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UniProtKB - P04629 (NTRK1_HUMAN)

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Protein

High affinity nerve growth factor receptor

Gene

NTRK1

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

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:17196528). 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.By similarity9 Publications
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.1 Publication

Miscellaneous

Trk also stands for tropomyosin-related kinase since it was first isolated as an oncogenic protein which was the result of a fusion between the tropomyosin gene TPM3 and NTRK1.

Catalytic activityi

ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate.PROSITE-ProRule annotation2 Publications

Enzyme regulationi

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).By similarity

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Binding sitei544ATPPROSITE-ProRule annotation1
Active sitei650Proton acceptorPROSITE-ProRule annotation1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Nucleotide bindingi516 – 524ATPPROSITE-ProRule annotation9

GO - Molecular functioni

  • ATP binding Source: UniProtKB-KW
  • GPI-linked ephrin receptor activity Source: Ensembl
  • kinase binding Source: Ensembl
  • nerve growth factor binding Source: UniProtKB
  • nerve growth factor receptor activity Source: UniProtKB
  • neurotrophin binding Source: ProtInc
  • neurotrophin p75 receptor binding Source: Ensembl
  • protein homodimerization activity Source: UniProtKB
  • protein tyrosine kinase activity Source: UniProtKB
  • transmembrane receptor protein tyrosine kinase activity Source: UniProtKB
Complete GO annotation...

GO - Biological processi

Complete GO annotation...

Keywordsi

Molecular functionDevelopmental protein, Kinase, Receptor, Transferase, Tyrosine-protein kinase
Biological processDifferentiation, Neurogenesis
LigandATP-binding, Nucleotide-binding

Enzyme and pathway databases

BRENDAi2.7.10.1. 2681.
ReactomeiR-HSA-167021. PLC-gamma1 signalling.
R-HSA-167044. Signalling to RAS.
R-HSA-170968. Frs2-mediated activation.
R-HSA-170984. ARMS-mediated activation.
R-HSA-177504. Retrograde neurotrophin signalling.
R-HSA-187024. NGF-independant TRKA activation.
R-HSA-187042. TRKA activation by NGF.
R-HSA-187706. Signalling to p38 via RIT and RIN.
R-HSA-198203. PI3K/AKT activation.
R-HSA-198745. Signalling to STAT3.
SignaLinkiP04629.
SIGNORiP04629.

Names & Taxonomyi

Protein namesi
Recommended name:
High affinity nerve growth factor receptor (EC:2.7.10.12 Publications)
Alternative name(s):
Neurotrophic tyrosine kinase receptor type 1
TRK1-transforming tyrosine kinase protein
Tropomyosin-related kinase A
Tyrosine kinase receptor
Tyrosine kinase receptor A
Short name:
Trk-A
gp140trk1 Publication
p140-TrkA
Gene namesi
Name:NTRK1
Synonyms:MTC, TRK1 Publication, TRKA1 Publication
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo
Proteomesi
  • UP000005640 Componenti: Chromosome 1

Organism-specific databases

HGNCiHGNC:8031. NTRK1.

Subcellular locationi

Topology

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Topological domaini33 – 423ExtracellularSequence analysisAdd BLAST391
Transmembranei424 – 439HelicalSequence analysisAdd BLAST16
Topological domaini440 – 796CytoplasmicSequence analysisAdd BLAST357

GO - Cellular componenti

Complete GO annotation...

