| IED ID | IndEnz0002015651 |
| Enzyme Type ID | protease015651 |
| Protein Name |
High affinity nerve growth factor receptor EC 2.7.10.1 Neurotrophic tyrosine kinase receptor type 1 TRK1-transforming tyrosine kinase protein Tropomyosin-related kinase A Tyrosine kinase receptor Tyrosine kinase receptor A Trk-A gp140trk p140-TrkA |
| Gene Name | NTRK1 MTC TRK TRKA |
| Organism | Homo sapiens (Human) |
| Taxonomic Lineage | cellular organisms Eukaryota Opisthokonta Metazoa Eumetazoa Bilateria Deuterostomia Chordata Craniata Vertebrata Gnathostomata (jawed vertebrates) Teleostomi Euteleostomi Sarcopterygii Dipnotetrapodomorpha Tetrapoda Amniota Mammalia Theria Eutheria Boreoeutheria Euarchontoglires Primates Haplorrhini Simiiformes Catarrhini Hominoidea (apes) Hominidae (great apes) Homininae Homo Homo sapiens (Human) |
| Enzyme Sequence | MLRGGRRGQLGWHSWAAGPGSLLAWLILASAGAAPCPDACCPHGSSGLRCTRDGALDSLHHLPGAENLTELYIENQQHLQHLELRDLRGLGELRNLTIVKSGLRFVAPDAFHFTPRLSRLNLSFNALESLSWKTVQGLSLQELVLSGNPLHCSCALRWLQRWEEEGLGGVPEQKLQCHGQGPLAHMPNASCGVPTLKVQVPNASVDVGDDVLLRCQVEGRGLEQAGWILTELEQSATVMKSGGLPSLGLTLANVTSDLNRKNVTCWAENDVGRAEVSVQVNVSFPASVQLHTAVEMHHWCIPFSVDGQPAPSLRWLFNGSVLNETSFIFTEFLEPAANETVRHGCLRLNQPTHVNNGNYTLLAANPFGQASASIMAAFMDNPFEFNPEDPIPVSFSPVDTNSTSGDPVEKKDETPFGVSVAVGLAVFACLFLSTLLLVLNKCGRRNKFGINRPAVLAPEDGLAMSLHFMTLGGSSLSPTEGKGSGLQGHIIENPQYFSDACVHHIKRRDIVLKWELGEGAFGKVFLAECHNLLPEQDKMLVAVKALKEASESARQDFQREAELLTMLQHQHIVRFFGVCTEGRPLLMVFEYMRHGDLNRFLRSHGPDAKLLAGGEDVAPGPLGLGQLLAVASQVAAGMVYLAGLHFVHRDLATRNCLVGQGLVVKIGDFGMSRDIYSTDYYRVGGRTMLPIRWMPPESILYRKFTTESDVWSFGVVLWEIFTYGKQPWYQLSNTEAIDCITQGRELERPRACPPEVYAIMRGCWQREPQQRHSIKDVHARLQALAQAPPVYLDVLG |
| Enzyme Length | 796 |
| Uniprot Accession Number | P04629 |
| Absorption | |
| Active Site | ACT_SITE 650; /note="Proton acceptor"; /evidence="ECO:0000255|PROSITE-ProRule:PRU00159, ECO:0000255|PROSITE-ProRule:PRU10028" |
| Activity Regulation | ACTIVITY 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 (By similarity). Regulated by NGFR (By similarity). {ECO:0000250|UniProtKB:Q3UFB7}. |
| Binding Site | BINDING 544; /note=ATP; /evidence=ECO:0000255|PROSITE-ProRule:PRU00159 |
| Calcium Binding | |
| catalytic Activity | CATALYTIC ACTIVITY: Reaction=ATP + L-tyrosyl-[protein] = ADP + H(+) + O-phospho-L-tyrosyl-[protein]; Xref=Rhea:RHEA:10596, Rhea:RHEA-COMP:10136, Rhea:RHEA-COMP:10137, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, ChEBI:CHEBI:46858, ChEBI:CHEBI:82620, ChEBI:CHEBI:456216; EC=2.7.10.1; Evidence={ECO:0000255|PROSITE-ProRule:PRU10028, ECO:0000269|PubMed:1281417, ECO:0000269|PubMed:2927393}; |
| DNA Binding | |
| EC Number | 2.7.10.1 |
| Enzyme Function | 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 (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. {ECO:0000250|UniProtKB:P35739, ECO:0000250|UniProtKB:Q3UFB7, ECO:0000269|PubMed:11244088, ECO:0000269|PubMed:1281417, ECO:0000269|PubMed:15488758, ECO:0000269|PubMed:17196528, ECO:0000269|PubMed:1849459, ECO:0000269|PubMed:1850821, ECO:0000269|PubMed:22649032, ECO:0000269|PubMed:27445338, ECO:0000269|PubMed:27676246, ECO:0000269|PubMed:8155326, ECO:0000269|PubMed:8325889}.; FUNCTION: [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. {ECO:0000269|PubMed:15488758}. |
| Temperature Dependency | |
| PH Dependency | |
| Pathway | |
| nucleotide Binding | NP_BIND 516..524; /note=ATP; /evidence=ECO:0000255|PROSITE-ProRule:PRU00159 |
