Trk receptor

Source: Wikipedia, the free encyclopedia.
Trk receptor
Identifiers
SymbolTrk
InterProIPR020777
Membranome1342

Trk receptors are a family of

signaling cascades
. However, the activation of these receptors also has significant effects on functional properties of neurons.

The common

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 (often pronounced 'track') stands for tropomyosin receptor kinase or tyrosine receptor kinase[1][4] (and not "tyrosine kinase receptor" nor "tropomyosin-related kinase", as has been commonly mistaken).

The family of Trk receptors is named for the

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,

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

Main article: Tropomyosin receptor kinase A

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.[8][9][10] 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.[11]

TrkB

Main article: Tropomyosin receptor kinase B

development and plasticity, long-term potentiation, and apoptosis.[12]

Although both BDNF and NT-4 have high specificity to TrkB, they are not interchangeable.[13] 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.[13]

Recently, studies have also indicated that TrkB receptor is associated with Alzheimer's disease[12] and post-intracerebral hemorrhage depression.[14]

TrkC

Main article: Tropomyosin receptor kinase C

proprioceptive sensory neurons.[3] The axons of these proprioceptive sensory neurons are much thicker than those of nociceptive sensory neurons, which express trkA.[3]

Regulation by p75NTR

p75NTR (p75 neurotrophin receptor) 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.[3] Although the dissociation constants of p75NTR and TrkA are remarkably similar, their kinetics are quite different.[3] Reduction and mutation of cytoplasmic and transmembrane domains of either TrkA or p75NTR prevent the formation of high-affinity binding sites on TrkA.[3] However, the binding of ligands in p75NTR is not required to promote high-affinity binding.[3] Therefore, the data suggest that the presence of p75NTR affects the conformation of TrkA, preferentially the state with high-affinity binding site for NGF.[3] Surprisingly, although the presence of p75NTR is essential to promote high-affinity binding, the NT3 binding to the receptor is not required.[3]

Apart from affecting the affinity and specificity for Trk receptors, the P75 neurotrophin receptor (P75NTR) 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.[15] 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.[16]

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.[16]

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.[15]

Control of target innervation

Each of the neurotrophins mentioned above[

growth cones; even when neurons received adequate trophic (sustaining and nourishing) support, one experiment showed they did not grow into relating compartments without NGF.[vague][15] NGF increases the innervation of tissues that receive sympathetic or sensory innervation and induces aberrant innervation in tissues that are normally not innervated.[15]

NGF/TrkA signaling upregulates BDNF, which is transported to both peripheral and central terminals of nocireceptive sensory neurons.

NT-4 binding acutely sensitizing nocireceptive pathway that require the presence of mast cells.[15]

Sensory neuron function

Trk receptors and their ligands (neurotrophins) also affect neurons' functional properties.

afferent neurons and motor neurons.[15] Increased NT-3/trkC binding results in larger monosynaptic excitatory postsynaptic potentials (EPSPs) and reduced polysynaptic components.[15] On the other hand, increased NT-3 binding to trkB to BDNF[vague] has the opposite effect, reducing the size of monosynaptic excitatory postsynaptic potentials (EPSPs) and increasing polysynaptic signaling.[15]

Formation of ocular dominance column

In the development of mammalian visual system, axons from each eyes crosses through the lateral geniculate nucleus (LGN) and terminate in separate layers of striate cortex. However, axons from each LGN can only be driven by one side of the eye, but not both together. These axons that terminate in layer IV of the striate cortex result in ocular dominance columns. A study shows that The density of innervating axons in layer IV from LGN can be increased by exogenous BDNF and reduced by a scavenger of endogenous BDNF.[15] Therefore, it raises the possibility that both of these agents are involved in some sorting mechanism that is not well comprehended yet.[15] Previous studies with cat model has shown that monocular deprivation occurs when input to one of the mammalian eyes is absent during the critical period (critical window). However, A study demonstrated that the infusion of NT-4 (a ligand of trkB) into the visual cortex during the critical period has been shown to prevent many consequences of monocular deprivation.[15] Surprisingly, even after losing responses during the critical period, the infusion of NT-4 has been shown to be able to restore them.[15]

Synaptic strength and plasticity

In mammalian

interneurons.[15] LTP can be greatly reduced by BDNF mutants.[15] In a similar study on a mouse mutant with reduced expression of trkB receptors, LTP of CA1 cells reduced significantly.[15] TrkB loss has also been linked to interfere with the memory acquisition and consolidation in many learning paradigm.[15]