Keywords - Cellular componenti

Cell membrane, Endosome, Membrane

Pathology & Biotechi

Involvement in diseasei

Congenital insensitivity to pain with anhidrosis (CIPA)12 Publications
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionCharacterized 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.
See also OMIM:256800
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_00962493L → P in CIPA; aberrantly processed; shows diminished autophosphorylation in neuronal cells. 2 Publications1
Natural variantiVAR_009625213L → P in CIPA; aberrantly processed; shows diminished autophosphorylation in neuronal cells. 2 PublicationsCorresponds to variant dbSNP:rs747711259Ensembl.1
Natural variantiVAR_068481359Y → C in CIPA. 1 PublicationCorresponds to variant dbSNP:rs121964869Ensembl.1
Natural variantiVAR_068482492E → K in CIPA. 1 PublicationCorresponds to variant dbSNP:rs144901788Ensembl.1
Natural variantiVAR_077472517G → E in CIPA; following transfection in neuroblastoma cells and NGF treatment, small decrease in the percentage of cells differentiated into neuronal phenotype, but in differentiated cells, the average neurite length is comparable to wild-type; no effect on N-glycosylation, subcellular location, nor on basal and NGF-induced autophosphorylation; loss of NGF-stimulated calcium flux. 1 PublicationCorresponds to variant dbSNP:rs606231467Ensembl.1
Natural variantiVAR_077473522G → E in CIPA; no effect on N-glycosylation, nor on subcellular location; reduced basal autophosphorylation and complete loss of NGF-induced autophosphorylation; loss of NGF-stimulated calcium flux. 1 Publication1
Natural variantiVAR_009626522G → R in CIPA; processed as wild-type but shows significantly diminished autophosphorylation in both neuronal and non-neuronal cells. 2 Publications1
Natural variantiVAR_077474572I → S in CIPA. 1 Publication1
Natural variantiVAR_004103577G → R in CIPA; loss of function; processed as wild-type but shows significantly diminished autophosphorylation in both neuronal and non-neuronal cells. 4 PublicationsCorresponds to variant dbSNP:rs121964866Ensembl.1
Natural variantiVAR_009627587M → V in CIPA. 1 PublicationCorresponds to variant dbSNP:rs121964870Ensembl.1
Natural variantiVAR_009630649R → W in CIPA; processed as wild-type but shows significantly diminished autophosphorylation in both neuronal and non-neuronal cells. 2 PublicationsCorresponds to variant dbSNP:rs369353892Ensembl.1
Natural variantiVAR_009631654R → C in CIPA; processed as wild-type but shows significantly diminished autophosphorylation in both neuronal and non-neuronal cells. 3 PublicationsCorresponds to variant dbSNP:rs764992664Ensembl.1
Natural variantiVAR_077475657L → P in CIPA; following transfection in neuroblastoma cells and NGF treatment, loss of differentiation into neuronal phenotype; partially decreased N-glycosylation; reduced expression at the plasma membrane; reduced basal autophosphorylation and complete loss of NGF-induced autophosphorylation; loss of NGF-stimulated calcium flux. 1 Publication1
Natural variantiVAR_009632674D → Y in CIPA; unknown pathological significance; might impair the function of the enzyme without compromising autophosphorylation. 2 PublicationsCorresponds to variant dbSNP:rs80356677Ensembl.1
Natural variantiVAR_009633695P → L in CIPA. 1 PublicationCorresponds to variant dbSNP:rs121964868Ensembl.1
Natural variantiVAR_077476699I → T in CIPA; partially decreased N-glycosylation; reduced expression at the plasma membrane; reduced basal autophosphorylation and complete loss of NGF-induced autophosphorylation; loss of NGF-stimulated calcium flux. 1 Publication1
Natural variantiVAR_009634714G → S in CIPA; processed as wild-type but shows significantly diminished autophosphorylation in both neuronal and non-neuronal cells. 2 PublicationsCorresponds to variant dbSNP:rs770727871Ensembl.1
Natural variantiVAR_077477717L → R in CIPA; found in a compound heterozygote also carrying an premature stop codon at position 558. 1 Publication1
Natural variantiVAR_077478752C → S in CIPA; unknown pathological significance; following transfection in neuroblastoma cells and NGF treatment, no effect on neurite outgrowth, nor neurite length; no effect on N-glycosylation, subcellular location, basal and NGF-induced autophosphorylation, nor on NGF-stimulated calcium flux. 1 Publication1
Natural variantiVAR_077479763C → S in CIPA; following transfection in neuroblastoma cells and NGF treatment, decreased percentage of cells differentiated into neuronal phenotype and reduced neurite length compared with wild-type; slightly decreased N-glycosylation; reduced expression at the plasma membrane; reduced basal and NGF-induced autophosphorylation; small reduction in NGF-stimulated calcium flux. 1 Publication1
Natural variantiVAR_077480771R → C in CIPA; partially decreased N-glycosylation; reduced expression at the plasma membrane; reduced basal autophosphorylation and complete loss of NGF-induced autophosphorylation; loss of NGF-stimulated calcium flux. 1 Publication1
Natural variantiVAR_009635780R → P in CIPA; loss of function. 1 PublicationCorresponds to variant dbSNP:rs35669708Ensembl.1
Chromosomal aberrations involving NTRK1 are found in papillary thyroid carcinomas (PTCs) (PubMed:2869410, PubMed:7565764, PubMed:1532241). Translocation t(1;3)(q21;q11) with TFG generates the TRKT3 (TRK-T3) transcript by fusing TFG to the 3'-end of NTRK1 (PubMed:7565764). A rearrangement with TPM3 generates the TRK transcript by fusing TPM3 to the 3'-end of NTRK1 (PubMed:2869410). An intrachromosomal rearrangement that links the protein kinase domain of NTRK1 to the 5'-end of the TPR gene forms the fusion protein TRK-T1. TRK-T1 is a 55 kDa protein reacting with antibodies against the C-terminus of the NTRK1 protein (PubMed:1532241).3 Publications

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi496Y → F: Loss of interaction with SHC1 and altered phosphorylation of SHC1. Altered neurite outgrowth and altered activation of the MAPK pathway; when associated with F-791. 1 Publication1
Mutagenesisi544K → N: Loss of kinase activity. 2 Publications1
Mutagenesisi791Y → F: Loss of interaction with PLCG1 and altered phosphorylation of PLCG1. Altered neurite outgrowth and altered activation of the MAPK pathway; when associated with F-496. 2 Publications1

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sitei398 – 399Breakpoint for translocation to form TRK and TRK-T32
Sitei486Breakpoint for translocation to form TRK-T11

Keywords - Diseasei

Disease mutation, Proto-oncogene

Organism-specific databases

DisGeNETi4914.
MalaCardsiNTRK1.
MIMi256800. phenotype.
OpenTargetsiENSG00000198400.
Orphaneti99361. Familial medullary thyroid carcinoma.
642. Hereditary sensory and autonomic neuropathy type 4.
64752. Hereditary sensory and autonomic neuropathy type 5.
146. Papillary or follicular thyroid carcinoma.
PharmGKBiPA31817.

