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| biopax3:comment |
FUNCTION: 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, it 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. Upon dimeric NGF ligand-binding, undergoes homodimerization, autophosphorylation and activation. 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. CATALYTIC ACTIVITY: ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate. ENZYME REGULATION: The pro-survival signaling effect of NTRK1 in neurons requires its endocytosis into signaling early endosomes and its retrograde axonal transport. This is regulated by different proteins including CFL1, RAC1 and SORT1. NTF3 is unable to induce this signaling probably due to the lability of the NTF3- NTRK1 complex in endosomes. SH2D1A inhibits the autophosphorylation of the receptor, and alters the recruitment and activation of downstream effectors and signaling cascades. Regulated by NGFR. SUBUNIT: Exists in a dynamic equilibrium between monomeric (low affinity) and dimeric (high affinity) structures. Homodimerization is induced by binding of a NGF dimer. Interacts with SQSTM1; bridges NTRK1 to NGFR. Forms a ternary complex with NGFR and KIDINS220; this complex is affected by the expression levels of KIDINS220 and an increase in KIDINS220 expression leads to a decreased association of NGFR and NTRK1. Interacts (phosphorylated upon activation by NGF) with SHC1; mediates SHC1 phosphorylation and activation. Interacts (phosphorylated upon activation by NGF) with PLCG1; mediates PLCG1 phosphorylation and activation. Interacts (phosphorylated) with SH2B1 and SH2B2. Interacts with GRB2. Interacts with PIK3R1. Interacts with FRS2. Interacts with SORT1; may regulate NTRK1 anterograde axonal transport. Interacts with NRADD (By similarity). Interacts with SH2D1A; regulates NTRK1. Interacts with RAB7A (By similarity). SUBCELLULAR LOCATION: Cell membrane; Single-pass type I membrane protein (By similarity). Early endosome membrane; Single-pass type I membrane protein. Note=Internalized to endosomes upon binding of NGF or NTF3 and further transported to the cell body via a retrograde axonal transport. DEVELOPMENTAL STAGE: First detected at E13.5, a time coinciding with the requirement of sympathetic neurons for NGF. DOMAIN: The transmembrane domain mediates interaction with KIDINS220 (By similarity). DOMAIN: The extracellular domain mediates interaction with NGFR (By similarity). PTM: Ligand-mediated autophosphorylation. Interaction with SQSTM1 is phosphotyrosine-dependent. Autophosphorylation at Tyr-499 mediates interaction and phosphorylation of SHC1. PTM: N-glycosylated (By similarity). PTM: Ubiquitinated. Undergoes polyubiquitination upon activation; regulated by NGFR. Ubiquitination regulates the internalization of the receptor. DISRUPTION PHENOTYPE: Mice die early after birth due to severe sensory and sympathetic neuropathies characterized by extensive neuronal cell loss in trigeminal, sympathetic and dorsal root ganglia, as well as a decrease in the cholinergic basal forebrain projections to the hippocampus and cortex. There are for instance 35% fewer cells by E17.5 in the superior cervical glanglion, a major component of the sympathetic system. SIMILARITY: Belongs to the protein kinase superfamily. Tyr protein kinase family. Insulin receptor subfamily. SIMILARITY: Contains 2 Ig-like C2-type (immunoglobulin-like) domains. SIMILARITY: Contains 2 LRR (leucine-rich) repeats. SIMILARITY: Contains 1 LRRCT domain. SIMILARITY: Contains 1 protein kinase domain. SEQUENCE CAUTION: Sequence=BAE28644.1; Type=Erroneous initiation; GENE SYNONYMS:Ntrk1. COPYRIGHT: Protein annotation is derived from the UniProt Consortium (http://www.uniprot.org/). Distributed under the Creative Commons Attribution-NoDerivs License.,
SEQUENCE 799 AA; 87738 MW; 1A37F76A63564603 CRC64;
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| biopax3:xref | |
| biopax3:displayName |
NTRK1_MOUSE
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| biopax3:name |
2.7.10.1,
Neurotrophic tyrosine kinase receptor type 1,
Ntrk1
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| biopax3:entityFeature | |
| biopax3:organism | |
| biopax3:sequence |
MLRGQRLGQLGWHRPAAGLGSLMTSLMLACASAASCREVCCPVGPSGLRCTRAGSLDTLRGLRGAGNLTELYVENQQHLQRLEFEDLQGLGELRSLTIVKSGLRFVAPDAFRFTPRLSHLNLSSNALESLSWKTVQGLSLQDLTLSGNPLHCSCALFWLQRWEQEGLCGVHTQTLHDSGPGDQFLPLGHNTSCGVPTVKIQMPNDSVEVGDDVFLQCQVEGLALQQADWILTELEGAATVKKFGDLPSLGLILVNVTSDLNKKNVTCWAENDVGRAEVSVQVSVSFPASVHLGLAVEQHHWCIPFSVDGQPAPSLRWLFNGSVLNETSFIFTQFLESALTNETMRHGCLRLNQPTHVNNGNYTLLAANPYGQAAASVMAAFMDNPFEFNPEDPIPVSFSPVDGNSTSRDPVEKKDETPFGVSVAVGLAVSAALFLSALLLVLNKCGQRSKFGINRPAVLAPEDGLAMSLHFMTLGGSSLSPTEGKGSGLQGHIMENPQYFSDTCVHHIKRQDIILKWELGEGAFGKVFLAECYNLLNDQDKMLVAVKALKEASENARQDFQREAELLTMLQHQHIVRFFGVCTEGGPLLMVFEYMRHGDLNRFLRSHGPDAKLLAGGEDVAPGPLGLGQLLAVASQVAAGMVYLASLHFVHRDLATRNCLVGQGLVVKIGDFGMSRDIYSTDYYRVGGRTMLPIRWMPPESILYRKFSTESDVWSFGVVLWEIFTYGKQPWYQLSNTEAIECITQGRELERPRACPPDVYAIMRGCWQREPQQRLSMKDVHARLQALAQAPPSYLDVLG
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| biopax3:standardName |
High affinity nerve growth factor receptor
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