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Trk receptors are a family of
tyrosine kinases A tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to the tyrosine residues of specific proteins inside a cell. It functions as an "on" or "off" switch in many cellular functions. Tyrosine kinases belong to a larger cla ...
that regulates synaptic strength and plasticity in the mammalian
nervous system In biology, the nervous system is the highly complex part of an animal that coordinates its actions and sensory information by transmitting signals to and from different parts of its body. The nervous system detects environmental changes ...
. Trk receptors affect
neuron A neuron, neurone, or nerve cell is an electrically excitable cell that communicates with other cells via specialized connections called synapses. The neuron is the main component of nervous tissue in all animals except sponges and placozoa ...
al survival and differentiation through several
signaling cascade A biochemical cascade, also known as a signaling cascade or signaling pathway, is a series of chemical reactions that occur within a biological cell when initiated by a stimulus. This stimulus, known as a first messenger, acts on a receptor tha ...
s. However, the activation of these receptors also has significant effects on functional properties of neurons. The common
ligands In coordination chemistry, a ligand is an ion or molecule (functional group) that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's electr ...
of trk receptors are
neurotrophin Neurotrophins are a family of proteins that induce the survival, development, and function of neurons. They belong to a class of growth factors, secreted proteins that can signal particular cells to survive, differentiate, or grow. Growth fact ...
s, 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'' (often pronounced 'track') stands for tropomyosin receptor kinase or ''tyrosine'' receptor kinase (and not "''tyrosine'' kinase receptor" nor "tropomyosin-''related'' kinase", as has been commonly mistaken). The family of Trk receptors is named for the
oncogene An oncogene is a gene that has the potential to cause cancer. In tumor cells, these genes are often mutated, or expressed at high levels.
''trk'', whose identification led to the discovery of its first member,
TrkA 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'' gen ...
. ''Trk'', initially identified in a colon carcinoma, is frequently (25%) activated in thyroid papillary carcinomas. The oncogene was generated by a
mutation In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, m ...
in
chromosome 1 Chromosome 1 is the designation for the largest human chromosome. Humans have two copies of chromosome 1, as they do with all of the autosomes, which are the non- sex chromosomes. Chromosome 1 spans about 249 million nucleotide base pairs, which ...
that resulted in the fusion of the first seven
exon An exon is any part of a gene that will form a part of the final mature RNA produced by that gene after introns have been removed by RNA splicing. The term ''exon'' refers to both the DNA sequence within a gene and to the corresponding sequen ...
s of tropomyosin to the
transmembrane A transmembrane protein (TP) is a type of integral membrane protein that spans the entirety of the cell membrane. Many transmembrane proteins function as gateways to permit the transport of specific substances across the membrane. They frequent ...
and
cytoplasm In cell biology, the cytoplasm is all of the material within a eukaryotic cell, enclosed by the cell membrane, except for the cell nucleus. The material inside the nucleus and contained within the nuclear membrane is termed the nucleoplasm. ...
ic domains of the then-unknown TrkA receptor. Normal Trk receptors do not contain
amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha ...
or
DNA sequences A nucleic acid sequence is a succession of bases signified by a series of a set of five different letters that indicate the order of nucleotides forming alleles within a DNA (using GACT) or RNA (GACU) molecule. By convention, sequences are us ...
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 A protease (also called a peptidase, proteinase, or proteolytic enzyme) is an enzyme that catalyzes (increases reaction rate or "speeds up") proteolysis, breaking down proteins into smaller polypeptides or single amino acids, and spurring the ...
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 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'' gen ...
is a protein encoded by the NTRK1 gene and has the highest affinity to the binding
nerve growth factor 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 ...
(NGF) After NGF is bound to TrkA this leads to a ligand-induced dimerization causing the
autophosphorylation Autophosphorylation is a type of post-translational modification of proteins. It is generally defined as the phosphorylation of the kinase by itself. In eukaryotes, this process occurs by the addition of a phosphate group to serine, threonine o ...
of the
tyrosine kinase A tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to the tyrosine residues of specific proteins inside a cell. It functions as an "on" or "off" switch in many cellular functions. Tyrosine kinases belong to a larger cla ...
segment, which in turn activates the Ras/MAPK pathway and the
PI3K/Akt pathway The PI3K/AKT/mTOR pathway is an intracellular signaling pathway important in regulating the cell cycle. Therefore, it is directly related to cellular quiescence, proliferation, cancer, and longevity. PI3K activation phosphorylates and activates ...
. NGF is a neurotrophic factor, and the NGF/TrkA interaction is critical in both local and nuclear actions, regulating growth cones,
motility Motility is the ability of an organism to move independently, using metabolic energy. Definitions Motility, the ability of an organism to move independently, using metabolic energy, can be contrasted with sessility, the state of organisms th ...
, 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 Keratoconus (KC) is a disorder of the eye that results in progressive thinning of the cornea. This may result in blurry vision, double vision, nearsightedness, irregular astigmatism, and light sensitivity leading to poor quality-of-life. ...
, functional dyspepsia and, in some cases, over expression has been linked to cancer development. In other cases, such as
neuroblastoma Neuroblastoma (NB) is a type of cancer that forms in certain types of nerve tissue. It most frequently starts from one of the adrenal glands but can also develop in the neck, chest, abdomen, or spine. Symptoms may include bone pain, a lump in ...
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