Chemistry databases

ChEMBLiCHEMBL2815.
DrugBankiDB00321. Amitriptyline.
DB00619. Imatinib.
DB08896. Regorafenib.
GuidetoPHARMACOLOGYi1817.

Polymorphism and mutation databases

BioMutaiNTRK1.
DMDMi94730402.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Signal peptidei1 – 32Sequence analysisAdd BLAST32
ChainiPRO_000001672433 – 796High affinity nerve growth factor receptorAdd BLAST764

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Disulfide bondi36 ↔ 41Combined sources
Disulfide bondi40 ↔ 50Combined sources
Glycosylationi67N-linked (GlcNAc...) asparagineSequence analysis1
Glycosylationi95N-linked (GlcNAc...) asparagine1 Publication1
Glycosylationi121N-linked (GlcNAc...) asparagine1 Publication1
Disulfide bondi154 ↔ 191PROSITE-ProRule annotationCombined sources1 Publication
Glycosylationi188N-linked (GlcNAc...) asparagineCombined sources1 Publication1
Glycosylationi202N-linked (GlcNAc...) asparagineSequence analysis1
Disulfide bondi215 ↔ 265PROSITE-ProRule annotationCombined sources1 Publication
Glycosylationi253N-linked (GlcNAc...) asparagineSequence analysis1
Glycosylationi262N-linked (GlcNAc...) asparagineCombined sources1 Publication1
Glycosylationi281N-linked (GlcNAc...) asparagineCombined sources1 Publication1
Disulfide bondi300 ↔ 345Combined sources
Glycosylationi318N-linked (GlcNAc...) asparagineSequence analysis1
Glycosylationi323N-linked (GlcNAc...) asparagineSequence analysis1
Glycosylationi338N-linked (GlcNAc...) asparagineSequence analysis1
Glycosylationi358N-linked (GlcNAc...) asparagineCombined sources1 Publication1
Glycosylationi401N-linked (GlcNAc...) asparagineSequence analysis1
Modified residuei496Phosphotyrosine; by autocatalysis3 Publications1
Modified residuei676Phosphotyrosine; by autocatalysis1 Publication1
Modified residuei680Phosphotyrosine; by autocatalysis1 Publication1
Modified residuei681Phosphotyrosine; by autocatalysis1 Publication1
Modified residuei791Phosphotyrosine; by autocatalysis3 Publications1

Post-translational modificationi

Ligand-mediated autophosphorylation (PubMed:2927393, PubMed:1281417, PubMed:15488758, PubMed:7510697, PubMed:8155326, PubMed:8325889, PubMed:27676246). Interaction with SQSTM1 is phosphotyrosine-dependent. Autophosphorylation at Tyr-496 mediates interaction and phosphorylation of SHC1 (PubMed:15488758, PubMed:7510697, PubMed:8155326, PubMed:8325889).7 Publications
N-glycosylated (PubMed:2927393). Isoform TrkA-I and isoform TrkA-II are N-glycosylated.4 Publications
Ubiquitinated. Undergoes polyubiquitination upon activation; regulated by NGFR. Ubiquitination regulates the internalization of the receptor.By similarity

Keywords - PTMi

Disulfide bond, Glycoprotein, Phosphoprotein, Ubl conjugation

Proteomic databases

PaxDbiP04629.
PeptideAtlasiP04629.
PRIDEiP04629.

PTM databases

iPTMnetiP04629.
PhosphoSitePlusiP04629.

Expressioni

Tissue specificityi

Isoform TrkA-I is found in most non-neuronal tissues. Isoform TrkA-II is primarily expressed in neuronal cells. TrkA-III is specifically expressed by pluripotent neural stem and neural crest progenitors.2 Publications

Inductioni

Isoform TrkA-III is up-regulated upon hypoxia in cells normally expressing it.1 Publication

Gene expression databases

BgeeiENSG00000198400.
ExpressionAtlasiP04629. baseline and differential.
GenevisibleiP04629. HS.

Organism-specific databases

HPAiCAB004606.
HPA035799.
HPA076570.

