InnateDB: Systems Biology of the Innate Immune Response

Homo sapiens Protein: NTRK1

Summary

InnateDB Protein

IDBP-103636.7

Last Modified

2014-10-13 [Report errors or provide feedback]

Gene Symbol

NTRK1

Protein Name

neurotrophic tyrosine kinase, receptor, type 1

Synonyms

MTC; p140-TrkA; TRK; Trk-A; TRK1; TRKA;

Species

Homo sapiens

Ensembl Protein

ENSP00000357179

InnateDB Gene

IDBG-103632 (NTRK1)

Protein Structure

UniProt Annotation

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.Isoform TrkA-III is resistant to NGF, 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.

Subcellular Localization

Cell membrane {ECO:0000269PubMed:15488758}; Single-pass type I membrane protein {ECO:0000269PubMed:15488758}. Early endosome membrane {ECO:0000250}; Single-pass type I membrane protein {ECO:0000250}. Late endosome membrane {ECO:0000250}; Single-pass type I membrane protein {ECO:0000250}. Note=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 (By similarity). {ECO:0000250}.

Disease Associations

Congenital insensitivity to pain with anhidrosis (CIPA) [MIM:256800]: 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. {ECO:0000269PubMed:10090906, ECO:0000269PubMed:10233776, ECO:0000269PubMed:10330344, ECO:0000269PubMed:10567924, ECO:0000269PubMed:10861667, ECO:0000269PubMed:10982191, ECO:0000269PubMed:11310631, ECO:0000269PubMed:22302274, ECO:0000269PubMed:8696348}. Note=The disease is caused by mutations affecting the gene represented in this entry.Thyroid papillary carcinoma (TPC) [MIM:188550]: A common tumor of the thyroid that typically arises as an irregular, solid or cystic mass from otherwise normal thyroid tissue. Papillary carcinomas are malignant neoplasm characterized by the formation of numerous, irregular, finger-like projections of fibrous stroma that is covered with a surface layer of neoplastic epithelial cells. Note=The gene represented in this entry is involved in disease pathogenesis. Chromosomal aberrations involving NTRK1 are found in thyroid papillary carcinomas. Translocation t(1;3)(q21;q11) with TFG generates the TRKT3 (TRK-T3) transcript by fusing TFG to the 3'-end of NTRK1; a rearrangement with TPM3 generates the TRK transcript by fusing TPM3 to the 3'-end of NTRK1; 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.

Tissue Specificity

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. {ECO:0000269PubMed:15488758, ECO:0000269PubMed:8325889}.

Comments

Interactions

Number of Interactions

This gene and/or its encoded proteins are associated with 65 experimentally validated interaction(s) in this database.
They are also associated with 8 interaction(s) predicted by orthology.

Experimentally validated
Total	65 [view]
Protein-Protein	62 [view]
Protein-DNA	2 [view]
Protein-RNA	0
DNA-DNA	1 [view]
RNA-RNA	0
DNA-RNA	0

Predicted by orthology
Total	8 [view]

Gene Ontology

Molecular Function

Accession	GO Term
GO:0004672	protein kinase activity
GO:0004713	protein tyrosine kinase activity
GO:0004714	transmembrane receptor protein tyrosine kinase activity
GO:0005515	protein binding
GO:0005524	ATP binding
GO:0010465	nerve growth factor receptor activity
GO:0016772	transferase activity, transferring phosphorus-containing groups
GO:0042803	protein homodimerization activity
GO:0043121	neurotrophin binding
GO:0048406	nerve growth factor binding

Biological Process

GO:0000186	activation of MAPKK activity
GO:0006468	protein phosphorylation
GO:0007169	transmembrane receptor protein tyrosine kinase signaling pathway
GO:0007190	activation of adenylate cyclase activity
GO:0007202	activation of phospholipase C activity
GO:0007264	small GTPase mediated signal transduction
GO:0007265	Ras protein signal transduction
GO:0008285	negative regulation of cell proliferation
GO:0010623	developmental programmed cell death
GO:0010976	positive regulation of neuron projection development
GO:0018108	peptidyl-tyrosine phosphorylation
GO:0032320	positive regulation of Ras GTPase activity
GO:0043068	positive regulation of programmed cell death
GO:0043524	negative regulation of neuron apoptotic process
GO:0045766	positive regulation of angiogenesis
GO:0046579	positive regulation of Ras protein signal transduction
GO:0046777	protein autophosphorylation
GO:0048011	neurotrophin TRK receptor signaling pathway
GO:0048015	phosphatidylinositol-mediated signaling
GO:0048485	sympathetic nervous system development
GO:0051092	positive regulation of NF-kappaB transcription factor activity
GO:0060385	axonogenesis involved in innervation
GO:0070374	positive regulation of ERK1 and ERK2 cascade
GO:1990090	cellular response to nerve growth factor stimulus

Cellular Component

GO:0005768	endosome
GO:0005769	early endosome
GO:0005770	late endosome
GO:0005886	plasma membrane
GO:0005887	integral component of plasma membrane
GO:0031901	early endosome membrane
GO:0031902	late endosome membrane
GO:0043234	protein complex
GO:0043235	receptor complex

Protein Structure and Domains

PDB ID

InterPro

IPR000483 Cysteine-rich flanking region, C-terminal
IPR000719 Protein kinase domain
IPR001245 Serine-threonine/tyrosine-protein kinase catalytic domain
IPR002290 Serine/threonine/dual specificity protein kinase, catalytic domain
IPR007110 Immunoglobulin-like domain
IPR011009 Protein kinase-like domain
IPR020461 Tyrosine-protein kinase, neurotrophic receptor, type 1
IPR020635 Tyrosine-protein kinase, catalytic domain
IPR020777 Tyrosine-protein kinase, neurotrophic receptor

PFAM

PF01463
PF00069
PF07714

PRINTS

PR00109
PR01940
PR01939

PIRSF

SMART

SM00082
SM00220
SM00219

TIGRFAMs

Post-translational Modifications

Modification

Cross-References

SwissProt