Role of Trk oncogenes in cancer

Although originally identified as an oncogenic fusion in 1982,

precision medicine.[citation needed] Trk inhibitors are (in 2015) in clinical trials and have shown early promise in shrinking human tumors.[19]

Trk inhibitors in development

Rozlytrek) is a drug developed by Ignyta, Inc., which has antitumor activity. It is a selective pan-trk receptor tyrosine kinase inhibitor (TKI) targeting gene fusions in trkA, trkB, and trkC (coded by NTRK1, NTRK2, and NTRK3 genes) that is currently in phase 2 clinical testing.[20]

Originally targeting soft tissue sarcomas,

tissue-agnostic inhibitor of TrkA, TrkB, and TrkC developed by Array BioPharma for solid tumors with NTRK fusion mutations.[21]

Due to this development of effective TRK inhibitors, the European Society for Medical Oncology (ESMO) is recommending that testing for NTRK fusion mutations is performed in the work up for non small cell lung cancer.[22]

Activation pathway

Trk receptors dimerize in response to ligand, as do other tyrosine kinase receptors.[3] These dimers phosphorylate each other and enhance catalytic activity of the kinase.[3] Trk receptors affect neuronal growth and differentiation through the activation of different signaling cascades. The three known pathways are PLC, Ras/MAPK (mitogen-activated protein kinase) and the PI3K (phosphatidylinositol 3-kinase) pathways.[3] These pathways involve the interception of nuclear and mitochondrial cell-death programs.[3] These signaling cascades eventually led to the activation of a transcription factor, CREB (cAMP response element-binding), which in turn activate the target genes.[3]

PKC pathways

The binding of

diacyglycerol and inositol(1,4, 5).[3] Diacyglycerol may indirectly activate PI3 kinase or several protein kinase C (PKC) isoforms, whereas inositol(1,4, 5) promotes release of calcium from intracellular stores.[3]

Ras/MAPK pathway

The signaling through

K-Ras.[3] H-ras is found in lipid rafts, embedded within the plasma membrane, while K-Ras is predominantly found in disordered region of the membrane.[3] RAP, a vesicle bounded molecule that also takes part in the cascading, is localized in the intracellular region.[3]

The activation of these molecules result in two alternative

ERK5 is stimulated through the activation cascades of B-Raf, MEK5, and Erk 5.[3] However, whether PKC (protein kinase C) could activate MEK5 is not yet known.[3]

PI3 pathway

Forkhead family transcription factor), BAD, and GSK-3
.

TrkA vs TrkC

Some studies have suggested that NGF/TrkA coupling causes preferential activation of the Ras/MAPK pathway, whereas NT3/TrkC coupling causes preferential activation of the PI3 pathway.[3]

See also

  • TrkB receptor

References

  1. ^
    ISBN 9780071481274
    . Another common feature of neurotrophins is that they produce their physiologic effects by means of the tropomyosin receptor kinase (Trk) receptor family (also known as the tyrosine receptor kinase family). ...
    Trk receptors
    All neurotrophins bind to a class of highly homologous receptor tyrosine kinases known as Trk receptors, of which three types are known: TrkA, TrkB, and TrkC. These transmembrane receptors are glycoproteins whose molecular masses range from 140 to 145 kDa. Each type of Trk receptor tends to bind specific neurotrophins: TrkA is the receptor for NGF, TrkB the receptor for BDNF and NT-4, and TrkC the receptor for NT-3.However, some overlap in the specificity of these receptors has been noted.
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  12. ^ a b Chen, Z; Simon, MT & Perry, RT et al. (2007), Genetic Association of Neurotrophic Tyrosine Kinase Receptor Type 2 (NTRK2) With Alzheimer's Disease., vol. 67 issue: 1., Birmingham, Alabama.: Wiley-Liss.
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  16. ^ a b Berchtold, Nicole C.; MS, Carl W.; Cotman (2004). "BDNF and Alzheimer's Disease—What's the Connection?". Alzheimer Research Forum. Archived from the original on 2008-10-11. Retrieved 2008-11-26. {{cite journal}}: Cite journal requires |journal= (help).
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  20. ^ "Ignyta Announces Updated Data from Entrectinib Phase 1 Clinical Trials at the 2016 AACR Annual Meeting" (Press release). 17 April 2016.
  21. ^ "FDA approves larotrectinib for solid tumors with NTRK gene fusions". www.fda.gov. November 26, 2018.
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