Q3UFB7 (NTRK1_MOUSE) Reviewed, UniProtKB/Swiss-Prot
Last modified April 16, 2014. Version 89. History...
Names and origin
|Protein names||Recommended name:|
High affinity nerve growth factor receptor
Neurotrophic tyrosine kinase receptor type 1
|Organism||Mus musculus (Mouse) [Reference proteome]|
|Taxonomic identifier||10090 [NCBI]|
|Taxonomic lineage||Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Mus › Mus|
|Sequence length||799 AA.|
|Sequence processing||The displayed sequence is further processed into a mature form.|
|Protein existence||Evidence at protein level|
General annotation (Comments)
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. Ref.2 Ref.3 Ref.6
ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate.
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. Ref.4 Ref.5 Ref.6
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. 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. Ref.5
Cell membrane; Single-pass type I membrane protein By similarity. Early endosome membrane; Single-pass type I membrane protein. Late endosome membrane; Single-pass type I membrane protein By similarity. Note: 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 By similarity. Internalized to endosomes upon binding of NGF or NTF3 and further transported to the cell body via a retrograde axonal transport. Ref.6
First detected at E13.5, a time coinciding with the requirement of sympathetic neurons for NGF. Ref.3
The transmembrane domain mediates interaction with KIDINS220 By similarity.
The extracellular domain mediates interaction with NGFR By similarity.
Ligand-mediated autophosphorylation. Interaction with SQSTM1 is phosphotyrosine-dependent. Autophosphorylation at Tyr-499 mediates interaction and phosphorylation of SHC1.
N-glycosylated By similarity.
Ubiquitinated. Undergoes polyubiquitination upon activation; regulated by NGFR. Ubiquitination regulates the internalization of the receptor. Ref.4
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 ganglion, a major component of the sympathetic system. Ref.2
Contains 2 Ig-like C2-type (immunoglobulin-like) domains.
Contains 2 LRR (leucine-rich) repeats.
Contains 1 LRRCT domain.
Contains 1 protein kinase domain.
The sequence BAE28644.1 differs from that shown. Reason: Erroneous initiation.
Sequence annotation (Features)
|Feature key||Position(s)||Length||Description||Graphical view||Feature identifier|
|Signal peptide||1 – 33||33||Potential|
|Chain||34 – 799||766||High affinity nerve growth factor receptor||PRO_0000278537|
|Topological domain||34 – 420||387||Extracellular Potential|
|Transmembrane||421 – 441||21||Helical; Potential|
|Topological domain||442 – 799||358||Cytoplasmic Potential|
|Repeat||90 – 113||24||LRR 1|
|Repeat||116 – 137||22||LRR 2|
|Domain||148 – 219||72||LRRCT|
|Domain||196 – 285||90||Ig-like C2-type 1|
|Domain||205 – 368||164||Ig-like C2-type 2|
|Domain||513 – 784||272||Protein kinase|
|Nucleotide binding||519 – 527||9||ATP By similarity|
|Region||472 – 493||22||Interaction with SQSTM1 By similarity|
|Active site||653||1||Proton acceptor By similarity|
|Binding site||547||1||ATP By similarity|
|Site||499||1||Interaction with SHC1 By similarity|
|Site||794||1||Interaction with PLCG1 By similarity|
Amino acid modifications
|Modified residue||499||1||Phosphotyrosine; by autocatalysis By similarity|
|Modified residue||679||1||Phosphotyrosine; by autocatalysis By similarity|
|Modified residue||683||1||Phosphotyrosine; by autocatalysis By similarity|
|Modified residue||684||1||Phosphotyrosine; by autocatalysis By similarity|
|Modified residue||794||1||Phosphotyrosine; by autocatalysis By similarity|
|Glycosylation||67||1||N-linked (GlcNAc...) Potential|
|Glycosylation||121||1||N-linked (GlcNAc...) Potential|
|Glycosylation||190||1||N-linked (GlcNAc...) Potential|
|Glycosylation||204||1||N-linked (GlcNAc...) Potential|
|Glycosylation||255||1||N-linked (GlcNAc...) Potential|
|Glycosylation||264||1||N-linked (GlcNAc...) Potential|
|Glycosylation||320||1||N-linked (GlcNAc...) Potential|
|Glycosylation||325||1||N-linked (GlcNAc...) Potential|
|Glycosylation||341||1||N-linked (GlcNAc...) Potential|
|Glycosylation||361||1||N-linked (GlcNAc...) Potential|
|Glycosylation||404||1||N-linked (GlcNAc...) Potential|
|Disulfide bond||154 ↔ 193||By similarity|
|Disulfide bond||217 ↔ 267||By similarity|
|||"The transcriptional landscape of the mammalian genome."|
Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N., Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K., Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J. Hayashizaki Y.
