Trk receptor
Trk receptors are a family of tyrosine kinases that regulates synaptic strength and plasticity in the mammalian nervous system. Trk receptors affect neuronal survival and differentiation through several signaling cascades. However, the activation of these receptors also has significant effects on functional properties of neurons.
The common ligands of trk receptors are neurotrophins, a family of growth factors critical to the functioning of the nervous system. The binding of these molecules is highly specific. Each type of neurotrophin has different binding affinity toward its corresponding Trk receptor. The activation of Trk receptors by neurotrophin binding may lead to activation of signal cascades resulting in promoting survival and other functional regulation of cells.
Origin of the name ''trk''
The abbreviation trk stands for tropomyosin receptor kinase or tyrosine receptor kinase.The family of Trk receptors is named for the oncogene trk, whose identification led to the discovery of its first member, TrkA. Trk, initially identified in a colon carcinoma, is frequently activated in thyroid papillary carcinomas. The oncogene was generated by a mutation in chromosome 1 that resulted in the fusion of the first seven exons of tropomyosin to the transmembrane and cytoplasmic domains of the then-unknown TrkA receptor. Normal Trk receptors do not contain amino acid or DNA sequences related to tropomyosin.
Types and corresponding ligands
The three most common types of trk receptors are trkA, trkB, and trkC. Each of these receptor types has different binding affinity to certain types of neurotrophins. The differences in the signaling initiated by these distinct types of receptors are important for generating diverse biological responses.Neurotrophin ligands of Trk receptors are processed ligands, meaning that they are synthesized in immature forms and then transformed by protease cleavage. Immature neurotrophins are specific only to one common p75NTR receptor. However, protease cleavage generates neurotrophins that have higher affinity to their corresponding Trk receptors. These processed neurotrophins can still bind to p75NTR, but at a much lower affinity.
TrkA
is a protein encoded by the NTRK1 gene and has the highest affinity to the binding nerve growth factor After NGF is bound to TrkA this leads to a ligand-induced dimerization causing the autophosphorylation of the tyrosine kinase segment, which in turn activates the Ras/MAPK pathway and the PI3K/Akt pathway. NGF is a neurotrophic factor, and the NGF/TrkA interaction is critical in both local and nuclear actions, regulating growth cones, motility, and expression of genes encoding the biosynthesis of enzymes for neurotransmitters. Peptidergic nociceptive sensory neurons express mostly trkA and not trkB or trkC.The TrkA receptor is associated with several diseases such as Inflammatory arthritis, keratoconus, functional dyspepsia and, in some cases, over expression has been linked to cancer development. In other cases, such as neuroblastoma Trk A acts as a promising prognostic indicator as it has the potential to induce terminal differentiation of cancer cells in a context-dependent manner.
TrkB
has the highest affinity to the binding of brain-derived neurotrophic factor and NT-4. BDNF is a growth factor that has important roles in the survival and function of neurons in the central nervous system. The binding of BDNF to TrkB receptor causes many intracellular cascades to be activated, which regulate neuronal development and plasticity, long-term potentiation, and apoptosis.Although both BDNF and NT-4 have high specificity to TrkB, they are not interchangeable. In a mouse model study where BDNF expression was replaced by NT-4, the mouse with NT4 expression appeared to be smaller and exhibited decreased fertility.
Recently, studies have also indicated that TrkB receptor is associated with Alzheimer's disease and post-intracerebral hemorrhage depression.
TrkC
is ordinarily activated by binding with NT-3 and has little activation by other ligands. TrkC is mostly expressed by proprioceptive sensory neurons. The axons of these proprioceptive sensory neurons are much thicker than those of nociceptive sensory neurons, which express trkA.Regulation by p75NTR
affects the binding affinity and specificity of Trk receptor activation by neurotrophins. The presence of p75NTR is especially important in increasing the binding affinity of NGF to TrkA. Although the dissociation constants of p75NTR and TrkA are remarkably similar, their kinetics are quite different. Reduction and mutation of cytoplasmic and transmembrane domains of either TrkA or p75NTR prevent the formation of high-affinity binding sites on TrkA. However, the binding of ligands in p75NTR is not required to promote high-affinity binding. Therefore, the data suggest that the presence of p75NTR affects the conformation of TrkA, preferentially the state with high-affinity binding site for NGF. Surprisingly, although the presence of p75NTR is essential to promote high-affinity binding, the NT3 binding to the receptor is not required.Apart from affecting the affinity and specificity for Trk receptors, the P75 neurotrophin receptor can also reduce ligand-induced receptor ubiquitination, and delay receptor internalization and degradation.
Essential roles in differentiation and function
Precursor cell survival and proliferation
Numerous studies, both in vivo and in vitro, have shown that 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 not only increase the survival of both C and A delta classes of nocireceptor neurons, but also affect the functional properties of these neurons.4 As mentioned before, BDNF improves the survival and function of neurons in CNS, particularly cholinergic neurons of the basal forebrain, as well as neurons in the hippocampus and cortex.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 AD. BDNF improves survival of cholinergic neurons of the basal forebrain, as well as neurons in the hippocampus and cortex.
TrkC that expresses NT3 has been shown to promote proliferation and survival of cultured neural crest cells, oligodendrocyte precursors, and differentiation of hippocampal neuron precursors.
Control of target innervation
Each of the neurotrophins mentioned above promotes neurite outgrowth. NGF/TrkA signaling regulates the advance of sympathetic neuron growth cones; even when neurons received adequate trophic support, one experiment showed they did not grow into relating compartments without NGF. 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, which is transported to both peripheral and central terminals of nocireceptive sensory neurons. In the periphery, TrkB/BDNF binding and TrkB/NT-4 binding acutely sensitizing nocireceptive pathway that require the presence of mast cells.