Interactioni

Subunit structurei

Exists in a dynamic equilibrium between monomeric (low affinity) and dimeric (high affinity) structures. Homodimerization is induced by binding of a NGF dimer (PubMed:1281417, PubMed:10490030, PubMed:17196528). Interacts with SQSTM1; bridges NTRK1 to NGFR (PubMed:11244088). 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 (By similarity). Interacts with SH2D1A; regulates NTRK1 (By similarity). Interacts (phosphorylated upon activation by NGF) with SHC1; mediates SHC1 phosphorylation and activation (PubMed:8155326, PubMed:15488758). Interacts (phosphorylated upon activation by NGF) with PLCG1; mediates PLCG1 phosphorylation and activation (PubMed:7510697, PubMed:15488758). Interacts (phosphorylated) with SH2B1 and SH2B2 (By similarity). Interacts with GRB2 (PubMed:15488758). Interacts with PIK3R1 (PubMed:15488758). Interacts with FRS2 (PubMed:15488758). Interacts with SORT1; may regulate NTRK1 anterograde axonal transport (PubMed:21102451). Interacts with RAB7A (By similarity). Found in a complex, at least composed of KIDINS220, MAGI2, NTRK1 and RAPGEF2; the complex is mainly formed at late endosomes in a nerve growth factor (NGF)-dependent manner (By similarity). Interacts with RAPGEF2; the interaction is strengthened after NGF stimulation (By similarity). Interacts with PTPRS (By similarity).By similarity9 Publications

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sitei496Interaction with SHC11
Sitei791Interaction with PLCG11

Binary interactionsi

Show more details

GO - Molecular functioni

  • kinase binding Source: Ensembl
  • nerve growth factor binding Source: UniProtKB
  • neurotrophin binding Source: ProtInc
  • neurotrophin p75 receptor binding Source: Ensembl
  • protein homodimerization activity Source: UniProtKB
Complete GO annotation...

Protein-protein interaction databases

BioGridi110969. 1942 interactors.
DIPiDIP-5714N.
IntActiP04629. 17 interactors.
MINTiMINT-124106.
STRINGi9606.ENSP00000431418.

Chemistry databases

BindingDBiP04629.

Structurei

Secondary structure

1796
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Beta strandi38 – 40Combined sources3
Beta strandi43 – 46Combined sources4
Turni57 – 61Combined sources5
Beta strandi69 – 72Combined sources4
Helixi84 – 86Combined sources3
Beta strandi94 – 97Combined sources4
Helixi110 – 112Combined sources3
Beta strandi119 – 121Combined sources3
Turni133 – 135Combined sources3
Beta strandi142 – 144Combined sources3
Helixi154 – 156Combined sources3
Helixi157 – 164Combined sources8
Helixi171 – 173Combined sources3
Beta strandi178 – 181Combined sources4
Beta strandi195 – 199Combined sources5
Beta strandi211 – 218Combined sources8
Beta strandi227 – 230Combined sources4
Beta strandi234 – 238Combined sources5
Beta strandi244 – 253Combined sources10
Turni257 – 260Combined sources4
Beta strandi263 – 265Combined sources3
Beta strandi276 – 278Combined sources3
Beta strandi284 – 290Combined sources7
Beta strandi298 – 305Combined sources8
Beta strandi312 – 317Combined sources6
Beta strandi326 – 333Combined sources8
Beta strandi342 – 350Combined sources9
Helixi353 – 355Combined sources3
Beta strandi357 – 365Combined sources9
Beta strandi368 – 376Combined sources9
Helixi418 – 441Combined sources24
Beta strandi476 – 478Combined sources3
Helixi490 – 492Combined sources3
Turni494 – 496Combined sources3
Helixi507 – 509Combined sources3
Beta strandi510 – 517Combined sources8
Beta strandi520 – 522Combined sources3
Beta strandi524 – 533Combined sources10
Turni534 – 536Combined sources3
Beta strandi537 – 545Combined sources9
Helixi552 – 566Combined sources15
Beta strandi575 – 579Combined sources5
Beta strandi581 – 584Combined sources4
Beta strandi586 – 590Combined sources5
Helixi597 – 603Combined sources7
Beta strandi605 – 607Combined sources3
Helixi608 – 611Combined sources4
Beta strandi615 – 617Combined sources3
Beta strandi619 – 621Combined sources3
Helixi624 – 643Combined sources20
Beta strandi646 – 648Combined sources3
Helixi653 – 655Combined sources3
Beta strandi656 – 659Combined sources4
Helixi660 – 662Combined sources3
Beta strandi663 – 666Combined sources4
Helixi672 – 675Combined sources4
Helixi677 – 679Combined sources3
Beta strandi680 – 683Combined sources4
Turni684 – 686Combined sources3
Beta strandi687 – 689Combined sources3
Helixi691 – 693Combined sources3
Helixi696 – 701Combined sources6
Helixi706 – 721Combined sources16
Turni722 – 724Combined sources3
Turni727 – 730Combined sources4
Helixi733 – 742Combined sources10
Helixi754 – 763Combined sources10
Helixi768 – 770Combined sources3
Helixi774 – 786Combined sources13
Helixi789 – 793Combined sources5

