2009 Group 4 Project

From CellBiology

'Tropomyosin-related Kinase(Trk): a novel family of cell surface receptor tyrosine-kinase'


'Tropmyosin-related kinase receptors (also known as Trk or colloqiually as "Terk" receptors), are a specific family of Tyrosine kinase receptors originating from the Trk oncogene. Trk's are present and expressed at low levels, throughout mammalian tissue types and bear particular signifcance in embryological development, maintainence as well as growth of neuronal cell types[1][2]. During embryonic development, expression is significantly higher than in mature mammals as it is in neuronal expression[3]. Thus, Trks appear to be a major component of a highly intricate system of receptor complexes that mediate neurotropin and growth factor control of selective cell death or differentiation[4]. There are three particular sub-types of receptor within the Trk loci - Trk A, Trk B and Trk C - each of which is characterised by specific differences in structure and discrimination for different Neurotrophin ligands, and thus, distinct functions.[1]

What are neurotrophins? Neurotrophins are signalling proteins (growth factors) which are expressed mostly during embryological development to regulate neuronal tissue development[4]. There are four typical neurotropic factors – Nerve Growth Factor (NGF), Brain-derived Neurotrophic Factor (BDNF), Neurotrophin-3 (NT-3), and Neurotrophin-4 (NT-4). These factors are believed to regulate selective tissue death via Trk receptors and the low-affinity neurotrophin receptor p75NTR[4]. The Selectivty of NTs for various receptors is indicated in figure 1.

Figure 1: Specificity of Trk receptors for neurotrophin ligands: NGF binds significantly with TrkA. BDNF & NT-4 bind most significantly with TrkB. NT-3 binds most signifcatly with TrkC, however, NT-3 also elicits low-affinity binding with Trk's B and A.


  • Trk receptors are composed of an extracellular segment that binds polypeptide ligands, transmembrane helix, and cytoplasmic segment where the tyrosine kinase catalytic activity takes place.[5]
  • TrK receptors act as dimeric transmembrane proteins. Distally, three cysteine-rich motiffs and two Leucine-rich regions form a conserved NGF binding region which are common to all TrK's near the amino terminus (Figure 2).[5]
  • Additionally, the common binding region is flanked by a pair of extracellular immunoglobulin-like domains located proximally to the cell membrane[6]. The juxtamembrane complex contains a variable amino-acid sequence, which determines ligand bindng affinity and specificity. The localization of these peptides appears to be non-specific in tertiary NGF-TrKA complex structures, however their conformation within this complex indicate direct participation in complex binding[6].
  • Further NGF binding site affinity is generated through collaboration with the p75 protein/neurotrophin receptor (p75NTR)[7]. Furthermore, p75NTR regulates NT-3-TrkA and NT-4/5-TrkB mediated receptor activation by increasing signal transduction sensitivity of these neurotropins for receptor activation. This is achieved through allosteric distortion of Trk binding regions[7].
  • Intracellularly, Trk shares many of the highly conserved motifs of other tyrosine kinases with some distinct variations. There are 10 conserved tyrosines in the intracellular domain, three of which, are known to contribute to the autoregulatory loop within the kinase region (Figure 2)[8]. Overall, 8 of the 10 tyrosines contribute to the kinase region, either by regulating kinase activity directly or by inducing adaptor protein binding including those of the Ras and phosphatidylinositol pathways[8]. The two remaining tyrosine residues contribute to second-messenger events coupled by Shc and PLC-γ1 protein and are located outside the kinase domain[8].


Figure 2: Common structural features of Trk receptors: a Trk in dimer complex with various conserved regions and residues. Each Trk (A, B or C) is composed of a number of highly conserved elements. Variability mainly occurs in the ligand binding regions. Variations in binding site affinity can affect phosphorylative domain regions and adaptor protein association differently, thus stimulating different signalling events.

Trk receptors achieve their function primarily via neuroptrophin signaling. Their role is to bind with neuroptrophin which are a family of closely related proteins taking roles in the regulation of survival of the neurons. There are three types of trk receptors, namely trkA, trkB and trkC. These receptors have different binding affinity to certain types of neurotrophins (Figure 1). Hence, the signalling by these distinct receptors will result in various cellular functions. Trk receptors regulate cell survival, proliferation, axon and dendrite growth, the expression and activity of ion channels and neurotransmitter receptors[9]. TrK also regulate synaptic strength and plasticity in adult nervous system. As a family of tyrosine kinase receptors, TrK receptors are activated and regulated in a similar fashion. TrK receptor signaling are mainly regulated by MAP kinase, PI3K and PLC pathways.[10]