Science 309:1559-1563(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
Tissue: Embryo and Sympathetic ganglion.
|||"Severe sensory and sympathetic neuropathies in mice carrying a disrupted Trk/NGF receptor gene."|
Smeyne R.J., Klein R., Schnapp A., Long L.K., Bryant S., Lewin A., Lira S.A., Barbacid M.
Nature 368:246-249(1994) [PubMed] [Europe PMC] [Abstract]
Cited for: DISRUPTION PHENOTYPE, FUNCTION IN DEVELOPMENT OF THE NERVOUS SYSTEM.
|||"TrkA, but not TrkC, receptors are essential for survival of sympathetic neurons in vivo."|
Fagan A.M., Zhang H., Landis S., Smeyne R.J., Silos-Santiago I., Barbacid M.
J. Neurosci. 16:6208-6218(1996) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN SYMPATHETIC NEURONS SURVIVAL, DEVELOPMENTAL STAGE.
|||"p75 neurotrophin receptor reduces ligand-induced Trk receptor ubiquitination and delays Trk receptor internalization and degradation."|
Makkerh J.P., Ceni C., Auld D.S., Vaillancourt F., Dorval G., Barker P.A.
EMBO Rep. 6:936-941(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: UBIQUITINATION, ENZYME REGULATION.
|||"SLAM-associated protein as a potential negative regulator in Trk signaling."|
Lo K.Y., Chin W.H., Ng Y.P., Cheng A.W., Cheung Z.H., Ip N.Y.
J. Biol. Chem. 280:41744-41752(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: ENZYME REGULATION, INTERACTION WITH SH2D1A.
|||"Recruitment of actin modifiers to TrkA endosomes governs retrograde NGF signaling and survival."|
Harrington A.W., St Hillaire C., Zweifel L.S., Glebova N.O., Philippidou P., Halegoua S., Ginty D.D.
Cell 146:421-434(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN NGF AND NTF3 SIGNALING, ENZYME REGULATION, SUBCELLULAR LOCATION.
|+||Additional computationally mapped references.|
|AK081588 mRNA. No translation available.|
AK148691 mRNA. Translation: BAE28644.1. Different initiation.
|RefSeq||NP_001028296.1. NM_001033124.1. |
3D structure databases
|SMR||Q3UFB7. Positions 36-391, 504-797. |
Protein-protein interaction databases
|BioGrid||201868. 7 interactions.|
Protocols and materials databases
Genome annotation databases
|Ensembl||ENSMUST00000029712; ENSMUSP00000029712; ENSMUSG00000028072. |
|UCSC||uc008psw.1. mouse. |
|MGI||MGI:97383. Ntrk1. |
Enzyme and pathway databases
|Reactome||REACT_188257. Signal Transduction. |
Gene expression databases
Family and domain databases
|Gene3D||22.214.171.124. 2 hits. |
|InterPro||IPR007110. Ig-like_dom. |
|Pfam||PF07714. Pkinase_Tyr. 1 hit. |
|PRINTS||PR01939. NTKRECEPTOR. |
|SMART||SM00409. IG. 1 hit. |
SM00219. TyrKc. 1 hit.
|SUPFAM||SSF56112. SSF56112. 1 hit. |
|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.
|Accession||Primary (citable) accession number: Q3UFB7|
|Entry status||Reviewed (UniProtKB/Swiss-Prot)|
|Annotation program||Chordata Protein Annotation Program|