TRK-A Antibody – Mouse Monoclonal

This gene encodes a member of the neurotrophic tyrosine kinase receptor (NTKR) family. This kinase is a membrane-bound receptor that, upon neurotrophin binding, phosphorylates itself and members of the MAPK pathway. The presence of this kinase leads to cell differentiation and may play a role in specifying sensory neuron subtypes. Mutations in this gene have been associated with congenital insensitivity to pain, anhidrosis, self-mutilating behavior, mental retardation and cancer. Alternate transcriptional splice variants of this gene have been found, but only three have been characterized to date. [provided by RefSeq, Jul 2008]

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. Ref.12 Ref.13 Ref.14 Ref.16 Ref.17 Ref.18Isoform 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. Ref.12 Ref.13 Ref.14 Ref.16 Ref.17 Ref.18

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

By similarity. Regulated by NGFR

By similarity. Ref.19

Subunit structure: 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

By similarity. Interacts with SH2D1A; regulates NTRK1

By similarity. 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 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.15 Ref.16 Ref.17 Ref.18 Ref.19 Ref.23

Subcellular location: Cell membrane; Single-pass type I membrane protein. Early endosome membrane; Single-pass type I membrane protein

By similarity. Late endosome membrane; Single-pass type I membrane protein

By similarity. 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. Ref.18

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. Ref.14 Ref.18

Induction: Isoform TrkA-III is up-regulated upon hypoxia in cells normally expressing it. Ref.18 Ref.19

Domain: The transmembrane domain mediates interaction with KIDINS220

By similarity.The extracellular domain mediates interaction with NGFR

By similarity.

Post-translational modification: Ligand-mediated autophosphorylation. Interaction with SQSTM1 is phosphotyrosine-dependent. Autophosphorylation at Tyr-496 mediates interaction and phosphorylation of SHC1.N-glycosylated

Probable. Isoform TrkA-I is N-glycosylated. Ref.18 Ref.23Ubiquitinated. Undergoes polyubiquitination upon activation; regulated by NGFR. Ubiquitination regulates the internalization of the receptor

By similarity.

Involvement in disease: 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.Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.24 Ref.25 Ref.26 Ref.28 Ref.31 Ref.32 Ref.33 Ref.34 Ref.35 Ref.37Thyroid 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.

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.

Sequence similarities: Belongs to the protein kinase superfamily. Tyr protein kinase family. Insulin receptor subfamily.Contains 2 Ig-like C2-type (immunoglobulin-like) domains.Contains 2 LRR (leucine-rich) repeats.Contains 1 LRRCT domain.Contains 1 protein kinase domain.

Sequence caution: The sequence CAA27243.1 differs from that shown. Reason: Erroneous termination at position 786. Translated as Gln.The sequence CAA27243.1 differs from that shown. Reason: Frameshift at position 769. The sequence CAA27243.1 differs from that shown. Reason: Contaminating sequence. Sequence of unknown origin in the N-terminal part.The sequence CAA29888.1 differs from that shown. Reason: Contaminating sequence. Sequence of unknown origin in the N-terminal part.The sequence CAA44719.1 differs from that shown. Reason: Contaminating sequence. Sequence of unknown origin in the N-terminal part.The sequence CAA59936.1 differs from that shown. Reason: Contaminating sequence. Sequence of unknown origin in the N-terminal part.