TRKA

TRKA is a member of the neurotrophic tyrosine kinase receptor (NTKR) family. It is a membrane-bound receptor that, upon neurotrophin binding, phosphorylates itself and members of the MAPK pathway. Isoform TrkA-III promotes angiogenesis and has oncogenic activity when overexpressed. 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. The presence of TRKA leads to cell differentiation and may play a role in specifying sensory neuron subtypes. Mutations in TRKA gene have been associated with congenital insensitivity to pain, anhidrosis, self-mutilating behavior, mental retardation and cancer. It was originally identified as an oncogene as it is commonly mutated in cancers, particularly colon and thyroid carcinomas. TRKA is required for high-affinity binding to nerve growth factor (NGF), neurotrophin-3 and neurotrophin-4/5 but not brain-derived neurotrophic factor (BDNF). Known substrates for the Trk receptors are SHC1, PI 3-kinase, and PLC-gamma-1. TRKA has a crucial role in the development and function of the nociceptive reception system as well as establishment of thermal regulation via sweating. It also activates ERK1 by either SHC1- or PLC-gamma-1-dependent signaling pathway. Defects in NTRK1 are a cause of congenital insensitivity to pain with anhidrosis and thyroid papillary carcinoma.

TRKA Related Areas

Enzyme>>Protein Kinase>>Receptor Tyrosine Kinase>>TrkA/NTRK1

Neuroscience>>Neurotrophic Factor & Receptor>>Neurotrophin & Receptor>>TrkA/NTRK1

Signal Transduction>>Protein Kinase>>Receptor Tyrosine Kinase>>TrkA/NTRK1

Cancer>>Growth Factor & Receptor>> Neurotrophin & Receptor>>TrkA/NTRK1

Cancer>>Growth Factor & Receptor>>Receptor Tyrosine Kinase>>TrkA/NTRK1

TRKA Alternative Names

TRKA, NTRK1, TRK, TRK1, DKFZp781I14186, MTC, p140-TrkA [Homo sapiens]

TrkA, NTRK1, Tkr, trk, C80751 [Mus musculus]

Summaries for TRKA

Entrez Gene summary for TRKA:

NTRK1 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 NTRK1 gene have been associated with congenital insensitivity to pain, anhidrosis, self-mutilating behavior, mental retardation and cancer. Alternate transcriptional splice variants of  NTRK1 gene have been found, but only three have been characterized to date. [provided by RefSeq, Jul 2008]

OMIM - description for TRKA:

The TRKA gene encodes the neurotrophic tyrosine kinase-1 receptor and belongs to a family of nerve growth factor receptors whose ligands include neurotrophins. Neurotrophins and their receptors play an important role in regulating development of both the central and the peripheral nervous systems. Bothwell , Carter and Lewin , and Bibel and Barde reviewed neurotrophins and their receptors. Nerve growth factor receptor (NGFR) is also referred to as p75(NTR) due to its molecular mass and its ability to bind at low affinity not only NGF , but also other neurotrophins, including brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NTF3), and neurotrophin-4 (NTF4). Higher affinity binding of NGFR can achieved by association with higher molecular mass, low-affinity neurotrophin receptors, namely the tropomyosin receptor kinases, TRKA (NTRK1), TRKB (NTRK2), and TRKC (NTRK3). TRKA, TRKB, and TRKC are specific for or 'preferred by' NGF, NTF4 and BDNF, and NTF3, respectively . NTF3 also binds to TRKA and TRKB, but with significantly lower affinity.

Wikipedia summary for TRKA:

High affinity nerve growth factor receptor also known as neurotrophic tyrosine kinase receptor type 1 or TRK1-transforming tyrosine kinase protein or Trk-A is a protein that in humans is encoded by the TRKA gene.

TRKA 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 (autophosphorylation) 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 TRKA gene have been associated with congenital insensitivity to pain with anhidrosis, self-mutilating behavior, mental retardation and cancer. Alternate transcriptional splice variants of TRKA gene have been found, but only three have been characterized to date.

Human TRKA Protein General Information

 

• Protein names: Tropomyosin-related kinase A, Short name=TRKA
• Sequence length: 796 AA.
• Domain: The transmembrane domain mediates interaction with KIDINS220 . The extracellular domain mediates interaction with NGFR
• 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.
• 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.23 Ubiquitinated. Undergoes polyubiquitination upon activation; regulated by NGFR. Ubiquitination regulates the internalization of the receptor
• 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.
• Subcellular location: Cell membrane; Single-pass type I membrane protein. Early 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
• 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.
• Involvement in disease: Defects in NTRK1 are a cause of congenital insensitivity to pain with anhidrosis (CIPA) [MIM:256800]. CIPA is 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. Defects in NTRK1 are a cause of thyroid papillary carcinoma (TPC) [MIM:188550]. TPC is 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=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.
• Catalytic activity: ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate.
• Enzyme regulation: The pro-survival signaling effect of TRKA 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.
• Induction: Isoform TrkA-III is up-regulated upon hypoxia in cells normally expressing it.
• Miscellaneousn: 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 caution: The sequence differs from that shown. Reason: Erroneous termination at position . Translated as Gln.
  The sequence differs from that shown. Reason: Frameshift at position .
  The sequence differs from that shown. Reason: Contaminating sequence. Sequence of unknown origin in the N-terminal part.
  The sequence differs from that shown. Reason: Contaminating sequence. Sequence of unknown origin in the N-terminal part.
  The sequence differs from that shown. Reason: Contaminating sequence. Sequence of unknown origin in the N-terminal part.
  The sequence differs from that shown. Reason: Contaminating sequence. Sequence of unknown origin in the N-terminal part.

General information above from UniProt

Function for TRKA Protein

UniProtKB:

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 TRKA 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-TRKA signaling that promotes neuronal precursors differentiation. Isoform TrkA-III promotes angiogenesis and has oncogenic activity when overexpressed.

Genatlas:

• nerve growth factor receptor, high affinity (dimeric form)
• involved in the survival differentiation and maintenance of many neural and non neural cell types

Phenotype Information for TRKA

• Gene/Locus: NTRK1, TRKA, MTC
• Phenotype: Insensitivity to pain, congenital, with anhidrosis
  Medullary thyroid carcinoma, familial

Phenotype Information for TRKA from OMIM (Online Mendelian Inheritance in Man)

Drugs for TRKA

Target	Drug Name	Disease	Drug Status
TRKA	Lestaurtinib	Acute myelogenous leukemia	Approved by FDA as orphan drug
TRKA	Lestaurtinib	Myeloid leukemia	Phase III
TRKA	Lestaurtinib	AML, prostate, pancreatic cancer, solid tumours	Phase II
TRKA	AZD6918	Solid tumours; Advanced Solid Malignancies	Terminated in Phase I

Drugs for TRKA from TTD (Therapeutic Targets Database)