Trk receptor

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Trk receptor
Identifiers
SymbolTrk
InterPro IPR020777
Membranome 1342

Trk receptors are a family of tyrosine kinases that regulates synaptic strength and plasticity in the mammalian nervous system. [1] [2] 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.

Contents

The common ligands of trk receptors are neurotrophins, a family of growth factors critical to the functioning of the nervous system. [3] 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 (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 oncogene trk, whose identification led to the discovery of its first member, TrkA. [2] Trk, initially identified in a colon carcinoma, is frequently (25%) activated in thyroid papillary carcinomas. [5] 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. [4] 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, [3] 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

TrkA is a protein encoded by the NTRK1 gene and has the highest affinity to the binding nerve growth factor (NGF) [4] 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. [6] 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. [7] 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. [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

TrkB has the highest affinity to the binding of brain-derived neurotrophic factor (BDNF) 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. [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

TrkC is ordinarily activated by binding with NT-3 and has little activation by other ligands. (TrkA and TrkB also bind NT-3, but to a lesser extent. [3] ) TrkC is mostly expressed by 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[ vague ] promotes neurite outgrowth. [15] NGF/TrkA signaling regulates the advance of sympathetic neuron 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. [15] In the periphery, TrkB/BDNF binding and TrkB/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. [15] Both NT-3 and BDNF are important in the regulation and development of synapses formed between 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 hippocampus, the axons of the CA3 pyramidal cells project into CA1 cells through the Schaffer collaterals. The long-term potentiation (LTP) may induce in either of these pathways, but it is specific only to the one that is stimulated with tetanus.[ vague ] The stimulated axon does not impact spill over to the other pathway. TrkB receptors are expressed in most of these hippocampal neurons, including dentate granule cells, CA3 and CA1 pyramidal cells, and inhibitory 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, [17] only recently has there been a renewed interest in the Trk family as it relates to its role in human cancers because of the identification of NTRK1 (TrkA), NTRK2 (TrkB) and NTRK3 (TrkC) gene fusions and other oncogenic alterations in a number of tumor types. [18] More specifically, differential expression of Trk receptors closely correlates to prognosis and outcome in a number of cancers, such as neuroblastoma. Trk A is seen as a good prognosis marker, as it can induce terminal differentiation of cells, while Trk B is associated with a poor prognosis, due to its correlation with MYCN amplification. [ citation needed ] As a result, Trk inhibitors have been explored as a potential treatment avenue in the field of 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

Entrectinib (formerly RXDX-101, trade name 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, Larotrectinib (tradename Vitrakvi) was approved in November 2018 as a 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 neurotrophin will lead to the phosphorylation of phospholipase C (PLC) by trk receptor. This phosphorylation of PLC induces an enzyme to catalyze the breakdown of lipids to 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 Ras/MAPK pathway is important for the neurotrophin-induced differentiation of neuronal and neuroblastoma cells. [3] Phosphorylation of tyrosine residues in the Trk receptors led to the activation of Ras molecules, H-Ras and 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 MAP kinase pathways. [3] Erk 1,2 can be stimulated through the activation cascades of K-Ras, Raf1, and MEK 1,2, whereas 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

PI3 pathway signaling is critical for both mediation of neurotrophin-induced survival and regulation of vesicular trafficking. [3] The trk receptor stimulates PI3K heterodimers, which causes the activation of kinases PDK-1 and Akt. [3] Akt in turn stimulates FRK (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

Related Research Articles

<span class="mw-page-title-main">Brain-derived neurotrophic factor</span> Protein found in humans

Brain-derived neurotrophic factor (BDNF), or abrineurin, is a protein that, in humans, is encoded by the BDNF gene. BDNF is a member of the neurotrophin family of growth factors, which are related to the canonical nerve growth factor (NGF), a family which also includes NT-3 and NT-4/NT-5. Neurotrophic factors are found in the brain and the periphery. BDNF was first isolated from a pig brain in 1982 by Yves-Alain Barde and Hans Thoenen.

<span class="mw-page-title-main">Neurotrophin</span>

Neurotrophins are a family of proteins that induce the survival, development, and function of neurons.