  • Trk A

Trk A also known as Neurotrophic tyrosine-kinase receptor (type 1), is a high affinity receptor for nerve growth factor (NGF). Binding of NGF to TrK A leads to the recruitment of proteins that interact with specific phosphotyrosine residues in the cytoplasmic domains of Trk receptor A. Such interactions activate signaling pathways, such as the Ras, PI3K, and PLC pathways and result in activation of gene expression, neuronal growth and proliferation[9][10]

  • Trk B

Trk B also known as Neurotrophic tyrosine-kinase receptor (type 2), is a high affinity receptor for brain derived growth factor (BDNF) and neurotrophin-4 (NT4). Trk Bs are consisted of 3 isoforms in human central nervous system. The isoform (TK+) is a typical tyrosine kinase receptor, which transduces the BDNF signal via pathways such as Ras-ERK, PI3K and PLCγ. The other two isoforms, TKT1 and TKT2 are distinct from the typical kinase receptors as the C-terminal sequences are T1 and T2 specific.[9][10]

  • Trk C

Trk C also known as Neurotrophic tyrosine-kinase receptor is a high affinity receptor for neurotrophin-3 (NT3). Binding of NT3 on Trk C triggers the neuronal growth from neural stem cells in a process known as neurogenesis. NT3 is particularly important in proprioceptive neuron growth[10].

Demonstration of function in Knock-out mice:Multiple studies of utilizing transgenic mouse models have been employed to highlight the effects of Trk deficiency on embryological development of mice.

  • Trk Defective: Overall, Trk defective mice demonstrate a significant reduction in survival over a 30 day period[4]. Specifically, such knockouts result in impaired olfactory function, as well as poor pain and thermoception responses. This is attributed to a >70% reduction in neuronal cells in the dorsal root, trigeminal and sympathetic ganglia over this period. Multiple other pathological conditions exist but it is unclear as to whether these are attributable to Trk deficiency or secondary to extremely impaired nervous function[4].
  • Trk A defective: Trk A defective mice lack the ability to perceive painful and thermoceptive stimuli. This is attributed to the malformation of applicable peripheral sensory neurons during embryonic and post-natal development[3].
  • Trk B Defective: inactivation of the Trk B gene product results in significant neurological deficiencies, poor feeding responses and poor touch perception. Overall, this is perceived to be due to a >80% depletion of catecholaminergic neurons known to relay sensory input from the gastrointestinal, cardiovascular and pulmonary systems[3].
  • Trk C Defective: Defective mice demonstrate unusual postural responses as well as severely impaired proprioception. It is believed that these deficiencies are attributable to an absolute deficiency of Ia muscle afferents that innervate proprioceptive spindle fibres during embryological development[3].

Dynamic Process

Figure 3: Overview of dynamic processes shared by Trk receptors. Multiple transduction pathways are employed to illicit specific responses regulating survival and differentiation. The end point of signal transduction is often gene regulation and may involve Calcium second messenger events to preciptate expressor/repressor protein dissociation/association from promoter regions.
NGF binding to ligation region facilitates dimerisation of Trk Receptor monomers into the signal transductive unit- activating the kinase unit[11]. Phosphorylation of the autoregulatory loop tyrosines of the cytoplasmic domain further activates the kinase. Phosphorylation of an additional five tyrosines within this region promotes signalling by providing docking sites for adaptor proteins which regulate signalling-cascade couples. Overall, the purpose of this process appears to be to facilitate down-stream phosphorylation and gene expression regulation(Eg. upregulation of Neuronal Factor Kappa B) via multiple transductive pathways, many of which, are synonymous with tyrosine kinase receptor activity.[11] Thus, the autophosphorylation of intracellular domain tyrosine residues precipitates the association of second-messenger adaptor proteins which may or may not themselves be phosphorylated in order to illicit the desired signalling event (Figure 3).

co-operation with p75NTR: Association with p75NTR(also known as the "low affinity neurotropin receptor") appears to be an integral component of regulation of Trk's. This combination of Trk and p75NTR proteins results in the formation of a high-affinity binding site within the Trk binding region, increasing the responsiveness of receptors for thier ligands[7]. Additionally, coordination with p75NTR has been implicated in a reduction in ubiquitination, delay of internalisation of receptors during sensitisation, and overall decreases the apoptotic potential of cell lines [12] .