| Features | Active site (1); Alternative sequence (3); Beta strand (37); Binding site (1); Chain (1); Disulfide bond (5); Domain (4); Erroneous termination (1); Frameshift (1); Glycosylation (13); Helix (24); Modified residue (5); Motif (2); Mutagenesis (6); Natural variant (45); Nucleotide binding (1); Region (1); Repeat (2); Sequence caution (4); Sequence conflict (3); Signal peptide (1); Site (4); Topological domain (2); Transmembrane (1); Turn (8) |
| Keywords | 3D-structure;ATP-binding;Alternative splicing;Cell membrane;Chromosomal rearrangement;Developmental protein;Differentiation;Disease variant;Disulfide bond;Endosome;Glycoprotein;Immunoglobulin domain;Kinase;Leucine-rich repeat;Membrane;Neurogenesis;Nucleotide-binding;Phosphoprotein;Proto-oncogene;Receptor;Reference proteome;Repeat;Signal;Transferase;Transmembrane;Transmembrane helix;Tyrosine-protein kinase;Ubl conjugation |
| Interact With | P05067-4; P22681; P01138; P01138; Itself; P18031; Q99523; Q13501; O75385; Q8K4V6 |
| Induction | INDUCTION: Isoform TrkA-III is up-regulated upon hypoxia in cells normally expressing it. {ECO:0000269|PubMed:15488758}. |
| Subcellular Location | SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:1281417, ECO:0000269|PubMed:15488758, ECO:0000269|PubMed:17196528, ECO:0000269|PubMed:27676246, ECO:0000269|PubMed:2927393}; Single-pass type I membrane protein {ECO:0000269|PubMed:1281417, ECO:0000269|PubMed:15488758}. Early endosome membrane {ECO:0000250|UniProtKB:P35739}; Single-pass type I membrane protein {ECO:0000250|UniProtKB:P35739}. Late endosome membrane {ECO:0000250|UniProtKB:P35739}; Single-pass type I membrane protein {ECO:0000250|UniProtKB:P35739}. Recycling endosome membrane {ECO:0000250|UniProtKB:P35739}; Single-pass type I membrane protein {ECO:0000250|UniProtKB:P35739}. Note=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. {ECO:0000250|UniProtKB:P35739, ECO:0000269|PubMed:1281417}. |
| Modified Residue | MOD_RES 496; /note="Phosphotyrosine; by autocatalysis"; /evidence="ECO:0000269|PubMed:15488758, ECO:0000269|PubMed:27676246, ECO:0000269|PubMed:8155326"; MOD_RES 676; /note="Phosphotyrosine; by autocatalysis"; /evidence="ECO:0000269|PubMed:8155326"; MOD_RES 680; /note="Phosphotyrosine; by autocatalysis"; /evidence="ECO:0000269|PubMed:15488758, ECO:0000269|PubMed:8155326"; MOD_RES 681; /note="Phosphotyrosine; by autocatalysis"; /evidence="ECO:0000269|PubMed:15488758, ECO:0000269|PubMed:8155326"; MOD_RES 791; /note="Phosphotyrosine; by autocatalysis"; /evidence="ECO:0000269|PubMed:15488758, ECO:0000269|PubMed:7510697, ECO:0000269|PubMed:8155326" |
| Post Translational Modification | PTM: 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). {ECO:0000269|PubMed:1281417, ECO:0000269|PubMed:15488758, ECO:0000269|PubMed:27676246, ECO:0000269|PubMed:28177573, ECO:0000269|PubMed:2927393, ECO:0000269|PubMed:7510697, ECO:0000269|PubMed:8155326, ECO:0000269|PubMed:8325889}.; PTM: N-glycosylated (PubMed:2927393). Isoform TrkA-I and isoform TrkA-II are N-glycosylated. {ECO:0000269|PubMed:15488758, ECO:0000269|PubMed:17196528, ECO:0000269|PubMed:27676246, ECO:0000269|PubMed:2927393}.; PTM: 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). {ECO:0000250|UniProtKB:Q3UFB7, ECO:0000269|PubMed:27445338}. |
| Signal Peptide | SIGNAL 1..32; /evidence=ECO:0000255 |
| Structure 3D | NMR spectroscopy (3); X-ray crystallography (49) |
