View source for Trk receptor



==Overview==
'''Trk receptors''' are a family of [[receptor tyrosine kinase|tyrosine kinases]] that regulates [[Chemical synapse|synaptic]] strength and [[Synaptic plasticity|plasticity]] in the mammalian [[nervous system]].<ref name="pmid12676795">{{cite journal |author=Huang EJ, Reichardt LF |title=Trk receptors: roles in neuronal signal transduction |journal=Annu. Rev. Biochem. |volume=72 |issue= |pages=609–42 |year=2003 |pmid=12676795 |doi=10.1146/annurev.biochem.72.121801.161629 |url=http://dx.doi.org/10.1146/annurev.biochem.72.121801.161629}}</ref> Trk receptors affect [[neuron]]al survival and [[Cellular differentiation|differentiation]] through several [[signal cascade]]s. However, the activation of these receptors also has significant effects on functional properties of neurons.

The common [[ligands]] of trk receptors are [[neurotrophin]]s, a family of [[growth factor]]s critical to the functioning of the nervous system.<ref name=segal>Segal, Rosalind A. (2003) Selectivity in Neurotrophin  Signalling: Theme and   Variations. Annual Review of Neuroscience 26, 299-330.</ref> The [[Binding (molecular)|binding]] of these molecules is highly specific. Each type of neurotrophin has different binding [[Dissociation_constant#Protein-Ligand_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|'''t'''ropomyosin]]-[[Receptor (biochemistry)|'''r'''eceptor]]-[[kinase|'''k'''inase]] <ref name="pmid2869410">{{cite journal |author=Martin-Zanca D, Hughes SH, Barbacid M |title=A human oncogene formed by the fusion of truncated tropomyosin and protein tyrosine kinase sequences |journal=Nature |volume=319 |issue=6056 |pages=743–8 |year=1986 |pmid=2869410 |doi=10.1038/319743a0 |url=http://dx.doi.org/10.1038/319743a0}}</ref> (and not ''tyrosine'' kinase nor tropomyosin-''related'' kinase, as has been commonly mistaken).

The family of Trk receptors is named for the [[oncogene]] ''trk'', whose identifical led to the discovery of its first member, [[TrkA]]<ref name=pmid12676795/>.  ''trk'', initially identified in a [[colon carcinoma]], is frequently (25%) activated in [[thyroid cancer|thyroid papillary carcinoma]]s <ref name="pmid1751544">{{cite journal |author=Barbacid M, Lamballe F, Pulido D, Klein R |title=The trk family of tyrosine protein kinase receptors |journal=Biochim. Biophys. Acta |volume=1072 |issue=2-3 |pages=115–27 |year=1991 |pmid=1751544 |doi= |url=http://linkinghub.elsevier.com/retrieve/pii/0304-419X(91)90010-I}}</ref>. The oncogene was generated by a [[mutation]] in [[Chromosome 1 (human)|chromosome 1]] that resulted in the [[Fusion gene|fusion]] of the first seven [[exon]]s of tropomyosin to the [[transmembrane domain|transmembrane]] and [[cytoplasm]]ic domains of the then-unknown TrkA receptor <ref name="pmid2869410"/>.  Normal Trk receptors do not contain [[Primary structure|amino acid]] or [[DNA sequencing|DNA sequences]] related to tropomyosin.

==Trk receptor types and corresponding ligands==
The three most common types of trk receptors are trkA, trkB, and trkC. Each of these receptors 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 of biological responses. 

Neurotrophin ligands of Trk receptors are processed ligands,<ref name=segal/> 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===
{{main|TrkA}}
[[TrkA]] has the highest affinity to the binding [[nerve growth factor]] (NGF). NGF is important in both local and nuclear actions, regulating [[growth cones]], [[motility]], and [[Gene expression|expression of genes]] encoding the biosynthesis enzymes for neurotransmitters. [[Nocireceptive]] sensory neurons express mostly trkA and not trkB or trkC.

===TrkB===
{{main|TrkB}}
[[TrkB]] has the highest affinity to the binding [[brain-derived neurotrophic factor]] (BDNF) and [[NT-4]]. BDNF is 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 intercellular [[Biochemical cascade|cascades]] be activated, which regulate neuronal [[Neural development|development]] and [[Neuroplasticity|plasticity]], [[long-term potentiation]], and [[apoptosis]].<ref name=chen>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.</ref>

Although both BDNF and NT-4 have high specificity to TrkB, they are not interchangeable.<ref name=fan>Fan G, Egles C, Sun Y, Minichiello L, Renger JJ, et al. 2000. Knocking the NT4 gene into the BDNF locus rescues BDNF deficient mice and reveals distinct NT4 and BDNF activities.Nat. Neurosci. 3:350–57</ref> 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.<ref name=fan/>

Recently, studies have also indicated that TrkB receptor is associated with [[Alzheimer's disease]].<ref name=chen/>

===TrkC===
{{main|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.<ref name=segal/>) TrkC is mostly expressed by [[proprioceptive]] sensory neurons.<ref name=segal/> The [[axon]]s of these proprioceptive sensory neurons are much thicker than those of nocireceptive sensory neurons, which express trkA.<ref name=segal/>