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
1HE7X-ray2.00A285-413[»]
1SHCNMR-B489-500[»]
1WWAX-ray2.50X/Y278-386[»]
1WWWX-ray2.20X/Y282-382[»]
2IFGX-ray3.40A/B36-382[»]
2N90NMR-A/B410-447[»]
4AOJX-ray2.75A/B/C473-796[»]
4CRPNMR-A282-383[»]
4F0IX-ray2.30A/B498-796[»]
4GT5X-ray2.40A498-796[»]
4PMMX-ray2.00A501-787[»]
4PMPX-ray1.80A501-787[»]
4PMSX-ray2.80A501-787[»]
4PMTX-ray2.10A501-787[»]
4YNEX-ray2.02A502-796[»]
4YPSX-ray2.10A502-796[»]
5H3QX-ray2.10A473-796[»]
5JFSX-ray2.07A502-796[»]
5JFVX-ray1.59A502-796[»]
5JFWX-ray1.52A502-796[»]
5JFXX-ray1.63A502-796[»]
5KMIX-ray1.87A474-796[»]
5KMJX-ray2.04A474-796[»]
5KMKX-ray2.24A474-796[»]
5KMLX-ray2.01A474-796[»]
5KMMX-ray2.12A474-796[»]
5KMNX-ray2.14A474-796[»]
5KMOX-ray2.67A474-796[»]
ProteinModelPortaliP04629.
SMRiP04629.
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiP04629.

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Repeati90 – 113LRR 1Add BLAST24
Repeati116 – 137LRR 2Add BLAST22
Domaini148 – 193LRRCTAdd BLAST46
Domaini194 – 283Ig-like C2-type 1PROSITE-ProRule annotationAdd BLAST90
Domaini299 – 365Ig-like C2-type 2PROSITE-ProRule annotationAdd BLAST67
Domaini510 – 781Protein kinasePROSITE-ProRule annotationAdd BLAST272

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni469 – 490Interaction with SQSTM1By similarityAdd BLAST22

Domaini

The transmembrane domain mediates interaction with KIDINS220.By similarity
The extracellular domain mediates interaction with NGFR.By similarity

Sequence similaritiesi

Belongs to the protein kinase superfamily. Tyr protein kinase family. Insulin receptor subfamily.PROSITE-ProRule annotation

Keywords - Domaini

Immunoglobulin domain, Leucine-rich repeat, Repeat, Signal, Transmembrane, Transmembrane helix

Phylogenomic databases

eggNOGiENOG410IMMI. Eukaryota.
ENOG410XTGG. LUCA.
GeneTreeiENSGT00760000118818.
HOVERGENiHBG056735.
InParanoidiP04629.
KOiK03176.
OMAiPEVYAIM.
OrthoDBiEOG091G01JY.
PhylomeDBiP04629.
TreeFamiTF106465.

Family and domain databases

Gene3Di2.60.40.10. 2 hits.
3.80.10.10. 1 hit.
InterProiView protein in InterPro
IPR000483. Cys-rich_flank_reg_C.
IPR007110. Ig-like_dom.
IPR013783. Ig-like_fold.
IPR011009. Kinase-like_dom.
IPR032675. L_dom-like.
IPR001611. Leu-rich_rpt.
IPR031635. NTRK_C2.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR001245. Ser-Thr/Tyr_kinase_cat_dom.
IPR008266. Tyr_kinase_AS.
IPR020635. Tyr_kinase_cat_dom.
IPR020461. Tyr_kinase_neurotrophic_rcpt_1.
IPR020777. Tyr_kinase_NGF_rcpt.
IPR002011. Tyr_kinase_rcpt_2_CS.
PfamiView protein in Pfam
PF13855. LRR_8. 1 hit.
PF07714. Pkinase_Tyr. 1 hit.
PF16920. TPKR_C2. 1 hit.
PRINTSiPR01939. NTKRECEPTOR.
PR01940. NTKRECEPTOR1.
PR00109. TYRKINASE.
SMARTiView protein in SMART
SM00082. LRRCT. 1 hit.
SM00219. TyrKc. 1 hit.
SUPFAMiSSF48726. SSF48726. 2 hits.
SSF52058. SSF52058. 1 hit.
SSF56112. SSF56112. 1 hit.
PROSITEiView protein in PROSITE
PS50835. IG_LIKE. 1 hit.
PS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00109. PROTEIN_KINASE_TYR. 1 hit.
PS00239. RECEPTOR_TYR_KIN_II. 1 hit.