TrkB has the highest affinity to the binding of brain-derived neurotrophic factor (BDNF) and
NT-4 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 Receptor tyrosine kinas ...
. BDNF is a growth factor that has important roles in the survival and function of neurons in the
central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all p ...
. The binding of BDNF to TrkB receptor causes many intracellular cascades to be activated, which regulate neuronal development and plasticity,
long-term potentiation In neuroscience, long-term potentiation (LTP) is a persistent strengthening of synapses based on recent patterns of activity. These are patterns of synaptic activity that produce a long-lasting increase in signal transmission between two neurons ...
, and
apoptosis Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes ( morphology) and death. These changes in ...
.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. 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 Alzheimer's disease (AD) is a neurodegenerative disease that usually starts slowly and progressively worsens. It is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As ...
and post-intracerebral hemorrhage depression.


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.) TrkC is mostly expressed by proprioceptive sensory neurons. The
axon An axon (from Greek ἄξων ''áxōn'', axis), or nerve fiber (or nerve fibre: see spelling differences), is a long, slender projection of a nerve cell, or neuron, in vertebrates, that typically conducts electrical impulses known as action p ...
s of these proprioceptive sensory neurons are much thicker than those of nociceptive sensory neurons, which express trkA.


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. 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 site In biochemistry and molecular biology, a binding site is a region on a macromolecule such as a protein that binds to another molecule with specificity. The binding partner of the macromolecule is often referred to as a ligand. Ligands may includ ...
s 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 (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 Studies that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, and p ...
and
in vitro ''In vitro'' (meaning in glass, or ''in the glass'') studies are performed with microorganisms, cells, or biological molecules outside their normal biological context. Colloquially called " test-tube experiments", these studies in biology a ...
, have shown that neurotrophins have proliferation and differentiation effects on CNS neuro-epithelial precursors,
neural crest Neural crest cells are a temporary group of cells unique to vertebrates that arise from the embryonic ectoderm germ layer, and in turn give rise to a diverse cell lineage—including melanocytes, craniofacial cartilage and bone, smooth muscle, per ...
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 Neural crest cells are a temporary group of cells unique to vertebrates that arise from the embryonic ectoderm germ layer, and in turn give rise to a diverse cell lineage—including melanocytes, craniofacial cartilage and bone, smooth muscle, per ...
cells, oligodendrocyte precursors, and differentiation of hippocampal neuron precursors.


Control of target innervation

Each of the neurotrophins mentioned above promotes
neurite A neurite or neuronal process refers to any projection from the cell body of a neuron. This projection can be either an axon or a dendrite. The term is frequently used when speaking of immature or developing neurons, especially of cells in cultur ...
outgrowth. 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. 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 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 Receptor tyrosine kinas ...
binding acutely sensitizing nocireceptive pathway that require the presence of
mast cell A mast cell (also known as a mastocyte or a labrocyte) is a resident cell of connective tissue that contains many granules rich in histamine and heparin. Specifically, it is a type of granulocyte derived from the myeloid stem cell that is a par ...
s.


Sensory neuron function

Trk receptors and their ligands (neurotrophins) also affect neurons' functional properties. Both NT-3 and BDNF are important in the regulation and development of
synapse In the nervous system, a synapse is a structure that permits a neuron (or nerve cell) to pass an electrical or chemical signal to another neuron or to the target effector cell. Synapses are essential to the transmission of nervous impulses from ...
s formed between afferent neurons and
motor neuron A motor neuron (or motoneuron or efferent neuron) is a neuron whose cell body is located in the motor cortex, brainstem or the spinal cord, and whose axon (fiber) projects to the spinal cord or outside of the spinal cord to directly or indirect ...
s. Increased NT-3/trkC binding results in larger monosynaptic
excitatory postsynaptic potential In neuroscience, an excitatory postsynaptic potential (EPSP) is a postsynaptic potential that makes the postsynaptic neuron more likely to fire an action potential. This temporary depolarization of postsynaptic membrane potential, caused by the ...
s (EPSPs) and reduced
polysynaptic A reflex arc is a neural pathway that controls a reflex. In vertebrates, most sensory neurons do not pass directly into the brain, but synapse in the spinal cord. This allows for faster reflex actions to occur by activating spinal motor neurons ...
components. On the other hand, increased NT-3 binding to trkB to BDNF has the opposite effect, reducing the size of monosynaptic excitatory postsynaptic potentials (EPSPs) and increasing polysynaptic signaling.