==Regulation by P75NTR==

=====P75NTR increases binding affinity and specificity for Trk receptor=====
[[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.<ref name=segal/> Although the dissociation constants of p75NTR and TrkA are remarkably similar, their kinetics are quite different.<ref name=segal/> Reduction and mutation of cytoplasmic and transmembrane domains of either TrkA or P75NTR prevent the formation of high-affinity [[binding site]]s on TrkA.<ref name=segal/> However, the binding of ligands in p75NTR is not required to promote high-affinity binding.<ref name=segal/> Therefore, the data suggest that the presence of p75NTR affects the conformation of TrkA, preferentially the state with high-affinity binding site for NGF.<ref name=segal/> Surprisingly, although the presence of p75NTR is essential to promote high-affinity binding, the NT3 binding to the receptor is not required.<ref name=segal/>

Apart from affecting the affinity and specificity for Trk receptor, P75 neurotropins receptor (P75NTR) can also reduce ligand-induced receptor ubiquitination, delays receptor internalization, and degradation.<ref name= Makkerhl/> In an experiment by Makkerh in 2005, both TrkA and TrkB receptors were tested using similar method.<ref name= Makkerhl/> The only difference is that NGF was used to activate the TrkA receptor whereas BDNF was used for TrkB receptor.<ref name= Makkerhl/> 

=====TrkA and TrkB receptors activity are ligand-dependant=====
To test if TrkA and TrkB receptors activity are ligand-dependant, the receptors are treated with NGF and BDNF correspondingly.<ref name="Makkerhl">Makkerh, J. P., Ceni, C., Auld, D. S., Vaillancourt, F., Dorval, G., Barker, P. A. (2005). p75 neurotrophin receptor reduces ligand-induced Trk receptor ubiquitination and delays Trk receptor internalization and degradation. EMBO Rep 6, 936–941.[Medline].</ref> In vivo, the activity of these receptors is regulated by ubiquitination, the process in which protein undergoes modification by attachment of ubiquitin monomers.<ref name= Makkerhl/> These molecules usually have main function of labeling proteins for proteasomal degradation.<ref name= Makkerhl /> After being activated, Trk receptors may undergo endocytosis and will be either recycled or degraded.<ref name= Makkerhl /> Two types of cells were used to test the protocol, P12 cells and E16 mouse cortices.<ref name= Makkerhl /> An E16 mouse cortex was used in conjunction with BDNF, since it expresses abundant TrkB and lesser p75NTR.<ref name= Makkerhl/> On the other hands, P12 cells were treated with NGF, since it expresses more TrkA and p75NTR but not TrkB and TrkC.<ref name= Makkerhl/> The treated receptors were then immunoprecipitated and immunoblotted to be analyzed.<ref name= Makkerhl /> The result shows that TrkB phosphotyrosine (activated TrkB) content increased rapidly with the presence of BDNF compared with control (absence of BDNF) whereas TrkA phosphotyrosine content increased modestly when treated with NGF.<ref name= Makkerhl />

=====p75NTR reduces Trk ubiquitination=====
To test if p75NTR reduces Trk ubiquitination, HEK293 (human embryonic kidney 293 cells) were co-tranfected with plasmids encoding TrkA and Myc-tagged ubiquitin with the presence and absence of plasmid encoding P25NTR.<ref name= Makkerhl/> When treated with their corresponding neurotrophins, lower levels of ubiquitinated TrkA and TrkB are present in presence of p75NTR.<ref name= Makkerhl/> Vice versa, in the absence of p75NTR, ubiquitination content increases decreases significantly.<ref name= Makkerhl/>

=====p75NTR delays Trk receptor internalization=====
To test the hypothesis, HEK93 cells were subjected to biotinylation with the presence and absence of P25NTR.<ref name= Makkerhl/> Each samples were taken at different time points (0, 2, 5, and 15 mins), immunoblotted, and screened for the level of tyrosine-phosphorylated molecules.<ref name= Makkerhl/> The result shows increases in the level of tyrosine-phosphorylated molecules with the presence of p75NTR.<ref name= Makkerhl/> In absence of P25NTR, tyrosine-phosphorylated level fell below [[detection limit]] in 5 min.<ref name= Makkerhl/> The biotinylated [[protein complex]]es were lysed to show both tyrosine-phosphorylated molecules in the surface and those that been internalized.<ref name= Makkerhl/>

==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]].<ref name=huang2001>Huang E. J. and Reichardt L. F. (2001) Neutrophins: Roles in Neuronal Development and Function. Annual Review of Biochemistry 24, 677-746. CrossRef, Medline, ISI, Chemport, CSA.</ref> 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.<ref name=berch>{{ Citation | last1= Berchtold | first1= Nicole C. | last2= MS | first2= Carl W. | last3= Cotman | title= BDNF and Alzheimer's Disease—What's the Connection? | publisher= Alzheimer Research Forum | place= | volume=| edition=  | year=2004 |url=http://www.alzforum.org/res/for/journal/cotman/default.asp
| issn=|accessdate= Nov 26, 2008}}.</ref>

