Tropomyosin receptor kinase A (TrkA), also known as high affinity nerve growth factor receptor, neurotrophic tyrosine kinase receptor type 1, or TRK1-transforming tyrosine kinase protein (NTRK).
The abbreviation trk stands for tropomyosin receptor kinase or tyrosine receptor kinase.
TrKA is a protein that is encoded by the NTRK1 gene.
NTRK1 gene is located on chromosome 1.
This gene encodes a member of the neurotrophic tyrosine kinase receptor (NTKR) family.
TrKA kinase is a membrane-bound receptor that, upon neurotrophin binding, phosphorylates itself and members of the MAPK pathway.
Trk receptors are a family of tyrosine kinases that regulates synaptic strength and plasticity in the nervous system.
TrkA kinase is abhigh affinity catalytic receptor for the neurotrophin, Nerve Growth Factor (NGF).
This kinase leads to cell differentiation and may play a role in specifying sensory neuron subtypes.
Mutations in the NTRK1 gene have been associated with congenital insensitivity to pain, anhidrosis, self-mutilating behaviors, intellectual disability and/or cognitive impairment and certain cancers.
The NTRK1 gene mediates the multiple effects of NGF, which include neuronal differentiation and avoidance of programmed cell death.
Mutations in chromosome 1 result in the fusion of the first seven exons of tropomyosin to the transmembrane and cytoplasmic domains of the then-unknown TrkA receptor.
TrkA itself does not appear to be an oncogene.
Gene fusions involving NTRK1 have been shown to be oncogenic, leading to the constitutive TrkA activation.
NTRK1 fusions are estimated to occur in 3.3% of lung cancer as assessed through next generation sequencing or fluoresence in situ hybridization.
TrkA is targeted for proteasome-mediated destruction by an E3 ubiquitin ligase, controling the survival of a neuron.
Small molecules such as amitriptyline have been claimed to activate TrkA.
Recent identification of NTRK1 (TrkA), NTRK2 (TrkB) and NTRK3 (TrkC) gene fusions and other oncogenic alterations in a number of tumor types.
TRK inhibitors approved for treatment of adult and pediatric patients with solid tumors harboring an NTRK gene fusion.
((Entrectinib)) is a selective pan-trk receptor tyrosine kinase inhibitor (TKI) targeting gene fusions in trkA, trkB, and trkC
Trk receptors affect neuronal survival and differentiation.
The ligands of trk receptors are neurotrophins, a family of growth factors critical to the functioning of the nervous system.
Trk, is frequently (25%) activated in thyroid papillary carcinomas.
The three most common types of trk receptors are trkA, trkB, and trkC, which have different binding affinity to certain neurotrophins generating diverse biological responses.
TrkA has the highest affinity to the binding nerve growth factor (NGF), which is important in expression of genes encoding the biosynthesis of enzymes for neurotransmitters.
TrkB has the highest affinity to the binding of brain-derived neurotrophic factor (BDNF) and NT-4.
Brain-derived neurotrophic factor (BDNF), growth factor that has important roles in the survival and function of neurons in the CNS.
BDNF binding to the TrkB receptor causes intracellular cascades to be activated, regulating neuronal development, neuroplasticity, long-term potentiation, and apoptosis.
TrkB receptor may be associated with Alzheimer’s disease.
TrkC is mostly expressed by proprioceptive sensory neurons.
Neurotrophins have proliferation and differentiation effects on CNS neuro-epithelial precursors, neural crest cells, or precursors of the enteric nervous system.
TrkA that expresses NGF increases the survival of both C and A delta classes of nocireceptor neurons, but also affect the functional properties of these neurons.
BDNF improves the survival and function of neurons in CNS, particularly the forebrain, as well as neurons in the hippocampus and cortex.
Brain-derived neurotrophic factor (BDNF) belongs to the neurotrophin family of growth factors and affects the survival and function of neurons in the central nervous system, particularly in brain regions susceptible to degeneration in Alzheimer’s disease, and
improves survival of cholinergic neurons of the basal forebrain, as well as neurons in the hippocampus and cortex.
TrkC promotes proliferation and survival of cultured neural crest cells, oligodendrocyte precursors, and differentiation of hippocampal neuron precursors.
The above neurotrophins promote neurite outgrowth.
NGF/TrkA signaling regulates the advance of sympathetic neuron growth cones.
NGF increases the innervation of tissues that receive sympathetic or sensory innervation and induces aberrant innervation in tissues that are normally not innervated.
NGF/TrkA signaling upregulates BDNF.
BDNF is then transported to both peripheral and central terminals of nocireceptive sensory neurons.
NKRT rearrangements have been described in most solid tumors with variable frequencies: less than 1% in high prevalence tumors such as non-small cell lung cancer and breast cancer, 5-25% in some tumor types such as papillary thyroid cancer and in 90% of uncommon types secretary breast cancer.
TrkB/BDNF binding and TrkB/NT-4 binding acutely sensitizing the nocireceptive pathway that requires the presence of mast cells.
Trk receptors and their ligands, the neurotrophins, also affect neurons’ functional properties.
Both NT-3 and BDNF are important in the regulation and development of synapses between afferent neurons and motor neurons.
NT-3/trkC binding results in monosynaptic excitatory postsynaptic potentials and reduced polysynaptic components.
Increased NT-3 binding to trkB to BDNF reduces the size of monosynaptic excitatory postsynaptic potentials and increasing polysynaptic signaling.
NTRK1 (TrkA), NTRK2 (TrkB) and NTRK3 (TrkC) gene fusions and other oncogenic alterations occur in a number of tumor types.
Trk inhibitors have shown early promise in shrinking human tumors.
Trk receptors affect neuronal growth and differentiation through the activation of different signaling pathways: PLC, Ras/MAPK (mitogen-activated protein kinase) and the PI3K (phosphatidylinositol 3-kinase) pathways.
These signaling pathways activate a transcription factor, CREB (cAMP response element-binding), which in turn activate the target genes.
Ras/MAPK signaling pathway is important for the neurotrophin-induced differentiation of neuronal and neuroblastoma cells.
PI3K pathway signaling is critical for neurotrophin-induced survival and regulation of vesicular trafficking.
The trk receptor stimulates PI3K heterodimers.