Sequences (4)i

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

This entry describes 4 isoformsi produced by alternative splicing. AlignAdd to basket

Note: TrkA-I and TrkA-II isoforms have similar biological properties but are differentially expressed.
Isoform TrkA-II (identifier: P04629-1) [UniParc]FASTAAdd to basket
Also known as: TrkAII

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

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        10         20         30         40         50
MLRGGRRGQL GWHSWAAGPG SLLAWLILAS AGAAPCPDAC CPHGSSGLRC 
        60         70         80         90        100
TRDGALDSLH HLPGAENLTE LYIENQQHLQ HLELRDLRGL GELRNLTIVK 
       110        120        130        140        150
SGLRFVAPDA FHFTPRLSRL NLSFNALESL SWKTVQGLSL QELVLSGNPL 
       160        170        180        190        200
HCSCALRWLQ RWEEEGLGGV PEQKLQCHGQ GPLAHMPNAS CGVPTLKVQV 
       210        220        230        240        250
PNASVDVGDD VLLRCQVEGR GLEQAGWILT ELEQSATVMK SGGLPSLGLT 
       260        270        280        290        300
LANVTSDLNR KNVTCWAEND VGRAEVSVQV NVSFPASVQL HTAVEMHHWC 
       310        320        330        340        350
IPFSVDGQPA PSLRWLFNGS VLNETSFIFT EFLEPAANET VRHGCLRLNQ 
       360        370        380        390        400
PTHVNNGNYT LLAANPFGQA SASIMAAFMD NPFEFNPEDP IPVSFSPVDT 
       410        420        430        440        450
NSTSGDPVEK KDETPFGVSV AVGLAVFACL FLSTLLLVLN KCGRRNKFGI 
       460        470        480        490        500
NRPAVLAPED GLAMSLHFMT LGGSSLSPTE GKGSGLQGHI IENPQYFSDA 
       510        520        530        540        550
CVHHIKRRDI VLKWELGEGA FGKVFLAECH NLLPEQDKML VAVKALKEAS 
       560        570        580        590        600
ESARQDFQRE AELLTMLQHQ HIVRFFGVCT EGRPLLMVFE YMRHGDLNRF 
       610        620        630        640        650
LRSHGPDAKL LAGGEDVAPG PLGLGQLLAV ASQVAAGMVY LAGLHFVHRD 
       660        670        680        690        700
LATRNCLVGQ GLVVKIGDFG MSRDIYSTDY YRVGGRTMLP IRWMPPESIL 
       710        720        730        740        750
YRKFTTESDV WSFGVVLWEI FTYGKQPWYQ LSNTEAIDCI TQGRELERPR 
       760        770        780        790 
ACPPEVYAIM RGCWQREPQQ RHSIKDVHAR LQALAQAPPV YLDVLG
Note: Major isoform.
Length:796
Mass (Da):87,497
Last modified:May 2, 2006 - v4
Checksum:i6C15C721E336B601
GO
Isoform TrkA-I (identifier: P04629-2) [UniParc]FASTAAdd to basket
Also known as: TrkAI

The sequence of this isoform differs from the canonical sequence as follows:
     393-398: Missing.

Note: Has enhanced responsiveness to NTF3 neurotrophin.
Show »
Length:790
Mass (Da):86,880
Checksum:i25F05BADA8A2A50C
GO
Isoform 3 (identifier: P04629-3) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     1-71: MLRGGRRGQL...LPGAENLTEL → MKEAALICLA...SRCTNLLAAS
     393-398: Missing.

Show »
Length:760
Mass (Da):83,993
Checksum:i2452CA9C211243C9
GO
Isoform TrkA-III (identifier: P04629-4) [UniParc]FASTAAdd to basket
Also known as: TrkAIII

The sequence of this isoform differs from the canonical sequence as follows:
     192-284: GVPTLKVQVP...EVSVQVNVSF → V
     393-398: Missing.

Note: Constitutively active. Does not bind NGF and does not interact with GRB2 and FRS2.
Show »
Length:698
Mass (Da):77,145
Checksum:i580555F90386A5A7
GO

Sequence cautioni

The sequence CAA27243 differs from that shown. Contaminating sequence. Sequence of unknown origin in the N-terminal part.Curated
The sequence CAA27243 differs from that shown. Reason: Frameshift at position 769.Curated
The sequence CAA27243 differs from that shown. Reason: Erroneous termination at position 786. Translated as Gln.Curated
The sequence CAA29888 differs from that shown. Contaminating sequence. Sequence of unknown origin in the N-terminal part.Curated
The sequence CAA44719 differs from that shown. Contaminating sequence. Sequence of unknown origin in the N-terminal part.Curated
The sequence CAA59936 differs from that shown. Contaminating sequence. Sequence of unknown origin in the N-terminal part.Curated

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti263V → L in AAA36770 (PubMed:2927393).Curated1
Sequence conflicti300C → S in AAA36770 (PubMed:2927393).Curated1
Sequence conflicti529C → S in CAA59936 (PubMed:7565764).Curated1