<span class="mw-page-title-main">Nerve growth factor</span> Mammalian protein found in Homo sapiens

Nerve growth factor (NGF) is a neurotrophic factor and neuropeptide primarily involved in the regulation of growth, maintenance, proliferation, and survival of certain target neurons. It is perhaps the prototypical growth factor, in that it was one of the first to be described. Since it was first isolated by Nobel Laureates Rita Levi-Montalcini and Stanley Cohen in 1956, numerous biological processes involving NGF have been identified, two of them being the survival of pancreatic beta cells and the regulation of the immune system.

<span class="mw-page-title-main">Tropomyosin receptor kinase A</span> Protein-coding gene in the species Homo sapiens

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 is a protein that in humans is encoded by the NTRK1 gene.

<span class="mw-page-title-main">Tropomyosin receptor kinase B</span> Protein and coding gene in humans

Tropomyosin receptor kinase B (TrkB), also known as tyrosine receptor kinase B, or BDNF/NT-3 growth factors receptor or neurotrophic tyrosine kinase, receptor, type 2 is a protein that in humans is encoded by the NTRK2 gene. TrkB is a receptor for brain-derived neurotrophic factor (BDNF). The standard pronunciation for this protein is "track bee".

<span class="mw-page-title-main">Low-affinity nerve growth factor receptor</span> Human protein-coding gene

The p75 neurotrophin receptor (p75NTR) was first identified in 1973 as the low-affinity nerve growth factor receptor (LNGFR) before discovery that p75NTR bound other neurotrophins equally well as nerve growth factor. p75NTR is a neurotrophic factor receptor. Neurotrophic factor receptors bind Neurotrophins including Nerve growth factor, Neurotrophin-3, Brain-derived neurotrophic factor, and Neurotrophin-4. All neurotrophins bind to p75NTR. This also includes the immature pro-neurotrophin forms. Neurotrophic factor receptors, including p75NTR, are responsible for ensuring a proper density to target ratio of developing neurons, refining broader maps in development into precise connections. p75NTR is involved in pathways that promote neuronal survival and neuronal death.

<span class="mw-page-title-main">Tropomyosin receptor kinase C</span> Protein-coding gene in the species Homo sapiens

Tropomyosin receptor kinase C (TrkC), also known as NT-3 growth factor receptor, neurotrophic tyrosine kinase receptor type 3, or TrkC tyrosine kinase is a protein that in humans is encoded by the NTRK3 gene.

Neurotrophic factors (NTFs) are a family of biomolecules – nearly all of which are peptides or small proteins – that support the growth, survival, and differentiation of both developing and mature neurons. Most NTFs exert their trophic effects on neurons by signaling through tyrosine kinases, usually a receptor tyrosine kinase. In the mature nervous system, they promote neuronal survival, induce synaptic plasticity, and modulate the formation of long-term memories. Neurotrophic factors also promote the initial growth and development of neurons in the central nervous system and peripheral nervous system, and they are capable of regrowing damaged neurons in test tubes and animal models. Some neurotrophic factors are also released by the target tissue in order to guide the growth of developing axons. Most neurotrophic factors belong to one of three families: (1) neurotrophins, (2) glial cell-line derived neurotrophic factor family ligands (GFLs), and (3) neuropoietic cytokines. Each family has its own distinct cell signaling mechanisms, although the cellular responses elicited often do overlap.

<span class="mw-page-title-main">Neurotrophin-3</span> Protein-coding gene in the species Homo sapiens

Neurotrophin-3 is a protein that in humans is encoded by the NTF3 gene.

<span class="mw-page-title-main">Neurotrophin-4</span> Protein-coding gene in the species Homo sapiens

Neurotrophin-4 (NT-4), also known as neurotrophin-5 (NT-5), is a protein that in humans is encoded by the NTF4 gene. It is a neurotrophic factor that signals predominantly through the TrkB receptor tyrosine kinase. NT-4 was first discovered and isolated from xenopus and viper in the year 1991 by Finn Hallbook et.al

The ErbB family of proteins contains four receptor tyrosine kinases, structurally related to the epidermal growth factor receptor (EGFR), its first discovered member. In humans, the family includes Her1, Her2 (ErbB2), Her3 (ErbB3), and Her4 (ErbB4). The gene symbol, ErbB, is derived from the name of a viral oncogene to which these receptors are homologous: erythroblastic leukemia viral oncogene. Insufficient ErbB signaling in humans is associated with the development of neurodegenerative diseases, such as multiple sclerosis and Alzheimer's disease, while excessive ErbB signaling is associated with the development of a wide variety of types of solid tumor.