Mechanism of Trk Activation via multiple Signalling pathways

Tropomyosine receptor kinases (Trk) enhance neuronal cell growth and differentiation of neurites via the activation of various signalling pathways. PKC, PLCy1, Ras/MAPK and PI3 are the four well known pathways, which exhibit this activity. The latter process involves the activation of transcription factors that will bind onto a specific target gene, thus trigerring neuronal cell division and/ differentiation via production of specific proteins that inhibit apoptosis (Figure 3). Cite error: Closing </ref> missing for <ref> tag This occurs by the activation of the membrane bound receptor by a number of growth factors, cytokines and immunoglobins. [13] DAG is necessary for the further activation of the PKC and it remains bound to the cell membrane. IP3, a water soluble protein , in turn is released into the cytoplasm and leads to the release of Ca2+ reserves from the endoplasmic reticulum. This increase of calcium ions activates the classic isoforms of Protein Kinase C. [14]

Figure 4:Simplified PLC γ1 Pathway. Full sized animation

PLC-y1 Pathway

Phospholipase C, comes in many forms and plays an important role in the signal transduction for many processes, including proliferation, differentiation and motility. Its main function is to hydrolyze phosphatidylinositoldi phosphate (PIP2) into diacylglycerol (DAG) and inositoltriphosphate (IP3). [15] This occurs by the activation of the membrane bound receptor by a number of growth factors, cytokines and immunoglobins. [16] DAG is necessary for the further activation of the PKC and it remains bound to the cell membrane. IP3, a water soluble protein , in turn is released into the cytoplasm and leads to the release of Ca2+ reserves from the endoplasmic reticulum. This increase of calcium ions activates the classic isoforms of Protein Kinase C. [17]

Figure 5: Simplified Animation of PKC pathway. Full size animation

PKC Pathway

See also: Protein Kinase C

Protein Kinase C (PKC) is a family of nucleotide-independent, Ca2+-dependent serine kinases. [18]. At least 11 isozymes have been identified, [19] most PKC isozymes are ubiquitous and multiple members of the family can be coexpressed within the same cell leading to complex pathways. However, the basic signal transduction pathway involves the allosteric activation of PKC by the intracellular messengers diacylglycerol and Calcium ions. The inactive PKC is mainly found in the cytosol. Upon stimulation the PKC proteins translocate to the cell membrane. This translocation is the result of a cascade initiated by the binding of a number of extracellular ligands, such as, growth factors, hormones, and neurotransmitters to a G protein-coupled receptor (GPRC) found on the plasma membrane. This in turn activates a stimulating G protein which in turn activates phospholipase C (PLC). [20] A G protein is then activated, which then activates phospholipase C (PLC). The PLC cleaves phosphoinositol-4,5-bisphosphate (PIP2) into 1,2-diacylglycerol (DAG) and inositol-1.,4,5-triphosphate (IP3). [21] The IP3, couples to Ca2+ channels found on the endoplasmic reticulum releasing Ca2+ reserves. The increased concentration of calcium ions bind to inactive PKC molecules and then translocates to the plasma membrane, giving rise to the active PKC enzyme. [18] The PKC family plays a major role in cellular signal transduction. [22]Their main roles consist in the regulation of cell proliferation, differentiation, survival and apoptosis. [23]

Ras-MAPK (mitogen-activated protein kinase) Pathway

Activation of Ras-MAPK signalling pathway is predominantly essential for promoting neuronal cell growth and differentiation[24]. Several pathways derive from Trk receptors for activation of Ras molecules, which begin by formation of ligand-bound mitogen (BDNF or NGF) at an extracellular domain of the trk, causing receptor dimerization. This subsequently will lead to phosphorylation of the intracellular parts of the receptors, which activates Guanine Exchange factors (GEFs), such as sos, Grb2 and Shc. GEFs trigger the exchange of GDP bound to inactive Ras to GTP, resulting Ras to activate. The presence of activated Ras molecules, stimulate signaling via a major downstream pathway known as MAP kinase (mitogen-activated protein kinase)-although activated Ras, would be also capable of triggering several other downstream pathways such as PLC-y1 and PI3-kinases (Figure 4 & 6). [24]

Mitogen-activated protein kinase (MAPK) pathway involves a series of signalling cascade. Raf is the first component of MAPK, activated by Ras-GTP on the plasma membrane. [24] Raf then phosphorylates MEK1/2, which in turn activates the ERK1/2 by phosphorylation. ERK1/2 kinase would further phosphorylate a variety of downstream targets. These pathways may include phosphorylation of MAP 2-kinase by MAP 3-kinase on its serine and threonine amino-acid residues. Further phosphorylation of MAP- kinase by MAP 2-kinase on its serine and tyrosine amino-acid residues subsequently yields activated MAP-kinase. This results in activation of transcription factors that will lead to changes in gene expression[24] [25]. (Click here for well illustration of MAP-kinase pathway on You-tube). Nonetheless, aberrant Ras-MAPK signaling has been identified to be a possible factor responsible for the uncontrolled proliferation and malignancy. Also see:Cancer Biotherapy .[25]

Figure 6: The image depicts the role of PI3K/Akt signal transduction cascade along with the downstream activation in the formation of cancer cells.

