NTRK1

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 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, anhidrosis, self-mutilating behavior, cognitive disability and cancer. Alternate transcriptional splice variants of this gene have been found, but only three have been characterized to date. [provided by RefSeq, Jul 2008]

Neurotrophic Receptor Tyrosine Kinase 1

Receptor tyrosine kinase involved in the development and the maturation of the central and peripheral nervous systems through regulation of proliferation, differentiation and survival of sympathetic and nervous neurons. High affinity receptor for NGF which is its primary ligand (PubMed:1850821, PubMed:1849459, PubMed:1281417, PubMed:8325889, PubMed:15488758, PubMed:22649032, PubMed:17196528, PubMed:27445338).
Can also bind and be activated by NTF3/neurotrophin-3. However, NTF3 only supports axonal extension through NTRK1 but has no effect on neuron survival (By similarity).
Upon dimeric NGF ligand-binding, undergoes homodimerization, autophosphorylation and activation (PubMed:1281417).
Recruits, phosphorylates and/or activates several downstream effectors including SHC1, FRS2, SH2B1, SH2B2 and PLCG1 that regulate distinct overlapping signaling cascades driving cell survival and differentiation. Through SHC1 and FRS2 activates a GRB2-Ras-MAPK cascade that regulates cell differentiation and survival. Through PLCG1 controls NF-Kappa-B activation and the transcription of genes involved in cell survival. Through SHC1 and SH2B1 controls a Ras-PI3 kinase-AKT1 signaling cascade that is also regulating survival. In absence of ligand and activation, may promote cell death, making the survival of neurons dependent on trophic factors.
Isoform TrkA-III
Resistant to NGF, it constitutively activates AKT1 and NF-kappa-B and is unable to activate the Ras-MAPK signaling cascade. Antagonizes the anti-proliferative NGF-NTRK1 signaling that promotes neuronal precursors differentiation. Isoform TrkA-III promotes angiogenesis and has oncogenic activity when overexpressed.

AgingIEA:Ensembl
Axon guidanceIEA:Ensembl
Axonogenesis involved in innervationISS:UniProtKB
B cell differentiationIEA:Ensembl
Behavioral response to formalin induced painIEA:Ensembl
Cellular response to nerve growth factor stimulusManual Assertion Based On ExperimentIMP:UniProtKB
Cellular response to nicotineIEA:Ensembl
Circadian rhythmIEA:Ensembl
Detection of mechanical stimulus involved in sensory perception of painIEA:Ensembl
Detection of temperature stimulus involved in sensory perception of painIEA:Ensembl
Learning or memoryIEA:Ensembl
Mechanoreceptor differentiationIEA:Ensembl
Negative regulation of apoptotic processManual Assertion Based On ExperimentTAS:ARUK-UCL
Negative regulation of cell population proliferationManual Assertion Based On ExperimentIDA:UniProtKB
Negative regulation of neuron apoptotic processISS:UniProtKB
Nerve growth factor signaling pathwayManual Assertion Based On ExperimentIMP:UniProtKB
Neuron developmentIDA:MGI
Neuron projection developmentIDA:MGI
Neurotrophin TRK receptor signaling pathwayManual Assertion Based On ExperimentIDA:UniProtKB
Olfactory nerve developmentIEA:Ensembl
Peptidyl-tyrosine autophosphorylationManual Assertion Based On ExperimentIDA:MGI
Peptidyl-tyrosine phosphorylationManual Assertion Based On ExperimentIDA:UniProtKB
Positive regulation of angiogenesisIDA:UniProtKB
Positive regulation of ERK1 and ERK2 cascadeManual Assertion Based On ExperimentIDA:UniProtKB
Positive regulation of GTPase activityManual Assertion Based On ExperimentIDA:UniProtKB
Positive regulation of kinase activityManual Assertion Based On ExperimentIBA:GO_Central
Positive regulation of neuron projection developmentManual Assertion Based On ExperimentIDA:UniProtKB
Positive regulation of NF-kappaB transcription factor activityManual Assertion Based On ExperimentIDA:UniProtKB
Positive regulation of phosphatidylinositol 3-kinase signalingManual Assertion Based On ExperimentIBA:GO_Central
Positive regulation of programmed cell deathISS:UniProtKB
Positive regulation of protein phosphorylationManual Assertion Based On ExperimentTAS:BHF-UCL
Positive regulation of Ras protein signal transductionManual Assertion Based On ExperimentIDA:UniProtKB
Positive regulation of synapse assemblyIEA:Ensembl
Positive regulation of synaptic transmission, glutamatergicIEA:Ensembl
Programmed cell death involved in cell developmentISS:UniProtKB
Protein autophosphorylationManual Assertion Based On ExperimentIDA:UniProtKB
Protein phosphorylationManual Assertion Based On ExperimentIDA:UniProtKB
Regulation of protein kinase B signalingManual Assertion Based On ExperimentIBA:GO_Central
Response to axon injuryIEA:Ensembl
Response to electrical stimulusIEA:Ensembl
Response to hydrostatic pressureIEA:Ensembl
Response to nutrient levelsIEA:Ensembl
Response to radiationIEA:Ensembl
Response to xenobiotic stimulusIEA:Ensembl
Sertoli cell developmentIEA:Ensembl
Sympathetic nervous system developmentISS:UniProtKB
Transmembrane receptor protein tyrosine kinase signaling pathwayManual Assertion Based On ExperimentIBA:GO_Central

Cell membrane
Early endosome membrane
Late endosome membrane
Recycling endosome membrane
Rapidly internalized after NGF binding (PubMed:1281417).
Internalized to endosomes upon binding of NGF or NTF3 and further transported to the cell body via a retrograde axonal transport. Localized at cell membrane and early endosomes before nerve growth factor (NGF) stimulation. Recruited to late endosomes after NGF stimulation. Colocalized with RAPGEF2 at late endosomes.

Congenital insensitivity to pain with anhidrosis (CIPA):
Characterized by a congenital insensitivity to pain, anhidrosis (absence of sweating), absence of reaction to noxious stimuli, self-mutilating behavior, and mental retardation. This rare autosomal recessive disorder is also known as congenital sensory neuropathy with anhidrosis or hereditary sensory and autonomic neuropathy type IV or familial dysautonomia type II.

Extracellular: 33-423
Helical: 424-439
Cytoplasmic: 440-796

Ligand-mediated autophosphorylation (PubMed:2927393, PubMed:1281417, PubMed:15488758, PubMed:7510697, PubMed:8155326, PubMed:8325889, PubMed:27676246, PubMed:28177573).
Interaction with SQSTM1 is phosphotyrosine-dependent. Autophosphorylation at Tyr-496 mediates interaction and phosphorylation of SHC1 (PubMed:15488758, PubMed:7510697, PubMed:8155326, PubMed:8325889).
N-glycosylated (PubMed:2927393).
Isoform TrkA-I and isoform TrkA-II are N-glycosylated.
Ubiquitinated (PubMed:27445338).
Undergoes polyubiquitination upon activation; regulated by NGFR (PubMed:27445338).
Ubiquitination by NEDD4L leads to degradation (PubMed:27445338).
Ubiquitination regulates the internalization of the receptor (By similarity).