosphorylated on serine residues.DISRUPTION PHENOTYPE Embryos are present at the expected Mendelian rate at 15.5 dpc, but mutant mice display about 40% perinatal lethality. At 11.5 dpc, mutant embryos display mildly to severely dilated blood vessels with thinner walls. The dorsal aorta is particularly affected. Many embryos show massive dilatations, ruptures and blood leakage. Surviving animals display small size and hind limb ataxia at 13 days after birth. When held by their tails, they respond by stretching their hind legs pointing upwards. The diameter of their sciatic nerve is strongly reduced. At 3 days after birth, the number of Schwann cells is strongly reduced in sciatic nerve from mutant mice. Likewise, the number of sensory neurons in dorsal root ganglia is strongly reduced (PubMed:11559852). The initially reported gene disruption experiment finds that mice are born at the expected Mendelian rate, are fertile, and have no visible phenotype when young. However, after 4 months mutant mice develop skin alterations with severe ulcers on all extremities. Already before the onset of symptoms, mutant mice display decreased skin innervation and smaller dorsal root ganglia, plus impaired heat sensitivity (PubMed:11559852).MISCELLANEOUS Minor isoform that lacks exon 3.CAUTION The initial gene disruption experiment found a less pronounced phenotype than that reported in a later study (PubMed:11559852, PubMed:1317267). Both experiments disrupt expression of isoform 1 and NGF binding (PubMed:11559852, PubMed:1317267). The differences may be due to the presence of isoform 2; its expression is disrupted in the later experiment, but not in the initial experiment (PubMed:11559852).SEQUENCE CAUTION Truncated N-terminus.
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