PI3K (Phosphatidylinositol 3-kinase) Pathway

See also: Phosphatidylinositol 3-kinase

The role of PI3K is essential in promoting survival of neuronal cells.[26] PI3K directly activates Ras-dependent pathway through which Trk signaling promotes survival in many, but not all, neurons. In some cells PI3K can be activated through three adaptor proteins, Shc, Grb-2 and Gab-1. PI3K has an array of main effectors, which include the mitogen-transducing signal proteins such as protein kinase C, phosphoinositide-dependent kinases and mitogen activated protein kinases. They are either activated via interaction with lipid products of PI3K or through PI3K-dependent phosphorylation of proteins.[27] PI3K is activated by number of growth factor receptors with intrinsic and tyrosine kinase activity. BAD is an important protein in controlling cell survival and is a Bcl-2 family member which promotes apoptosis by binding to Bcl-xL. When BAD are phosphorylated by Akt or MAPKs, it involves in the regulation of signal transduction in neuronal cells [28] On the other hand, PI3K/Akt signal transduction cascade is predominantly important in the formation of neuronal tumours. This cascade promotes the growth and proliferation of cancer cells and its components represent attractive targets for the design of anticancer agents. mTOR which is a serine/threonine kinase acts on the downstream activation of PI3K for the mediation of prosurvival activity. This will inhibit apoptosis, resulting in the formation of cancer cells.[26][29]

Current Research

Cancer biotherapy via targeting ‘Ras / Ras-MAP-kinase’ signalling pathway

Recent studies have hypothesized that receptors responsible for Ras activation would be effective target for treating human cancers[24]. Based on this hypothesis, since 1995, therapies utilizing the inhibition of Ras activation have aroused a major interest. Farnesylation is a process by which small G-proteins like Ras are activated and adhered to the cell membrane. In a recent paper [30], farnesyl transferase inhibitors were used in order to block the farnesylation of Ras proteins. The results revealed promising hopes in animal models but unfortunately have not been effective in human cancer treatment[30]. The major downstream target of Ras-MAP-Kinase (MAPK) has also been taken as a subject for drug design. Sebolt and his colleagues showed that MAPK-inhibitors are effective in cancer therapy using mouse models [31] . It has been also suggested that Inhibition of the Ras-MAPK signaling pathway can serve as a potential therapy for NF1 in humans. [32]

Trk receptors can behave as signalling endosomes

In a recent publication, a hypothesized model was explained in which active Trk receptors are internalised into signaling endosomes during signalling transduction process. [33] The experiment that led to this understanding involved local application of NGF to axons and soma (cell bodies) of neuronal cells. It was shown that both ERK1/2 and ERK5 signaling cascades were activated. Surprisingly, application of NGF to neuronal cells at distance resulted only in activation of ERK5 pathway and NOT ERK1/2. It was then understood that activation of ERK5 in the cells somas required receptor internalisation due to inhibition by thermo-sensitive dynamin.[33] Further investigation was conducted by local application of specific Trk-inhibitor (K252a) at either the distal axon or cell body, which blockaded the activation of ERK5 in the cell soma in the presence of NGF. Therefore, the hypothesized model in which active Trk receptors are internalised into signalling endosomes is inevitable. Nonetheless, the mechanism through which distance affects the specificity of signalling would be the future topic of investigation. [33]

The interplay between miRNA and Trks (tropomyosin-related kinases)

MicroRNAs are tissue specific, small non-coding RNAs, which are involved in post-trancriptional-silencing mechanism (See also: miRNA Science Overview). In non-mammals, miRNAs have been discovered to be involved in developmental process of the nervous system. For instance, in Caenorhabditis elegans, miR-273 participate in a regulatory mechanism in which ensures for the morphgenesis and differentiation of receptor neurons. [34] Likewise, in mammalian brain tissue certain miRNAs have been identified, in which suggest an important role of these small molecules in modulating Trk receptors and development of nervous system. In addition, functional regulation of these miRNAs is also linked to tumorgenesis of nervous system. For instance, three neuronal miRNAs (9,125a and 125b) are found to be involved in human neuroblastoma cell proliferation by down-modulating TrkC isoform. [35]