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_0684806R → W1 PublicationCorresponds to variant dbSNP:rs201472270Ensembl.1
Natural variantiVAR_04971418G → E. Corresponds to variant dbSNP:rs1007211Ensembl.1
Natural variantiVAR_04146180Q → R1 PublicationCorresponds to variant dbSNP:rs55891455Ensembl.1
Natural variantiVAR_00962385R → S2 PublicationsCorresponds to variant dbSNP:rs543320028Ensembl.1
Natural variantiVAR_00962493L → P in CIPA; aberrantly processed; shows diminished autophosphorylation in neuronal cells. 2 Publications1
Natural variantiVAR_041462107A → V in an ovarian serous carcinoma sample; somatic mutation. 1 PublicationCorresponds to variant dbSNP:rs540521894Ensembl.1
Natural variantiVAR_009625213L → P in CIPA; aberrantly processed; shows diminished autophosphorylation in neuronal cells. 2 PublicationsCorresponds to variant dbSNP:rs747711259Ensembl.1
Natural variantiVAR_041463237T → M1 PublicationCorresponds to variant dbSNP:rs55909005Ensembl.1
Natural variantiVAR_041464238V → G1 PublicationCorresponds to variant dbSNP:rs56000394Ensembl.1
Natural variantiVAR_041465260R → G1 PublicationCorresponds to variant dbSNP:rs35116695Ensembl.1
Natural variantiVAR_068481359Y → C in CIPA. 1 PublicationCorresponds to variant dbSNP:rs121964869Ensembl.1
Natural variantiVAR_041466444R → Q1 PublicationCorresponds to variant dbSNP:rs56320207Ensembl.1
Natural variantiVAR_041467452R → C1 PublicationCorresponds to variant dbSNP:rs34900547Ensembl.1
Natural variantiVAR_068482492E → K in CIPA. 1 PublicationCorresponds to variant dbSNP:rs144901788Ensembl.1
Natural variantiVAR_077472517G → E in CIPA; following transfection in neuroblastoma cells and NGF treatment, small decrease in the percentage of cells differentiated into neuronal phenotype, but in differentiated cells, the average neurite length is comparable to wild-type; no effect on N-glycosylation, subcellular location, nor on basal and NGF-induced autophosphorylation; loss of NGF-stimulated calcium flux. 1 PublicationCorresponds to variant dbSNP:rs606231467Ensembl.1
Natural variantiVAR_077473522G → E in CIPA; no effect on N-glycosylation, nor on subcellular location; reduced basal autophosphorylation and complete loss of NGF-induced autophosphorylation; loss of NGF-stimulated calcium flux. 1 Publication1
Natural variantiVAR_009626522G → R in CIPA; processed as wild-type but shows significantly diminished autophosphorylation in both neuronal and non-neuronal cells. 2 Publications1
Natural variantiVAR_041468566M → T1 PublicationCorresponds to variant dbSNP:rs55892037Ensembl.1
Natural variantiVAR_077474572I → S in CIPA. 1 Publication1
Natural variantiVAR_004103577G → R in CIPA; loss of function; processed as wild-type but shows significantly diminished autophosphorylation in both neuronal and non-neuronal cells. 4 PublicationsCorresponds to variant dbSNP:rs121964866Ensembl.1
Natural variantiVAR_009627587M → V in CIPA. 1 PublicationCorresponds to variant dbSNP:rs121964870Ensembl.1
Natural variantiVAR_009628604H → Y6 PublicationsCorresponds to variant dbSNP:rs6336Ensembl.1
Natural variantiVAR_009629613G → V7 PublicationsCorresponds to variant dbSNP:rs6339Ensembl.1
Natural variantiVAR_009630649R → W in CIPA; processed as wild-type but shows significantly diminished autophosphorylation in both neuronal and non-neuronal cells. 2 PublicationsCorresponds to variant dbSNP:rs369353892Ensembl.1
Natural variantiVAR_009631654R → C in CIPA; processed as wild-type but shows significantly diminished autophosphorylation in both neuronal and non-neuronal cells. 3 PublicationsCorresponds to variant dbSNP:rs764992664Ensembl.1
Natural variantiVAR_077475657L → P in CIPA; following transfection in neuroblastoma cells and NGF treatment, loss of differentiation into neuronal phenotype; partially decreased N-glycosylation; reduced expression at the plasma membrane; reduced basal autophosphorylation and complete loss of NGF-induced autophosphorylation; loss of NGF-stimulated calcium flux. 1 Publication1
Natural variantiVAR_009632674D → Y in CIPA; unknown pathological significance; might impair the function of the enzyme without compromising autophosphorylation. 2 PublicationsCorresponds to variant dbSNP:rs80356677Ensembl.1
Natural variantiVAR_009633695P → L in CIPA. 1 PublicationCorresponds to variant dbSNP:rs121964868Ensembl.1
Natural variantiVAR_077476699I → T in CIPA; partially decreased N-glycosylation; reduced expression at the plasma membrane; reduced basal autophosphorylation and complete loss of NGF-induced autophosphorylation; loss of NGF-stimulated calcium flux. 1 Publication1
Natural variantiVAR_009634714G → S in CIPA; processed as wild-type but shows significantly diminished autophosphorylation in both neuronal and non-neuronal cells. 2 PublicationsCorresponds to variant dbSNP:rs770727871Ensembl.1
Natural variantiVAR_077477717L → R in CIPA; found in a compound heterozygote also carrying an premature stop codon at position 558. 1 Publication1
Natural variantiVAR_077478752C → S in CIPA; unknown pathological significance; following transfection in neuroblastoma cells and NGF treatment, no effect on neurite outgrowth, nor neurite length; no effect on N-glycosylation, subcellular location, basal and NGF-induced autophosphorylation, nor on NGF-stimulated calcium flux. 1 Publication1
Natural variantiVAR_077479763C → S in CIPA; following transfection in neuroblastoma cells and NGF treatment, decreased percentage of cells differentiated into neuronal phenotype and reduced neurite length compared with wild-type; slightly decreased N-glycosylation; reduced expression at the plasma membrane; reduced basal and NGF-induced autophosphorylation; small reduction in NGF-stimulated calcium flux. 1 Publication1
Natural variantiVAR_077480771R → C in CIPA; partially decreased N-glycosylation; reduced expression at the plasma membrane; reduced basal autophosphorylation and complete loss of NGF-induced autophosphorylation; loss of NGF-stimulated calcium flux. 1 Publication1
Natural variantiVAR_009635780R → P in CIPA; loss of function. 1 PublicationCorresponds to variant dbSNP:rs35669708Ensembl.1
Natural variantiVAR_009636780R → Q2 PublicationsCorresponds to variant dbSNP:rs35669708Ensembl.1
Natural variantiVAR_041469790V → I1 PublicationCorresponds to variant dbSNP:rs55948542Ensembl.1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_0419051 – 71MLRGG…NLTEL → MKEAALICLAPSVPPILTVK SWDTMQLRAARSRCTNLLAA S in isoform 3. 1 PublicationAdd BLAST71
Alternative sequenceiVSP_042152192 – 284GVPTL…VNVSF → V in isoform TrkA-III. CuratedAdd BLAST93
Alternative sequenceiVSP_002899393 – 398Missing in isoform TrkA-I, isoform 3 and isoform TrkA-III. 3 Publications6