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.<ref name=berch/>

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.<ref name=huang2001/>

====Control of target innervation====

Each of the neurotrophins mentioned above{{vague}} promotes [[neurite]] outgrowth.<ref name=huang2001/> NGF/TrkA signaling regulates the advance of [[Sympathetic nervous system|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}}<ref name=huang2001/> NGF increases the innervation of tissues that receive sympathetic or sensory innervation and induces aberrant innervation in tissues that are normally not innervated.<ref name=huang2001/>

NGF/TrkA signaling upregulates BDNF, which is transported to both peripheral and central terminals of nocireceptive sensory neurons.<ref name=huang2001/> In the periphery, TrkB/BDNF binding and TrkB/[[NT-4]] binding acutely sensitizing nocireceptive pathway that require the presence of [[mast cell]]s.<ref name=huang2001/>

====Sensory neuron function====
Trk receptors and their ligands (neurotrophins) also affect neurons' functional properties.<ref name=huang2001/> Both [[NT-3]] and BDNF are important in the regulation and development of [[synapse]]s formed between [[afferent neuron]]s and [[motor neuron]]s.<ref name=huang2001/> Increased NT-3/trkC binding results in larger [[Reflex arc|monosynaptic]] [[excitatory postsynaptic potential]]s (EPSPs) and reduced [[Reflex arc|polysynaptic]] components.<ref name=huang2001/> 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.<ref name=huang2001/>

====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 [[Visual cortex|striate cortex]]. However, axons from each LGN can only be driven by one side of the eye, but not both together. tThese 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.<ref name=huang2001/> Therefore, it raises the possibility that both of these agents are involved in some sorting mechanism that is not well comprehended yet.<ref name=huang2001/> 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.<ref name=huang2001/> Surprisingly, even after losing responses during the critical period, the infusion of NT-4 has been shown to be able to restore them.<ref name=huang2001/>

====Synaptic strength and plasticity====

In mammalian [[hippocampus]], the axons of the [[hippocampal subfields|CA3]] [[pyramidal cell]]s 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 gyrus|dentate]] [[granule cell]]s, CA3 and CA1 pyramidal cells, and inhibitory [[interneurons]].<ref name=huang2001/> Interestingly, LTP can be greatly reduced by BDNF mutants.<ref name=huang2001/> In a similar study on a mouse mutant with reduced expression of trkB receptors, LTP of CA1 cells reduced significantly.<ref name=huang2001/> TrkB loss has also been linked to interfere with the memory acquisition and consolidation in many learning paradigm.<ref name=huang2001/>

==Activation pathway==

Trk receptors [[dimerize]] in response to ligand, as do other tyrosine kinase receptors.<ref name=segal/> These dimers phosphorylate each other and enhance [[Catalysis|catalytic activity]] of the kinase.<ref name=segal/> 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.<ref name=segal/> These pathways involve the interception of nuclear and mitochondrial cell-death programs.<ref name=segal/> These signaling cascades eventually led to the activation of a [[transcription factor]], CREB (cAMP response element-binding), which in turn the activate target genes.<ref name=segal/>

====PKC pathways====
The binding of neutrophin will lead to the phosphorylation PLC by trk receptor. The phosphorylation of PLC induces an enzyme to catalyze the breakdown of lipids to diacyglycerol and inositol (1,4, 5).<ref name=segal/>  Diacyglycerol may indirectly activate PI3 kinase or several protein kinases C isoform, whereas inositol (1,4, 5) promotes release of calcium from intracellular stores.<ref name=segal/>

====Ras/MAPK pathway====
The signaling through [[Ras/MAPK pathway]] is important for the neurotrophin-induced differentiation of neuronal and neuroblastoma cells.<ref name=segal/> Phosphorylation of tyrosine residues in the Trk receptors led to the activation of Ras molecules, H-Ras and K-Ras.<ref name=segal/> H-ras is found in [[lipid raft]]s, embedded within the [[Cell membrane|plasma membrane]], while K-Ras is predominantly found in disordered region of the membrane.<ref name=segal/> RAP, a vesicle bounded molecule that also takes part in the cascading, is localized in the intracellular region.<ref name=segal/>

The activation of these molecules result in two alternative [[Mitogen-activated protein kinase|MAP kinase]] pathways.<ref name=segal/> Erk 1,2 can be stimulated through the activation cascades of K-Ras, Raf1, and MEK 1,2, whereas ERK 5 is stimulated through the activation cascades of B-Raf, MEK5, and Erk 5.<ref name=segal/> However, whether PKC (protein kinase C) could activate MEK5 is not yet known.<ref name=segal/>

====PI3 pathway====

[[Phosphoinositide 3-kinase|PI3 pathway]] signaling is critical for both mediation of neurotrophin-induced survival and regulation of vesicular trafficking.<ref name=segal/> The trk receptor stimulates P13 heterodimers, which causes the activation of kinases [[PDK-1]] and [[Akt]].<ref name=segal/> Akt in turn stimulates FRK (Forkhead family transcription factor), BAD, and [[GSK-3]].

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.<ref name=segal/>

==References==
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{{Receptor tyrosine kinases}}
[[Category:Tyrosine kinase receptors]]
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