<span class="mw-page-title-main">SHC3</span> Protein-coding gene in the species Homo sapiens

SHC-transforming protein 3 is a protein that in humans is encoded by the SHC3 gene.

<span class="mw-page-title-main">LINGO1</span> Protein-coding gene in the species Homo sapiens

Leucine rich repeat and Immunoglobin-like domain-containing protein 1 also known as LINGO-1 is a protein which is encoded by the LINGO1 gene in humans. It belongs to the family of leucine-rich repeat proteins which are known for playing key roles in the biology of the central nervous system. LINGO-1 is a functional component of the Nogo receptor also known as the reticulon 4 receptor.

Neurotrophic factor receptors or neurotrophin receptors are a group of growth factor receptors which specifically bind to neurotrophins.

<span class="mw-page-title-main">Cell surface receptor</span> Class of ligand activated receptors localized in surface of plama cell membrane

Cell surface receptors are receptors that are embedded in the plasma membrane of cells. They act in cell signaling by receiving extracellular molecules. They are specialized integral membrane proteins that allow communication between the cell and the extracellular space. The extracellular molecules may be hormones, neurotransmitters, cytokines, growth factors, cell adhesion molecules, or nutrients; they react with the receptor to induce changes in the metabolism and activity of a cell. In the process of signal transduction, ligand binding affects a cascading chemical change through the cell membrane.

In cellular biology, dependence receptors are proteins that mediate programmed cell death by monitoring the absence of certain trophic factors that otherwise serve as ligands (interactors) for the dependence receptors. A trophic ligand is a molecule whose protein binding stimulates cell growth, differentiation, and/or survival. Cells depend for their survival on stimulation that is mediated by various receptors and sensors, and integrated via signaling within the cell and between cells. The withdrawal of such trophic support leads to a form of cellular suicide.

<span class="mw-page-title-main">ANA-12</span> Chemical compound

ANA-12 is a selective, small-molecule non-competitive antagonist of TrkB, the main receptor of brain-derived neurotrophic factor (BDNF). The compound crosses the blood-brain-barrier and exerts central TrkB blockade, producing effects as early as 30 minutes and as long as 6 hours following intraperitoneal injection in mice. It blocks the neurotrophic actions of BDNF without compromising neuron survival.

<span class="mw-page-title-main">BNN-20</span> Chemical compound

BNN-20, also known as 17β-spiro-(androst-5-en-17,2'-oxiran)-3β-ol, is a synthetic neurosteroid, "microneurotrophin", and analogue of the endogenous neurosteroid dehydroepiandrosterone (DHEA). It acts as a selective, high-affinity, centrally active agonist of the TrkA, TrkB, and p75NTR, receptors for the neurotrophins nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), as well as for DHEA and DHEA sulfate (DHEA-S). The drug has been suggested as a potential novel treatment for Parkinson's disease and other conditions.

<span class="mw-page-title-main">BNN-27</span> Chemical compound

BNN-27, also known as 17α,20R-epoxypregn-5-ene-3β,21-diol, is a synthetic neurosteroid and "microneurotrophin" and analogue of the endogenous neurosteroid dehydroepiandrosterone (DHEA). It acts as a selective, high-affinity, centrally active agonist of the TrkA and p75NTR, receptors for nerve growth factor (NGF) and other neurotrophins, as well as for DHEA and DHEA sulfate (DHEA-S). BNN-27 has neuroprotective and neurogenic effects and has been suggested as a potential novel treatment for neurodegenerative diseases and brain trauma.

Neurotrophin mimetics are small molecules or peptide like molecules that can modulate the action of the neurotrophin receptor. One of the main causes of neurodegeneration involves changes in the expression of neurotrophins (NTs) and/or their receptors. Indeed, these imbalances or changes in their activity, lead to neuronal damage resulting in neurological and neurodegenerative conditions. The therapeutic properties of neurotrophins attracted the focus of many researchers during the years, but the poor pharmacokinetic properties, such as reduced bioavailability and low metabolic stability, the hyperalgesia, the inability to penetrate the blood–brain barrier and the short half-lives render the large neurotrophin proteins not suitable to be implemented as drugs.

References

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    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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