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
M23102 mRNA. Translation: AAA36770.1.
AB019488 Genomic DNA. Translation: BAA34355.1.
AK312704 mRNA. Translation: BAG35582.1.
DB265639 mRNA. No translation available.
AL158169 Genomic DNA. Translation: CAH70010.1.
BC062580 mRNA. Translation: AAH62580.1.
BC136554 mRNA. Translation: AAI36555.1.
BC144239 mRNA. Translation: AAI44240.1.
AY321513 Genomic DNA. Translation: AAP88292.1.
X03541 mRNA. Translation: CAA27243.1. Sequence problems.
X06704 mRNA. Translation: CAA29888.1. Sequence problems.
X85960 mRNA. Translation: CAA59936.1. Sequence problems.
X62947 mRNA. Translation: CAA44719.1. Sequence problems.
CCDSiCCDS1161.1. [P04629-1]
CCDS30890.1. [P04629-3]
CCDS30891.1. [P04629-2]
PIRiA30124. TVHUTT.
S23741.
RefSeqiNP_001007793.1. NM_001007792.1. [P04629-3]
NP_001012331.1. NM_001012331.1. [P04629-2]
NP_002520.2. NM_002529.3. [P04629-1]
UniGeneiHs.406293.

Genome annotation databases

EnsembliENST00000368196; ENSP00000357179; ENSG00000198400. [P04629-2]
ENST00000392302; ENSP00000376120; ENSG00000198400. [P04629-3]
ENST00000524377; ENSP00000431418; ENSG00000198400. [P04629-1]
GeneIDi4914.
KEGGihsa:4914.
UCSCiuc001fqf.2. human. [P04629-1]

Keywords - Coding sequence diversityi

Alternative splicing, Chromosomal rearrangement, Polymorphism

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.

Entry informationi

Entry nameiNTRK1_HUMAN
AccessioniPrimary (citable) accession number: P04629
Secondary accession number(s): B2R6T5
, B7ZM34, P08119, Q15655, Q15656, Q5D056, Q5VZS2, Q7Z5C3, Q9UIU7
Entry historyiIntegrated into UniProtKB/Swiss-Prot: August 13, 1987
Last sequence update: May 2, 2006
Last modified: June 7, 2017
This is version 225 of the entry and version 4 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome

Documents

  1. Human chromosome 1
    Human chromosome 1: entries, gene names and cross-references to MIM
  2. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  3. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  4. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  5. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  6. Human and mouse protein kinases
    Human and mouse protein kinases: classification and index
  7. SIMILARITY comments
    Index of protein domains and families