  • Apoptosis: Programmed cell death.
  • Autophosphorylation: is the term used to define the phosphorylation of a kinase protein catalysed by its own enzymatic activity.
  • BDNF: Brain-derived neurotrophic growth factor is a protein that promotes activation of tropomyosine receptor kinases (trk).
  • Dynamin: GTPase enzyme responsible for endocytosis in eukaryotic cells.
  • ERK: Extracellular regulated kinase.
  • Exons: Expressed regions of eukaryotic genes.
  • Farnesyl transferase inhibitors: a class of experimental cancer drug that blocks farnesylation of Ras proteins.
  • GTPases: are a large family of enzymes that can bind and hydrolyse guanosine triphosphate(GTP).
  • Isozymes: any of a group of enzymes that are similar in catalytic properties but are different in physical properties, such as isoelectric point.
  • Neurofibromatosis (NF): an inherited disorder that causes production of benign tumours on nerve tissues. There are two types of NF; NF1 and NF2. NF1 is the most common disease amongst infants, also known as Recklinghausen disease.
  • NGF: Nerve growth factor is a protein that promotes activation of tropomyosine receptor kinases (trk).
  • Phosphorylation: A process by which a phosphate group is added to a protein that is required for its cellular activation.
  • Proto-oncogene: normal cellular proteins that have the potential to cause uncontrolled cell growth when mutated.
  • Oncogene: a gene that enhances uncontrolled proliferation of cells when mutated and further expressed at high levels.
  • Ras: small G-proteins that belong to the superfamily of monomeric GTPases. They are involved in receptor-mediated signal transduction pathways.


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External Link/s

MAP Kinase pathway. Cell and Molecular Biology Videos, sponsored by : Garland Science Broadcaster.

Website: http://www.garlandscience.com

Group Reflection

In our teamwork, we not only achieved a great deal of collaboration toward our common goals; the work also reflected each member’s scientific assessment of the topic. Many challenges were faced and overcome over an 11-week period. The first challenge was ambiguity over the distinction between Trk and Tyrosine-kinases. After a few weeks of debate we eventually came to understand these distinctions through an extensive search of the literature using PubMed, and now know that Trk receptors are Tropomyosin-related kinase receptors and not, as is often but erroneously supposed, Tyrosine receptor kinases. Tropomyosine-related kinase (Trk) receptors are in fact classified as a subfamily of Tyrosine-kinase (TK) receptors.

Trk receptors share some functional similarities with Tyrosine-kinase receptors in that once activated by an extracellular ligand, their intracellular domain will be also activated by phosphorylation, which then stimulates a series of signaling cascades to activate its target gene. Unlike Tyrosine-receptor kinases, which are commonly found in various types of cells, Trks are specific to neuronal cells, particularly with respect to neuronal differentiation, growth and establishment of synaptic plasticity. Each trk receptor shows an interest and affinity to a specific neutrophin (growth factor). Based on our research we are now comfortable in relating this differential specificity to the ‘splice-variants’ present in receptor gene alleles. Furthermore, multiple transduction pathways carry specific responses regulating survival and differentiation. The latter process is often gene regulation by association/dissociation of expresser/repressor protein from promoter regions. PKC, PLCy1, Ras/MAPK and PI3 are the main four pathways involved in this activity. Interestingly, recent studies have pinpointed the Ras/MAP kinase pathway as an effective target for cancer biotherapy, and it has proven to be effective in the first experimental mouse model. Although the mechanism by which trk is involved in gene regulation is now largely understood, there are still many unanswered questions associated with it.

Our group found the experience of delegation, with each member contributing only in areas where they felt comfortable doing so, to be extremely useful. We are satisfied that we have adequately communicated our proficiency on this topic to our undergraduate peers at a technical level appropriate for this audience. Overall, this collaborative project was a very rewarding exercise that has instilled us with a renewed appreciation for the value of team-work and communication.

2009 Group Projects

Group 1 Meiosis | Group 2 Cell Death - Apoptosis | Group 3 Cell Division | Group 4 Trk Receptors | Group 5 The Cell Cycle | Group 6 Golgi Apparatus | Group 7 Mitochondria | Group 8 Cell Death - Necrosis | Group 9 Nucleus | Group 10 Cell Shape