| Cross Reference PDB | 1HE7; 1SHC; 1WWA; 1WWW; 2IFG; 2N90; 4AOJ; 4CRP; 4F0I; 4GT5; 4PMM; 4PMP; 4PMS; 4PMT; 4YNE; 4YPS; 5H3Q; 5I8A; 5JFS; 5JFV; 5JFW; 5JFX; 5KMI; 5KMJ; 5KMK; 5KML; 5KMM; 5KMN; 5KMO; 5KVT; 5WR7; 6D1Y; 6D1Z; 6D20; 6D22; 6DKB; 6DKG; 6DKI; 6DKW; 6IQN; 6J5L; 6NPT; 6NSP; 6NSS; 6PL1; 6PL2; 6PL3; 6PL4; 6PMA; 6PMB; 6PMC; 6PME; |
| Mapped Pubmed ID | 10629055; 10908605; 11007890; 11147812; 11157096; 11248116; 11263982; 11278445; 11285228; 11466412; 11668614; 11705863; 11784714; 11850535; 11859925; 12006576; 12102460; 12150951; 12208732; 12210794; 12237455; 12446789; 12536040; 14642435; 14691455; 14985763; 14988025; 15159601; 15167895; 15273715; 15362372; 15523689; 15632082; 15637590; 15950763; 15961390; 16091303; 16138253; 16284401; 16373086; 16483615; 16546643; 16586073; 16611639; 16704535; 16786155; 16805430; 16860569; 16862449; 16919030; 16935282; 16996570; 17143529; 17353931; 17447019; 17531524; 17617666; 17619016; 17635673; 17667845; 17671718; 17673289; 17721511; 17850422; 17971243; 18072090; 18203754; 18221326; 18270328; 18305571; 18319596; 18322713; 18419753; 18427551; 1850549; 18678285; 18719857; 18727839; 18780967; 19086053; 19115484; 19120874; 19167335; 19169037; 19177265; 19250380; 19330021; 19386345; 19399531; 19417027; 19435634; 19453261; 19564412; 19598235; 19635108; 19651702; 19730683; 19734938; 19749791; 19758420; 19816090; 19883730; 19913121; 19945432; 19957796; 20003389; 20186105; 20209132; 20219210; 20424473; 20542022; 20600627; 20628086; 20663926; 20680486; 20854189; 20943663; 20977883; 21123453; 21137076; 21150695; 21154590; 21184737; 21187090; 21236475; 21295543; 21317683; 21321391; 21364532; 21397006; 21419569; 21429417; 21481795; 21503896; 21570973; 21645891; 21728718; 21816277; 21849536; 21990266; 22128158; 22138126; 22272270; 22343487; 22410777; 22445970; 22454143; 22539856; 22561027; 22782892; 22902478; 22932111; 22939624; 22954667; 22992069; 23266087; 23400852; 23471969; 23489213; 23569426; 23589303; 23746174; 23841091; 23869086; 23948750; 24162815; 24369899; 24557415; 24585880; 24603864; 24736663; 24825909; 24900538; 24914455; 24965840; 25361003; 25389033; 25454499; 25491371; 25512530; 25619719; 25729923; 25840418; 25921289; 25948268; 26001971; 26005534; 26408608; 26459250; 26472021; 26496938; 26546295; 26564979; 26569118; 26716414; 26863915; 26962689; 27106707; 27184211; 27264679; 27551041; 27655914; 27766865; 27776007; 27802234; 27821809; 27912827; 28039433; 28097808; 28159414; 28192073; 28213521; 28215291; 28345382; 28356268; 28557340; 28591715; 28683589; 28719467; 28981924; 29037860; 29054434; 29215016; 29370427; 29420916; 29463555; 29507419; 29553955; 29672039; 29683819; 29715200; 29753009; 29761734; 29770739; 29802225; 29802376; 29904026; 29944371; 29958731; 30103559; 30134855; 30201336; 30242093; 30307573; 30366959; 30411541; 30461622; 30594749; 30709876; 30771434; 30808933; 30844834; 30848386; 30920961; 31059222; 31071716; 31235262; 31268127; 31406350; 31444087; 31610943; 31699609; 31760089; 31761448; 31792356; 31801826; 31838083; 31871300; 32316846; 32457407; 32585227; 32623639; 32880785; 32921229; 32931153; 32957504; 33037466; 33074583; 33143904; 33290352; 33422294; 33456567; 33479642; 33524004; 33536237; 33707574; 33811536; 33963905; 34440751; 34895532; 7806500; 7970708; 8226808; 8384556; 9099755; 9182757; 9560161; 9715270; |
| Motif | MOTIF 537..541; /note=DXXLL; /evidence=ECO:0000269|PubMed:26446845; MOTIF 607..611; /note=DXXLL; /evidence=ECO:0000269|PubMed:26446845 |
| Gene Encoded By | |
| Mass | 87,497 |
| Kinetics | |
| Metal Binding | |
| Rhea ID | RHEA:10596 |
| Cross Reference Brenda | 2.7.10.1; |