Formation of ocular dominance column

In the development of mammalian visual system, axons from each eyes crosses through the
lateral geniculate nucleus In neuroanatomy, the lateral geniculate nucleus (LGN; also called the lateral geniculate body or lateral geniculate complex) is a structure in the thalamus and a key component of the mammalian visual pathway. It is a small, ovoid, ventral projec ...
(LGN) and terminate in separate layers of
striate cortex The visual cortex of the brain is the area of the cerebral cortex that processes visual information. It is located in the occipital lobe. Sensory input originating from the eyes travels through the lateral geniculate nucleus in the thalamus a ...
. 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 Ocular dominance, sometimes called eye preference or eyedness, is the tendency to prefer visual input from one eye to the other. It is somewhat analogous to the laterality of right- or left- handedness; however, the side of the dominant eye and th ...
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. Therefore, it raises the possibility that both of these agents are involved in some sorting mechanism that is not well comprehended yet. 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. Surprisingly, even after losing responses during the critical period, the infusion of NT-4 has been shown to be able to restore them.


Synaptic strength and plasticity

In mammalian
hippocampus The hippocampus (via Latin from Greek , 'seahorse') is a major component of the brain of humans and other vertebrates. Humans and other mammals have two hippocampi, one in each side of the brain. The hippocampus is part of the limbic syste ...
, the axons of the CA3
pyramidal cell Pyramidal cells, or pyramidal neurons, are a type of multipolar neuron found in areas of the brain including the cerebral cortex, the hippocampus, and the amygdala. Pyramidal neurons are the primary excitation units of the mammalian prefrontal co ...
s project into CA1 cells through the Schaffer collaterals. The
long-term potentiation In neuroscience, long-term potentiation (LTP) is a persistent strengthening of synapses based on recent patterns of activity. These are patterns of synaptic activity that produce a long-lasting increase in signal transmission between two neurons ...
(LTP) may induce in either of these pathways, but it is specific only to the one that is stimulated with
tetanus Tetanus, also known as lockjaw, is a bacterial infection caused by ''Clostridium tetani'', and is characterized by muscle spasms. In the most common type, the spasms begin in the jaw and then progress to the rest of the body. Each spasm usually ...
. 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 cell A granule is a large particle or grain. It can refer to: * Granule (cell biology), any of several submicroscopic structures, some with explicable origins, others noted only as cell type-specific features of unknown function ** Azurophilic granul ...
s, CA3 and CA1 pyramidal cells, and inhibitory interneurons. LTP can be greatly reduced by BDNF mutants. In a similar study on a mouse mutant with reduced expression of trkB receptors, LTP of CA1 cells reduced significantly. TrkB loss has also been linked to interfere with the memory acquisition and consolidation in many learning paradigm.


Role of Trk oncogenes in cancer

Although originally identified as an oncogenic fusion in 1982, 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. More specifically, differential expression of Trk receptors closely correlates to prognosis and outcome in a number of cancers, such as
neuroblastoma Neuroblastoma (NB) is a type of cancer that forms in certain types of nerve tissue. It most frequently starts from one of the adrenal glands but can also develop in the neck, chest, abdomen, or spine. Symptoms may include bone pain, a lump in ...
. 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. As a result, Trk inhibitors have been explored as a potential treatment avenue in the field of
precision medicine Precision, precise or precisely may refer to: Science, and technology, and mathematics Mathematics and computing (general) * Accuracy and precision, measurement deviation from true value and its scatter * Significant figures, the number of digi ...
. Trk inhibitors are (in 2015) in clinical trials and have shown early promise in shrinking human tumors.


Trk inhibitors in development

Entrectinib (formerly RXDX-101, trade name Rozlytrek) is an investigational drug developed by Ignyta, Inc., which has potential antitumor activity. It is a selective pan-trk receptor
tyrosine kinase inhibitor A tyrosine kinase inhibitor (TKI) is a pharmaceutical drug that inhibits tyrosine kinases. Tyrosine kinases are enzymes responsible for the activation of many proteins by signal transduction cascades. The proteins are activated by adding a phosph ...
(TKI) targeting gene fusions in
trkA 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'' gen ...
, trkB, and trkC (coded by NTRK1,
NTRK2 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 recept ...
, and NTRK3 genes) that is currently in phase 2 clinical testing. 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 Array BioPharma is an American clinical stage, pharmaceutical company that focuses on oncology medication headquartered in Boulder, Colorado. The company is a subsidiary of Pfizer. History In 1998, the company was founded by Drs. Tony Piscopio, ...
for solid tumors with NTRK fusion mutations.


Activation pathway

Trk receptors dimerize in response to ligand, as do other tyrosine kinase receptors. These dimers phosphorylate each other and enhance
catalytic activity Catalysis () is the process of increasing the rate of a chemical reaction by adding a substance known as a catalyst (). Catalysts are not consumed in the reaction and remain unchanged after it. If the reaction is rapid and the catalyst recyc ...
of the kinase. 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. These pathways involve the interception of nuclear and mitochondrial cell-death programs. These signaling cascades eventually led to the activation of a
transcription factor In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The f ...
, CREB (cAMP response element-binding), which in turn activate the target genes.


PKC pathways

The binding of
neurotrophin Neurotrophins are a family of proteins that induce the survival, development, and function of neurons. They belong to a class of growth factors, secreted proteins that can signal particular cells to survive, differentiate, or grow. Growth fact ...
will lead to the phosphorylation of
phospholipase C Phospholipase C (PLC) is a class of membrane-associated enzymes that cleave phospholipids just before the phosphate group (see figure). It is most commonly taken to be synonymous with the human forms of this enzyme, which play an important role ...
(PLC) by trk receptor. This phosphorylation of PLC induces an enzyme to catalyze the breakdown of lipids to diacyglycerol and inositol(1,4, 5). Diacyglycerol may indirectly activate PI3 kinase or several
protein kinase C In cell biology, Protein kinase C, commonly abbreviated to PKC (EC 2.7.11.13), is a family of protein kinase enzymes that are involved in controlling the function of other proteins through the phosphorylation of hydroxyl groups of serine and ...
(PKC) isoforms, whereas inositol(1,4, 5) promotes release of calcium from intracellular stores.


Ras/MAPK pathway

The signaling through Ras/MAPK pathway is important for the neurotrophin-induced differentiation of neuronal and
neuroblastoma Neuroblastoma (NB) is a type of cancer that forms in certain types of nerve tissue. It most frequently starts from one of the adrenal glands but can also develop in the neck, chest, abdomen, or spine. Symptoms may include bone pain, a lump in ...
cells. Phosphorylation of tyrosine residues in the Trk receptors led to the activation of Ras molecules,
H-Ras GTPase HRas, from "Harvey Rat sarcoma virus", also known as transforming protein p21 is an enzyme that in humans is encoded by the gene. The ''HRAS'' gene is located on the short (p) arm of chromosome 11 at position 15.5, from base pair 522,241 ...
and
K-Ras ''KRAS'' ( Kirsten rat sarcoma virus) is a gene that provides instructions for making a protein called K-Ras, a part of the RAS/MAPK pathway. The protein relays signals from outside the cell to the cell's nucleus. These signals instruct the cell ...
. H-ras is found in lipid rafts, embedded within the
plasma membrane The cell membrane (also known as the plasma membrane (PM) or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of all cells from the outside environment (t ...
, while K-Ras is predominantly found in disordered region of the membrane. RAP, a vesicle bounded molecule that also takes part in the cascading, is localized in the intracellular region. The activation of these molecules result in two alternative
MAP kinase A mitogen-activated protein kinase (MAPK or MAP kinase) is a type of protein kinase that is specific to the amino acids serine and threonine (i.e., a serine/threonine-specific protein kinase). MAPKs are involved in directing cellular response ...
pathways. 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. However, whether PKC (protein kinase C) could activate MEK5 is not yet known.


PI3 pathway

PI3 pathway signaling is critical for both mediation of neurotrophin-induced survival and regulation of vesicular trafficking. The trk receptor stimulates PI3K heterodimers, which causes the activation of kinases PDK-1 and
Akt Protein kinase B (PKB), also known as Akt, is the collective name of a set of three serine/threonine-specific protein kinases that play key roles in multiple cellular processes such as glucose metabolism, apoptosis, cell proliferation, tran ...
. 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.


See also

* TrkB receptor


References

{{Portal bar, Biology, border=no Tyrosine kinase receptors