TrkA
Encyclopedia
High affinity nerve growth factor receptor also known as neurotrophic tyrosine kinase receptor type 1 or TRK1-transforming tyrosine kinase protein or Trk-A is a protein
that in humans is encoded by the NTRK1 gene
.
This gene encodes a member of the neurotrophic tyrosine kinase receptor (NTKR) family
. This kinase is a membrane-bound receptor that, upon neurotrophin
binding, phosphorylates itself (autophosphorylation
) and members of the MAPK pathway
. The presence of this kinase leads to cell differentiation and may play a role in specifying sensory neuron subtypes. Mutations in this gene have been associated with congenital insensitivity to pain with anhidrosis
, self-mutilating behavior, mental retardation
and cancer
. Alternate transcriptional splice variants of this gene have been found, but only three have been characterized to date.
for the neurotrophin
, Nerve Growth Factor
, or "NGF". As such, it mediates the multiple effects of NGF, which includes neuron
al differentiation
and survival.
The TrkA receptor is part of the large family of receptor tyrosine kinase
s. A "tyrosine kinase
" is an enzyme which is capable of adding a phosphate group to a/the certain tyrosine
s on target protein
s, or "substrates
". A receptor tyrosine kinase is a tyrosine kinase which is located at the cellular membrane, and is activated by binding of a ligand
via its extracellular
domain. Other example of tyrosine kinase receptors include the insulin receptor
, the Insulin-like growth factor 1 receptor, the MuSK receptor, the Vascular Endothelial Growth Factor (or VEGF) receptor, etc. The substrate proteins which are phosphorylated
by TrkA include PI3 kinase.
and TrkC
. Also, there are other neurotrophic factors structurally related to NGF: BDNF (for Brain-Derived Neurotrophic Factor), NT-3 (for Neurotrophin-3) and NT-4 (for Neurotrophin-4). While TrkA mediates the effects of NGF, TrkB
is bound and activated by BDNF, NT-4, and NT-3. Further, TrkC
binds and is activated by NT-3.
"). As opposed to TrkA, the LNGFR plays a somewhat less clear role in NGF biology. Some researchers have shown the LNGFR binds and serves as a "sink" for neurotrophins. Cells which express both the LNGFR and the Trk receptors might therefore have a greater activity - since they have a higher "microconcentration" of the neurotrophin. It has also been shown, however, that in the absence of a co-expressed TrkA, the LNGFR may signal a cell to die via apoptosis - so therefore cells expressing the LNGFR in the absence of Trk receptors may die rather than live in the presence of a neurotrophin.
.
In one study, a total absence of TrkA receptor was found in keratoconus
-affected corneas, along with an increased level of repressor isoform of Sp3 transcription factor
.
/proteasome
" system. In this system, a small (7-8 kd)protein called "ubiquitin
" is affixed to a target protein, and is thereby targeted for destruction by a structure called the "proteasome
". TrkA is targeted for proteasome-mediated destruction by an "E3 ubiquitin ligase
" called NEDD-4. This mechanism may be a distinct way to control the survival of a neuron. The extent and maybe type of TrkA ubiquitiniation can be regulated by the other, unrelated receptor for NGF, p75NTR [5].
with:
Small molecules such as amitriptyline
and gambogic acid
derivatives have been claimed to activate TrkA. Amitriptyline activates TrkA and facilitate the heterodimerisation of TrkA and TrkB
in the absence of NGF. Binding of Amitriptyline to TrkA occurs to the Leucine Rich Region (LRR) of the extracellular domain of the receptor, which is distinct from the NGF binding site. Amitryptiline possess neurotrophic activity both in-vitro and in-vivo (mouse model). Gambogic Amide, a derivative of Gambogic acid, selectively activates TrkA (but not TrkB
and TrkC
) both in-vitro and in-vivo by interacting with the cytoplasmic juxtamembrane domain of TrkA.
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
that in humans is encoded by the NTRK1 gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
.
This gene encodes a member of the neurotrophic tyrosine kinase receptor (NTKR) family
Trk receptor
Trk receptors are a family of tyrosine kinases that regulates synaptic strength and plasticity in the mammalian nervous system. Trk receptors affect neuronal survival and differentiation through several signal cascades...
. This kinase is a membrane-bound receptor that, upon neurotrophin
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 are capable of signaling particular cells to survive, differentiate, or grow. Growth factors such as neurotrophins that promote the...
binding, phosphorylates itself (autophosphorylation
Autophosphorylation
In biochemistry, autophosphorylation is the process in which a protein kinase attaches a phosphate group to itself. This usually lead to kinase activation or regulation, and phosphorylation of other kinase substrates....
) and members of the MAPK pathway
MAPK/ERK pathway
The MAPK/ERK pathway is a chain of proteins in the cell that communicates a signal from a receptor on the surface of the cell to the DNA in the nucleus of the cell. The signal starts when a growth factor binds to the receptor on the cell surface and ends when the DNA in the nucleus expresses a...
. The presence of this kinase leads to cell differentiation and may play a role in specifying sensory neuron subtypes. Mutations in this gene have been associated with congenital insensitivity to pain with anhidrosis
Congenital insensitivity to pain with anhidrosis
Congenital insensitivity to pain with anhidrosis is an extremely rare inherited disorder of the nervous system which prevents the sensation of pain, heat, cold, or any real nerve-related sensations ; however, patients can still feel pressure. CIPA is the fourth type of hereditary sensory and...
, self-mutilating behavior, mental retardation
Mental retardation
Mental retardation is a generalized disorder appearing before adulthood, characterized by significantly impaired cognitive functioning and deficits in two or more adaptive behaviors...
and cancer
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
. Alternate transcriptional splice variants of this gene have been found, but only three have been characterized to date.
Function
TrkA is the high affinity catalytic receptorCatalytic receptor
A Catalytic receptor is an integral membrane protein possessing both enzymatic catalytic and receptor functions.The following is a list of the five major families of catalytic receptors:...
for the neurotrophin
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 are capable of signaling particular cells to survive, differentiate, or grow. Growth factors such as neurotrophins that promote the...
, Nerve Growth Factor
Nerve growth factor
Nerve growth factor is a small secreted protein that is important for the growth, maintenance, and survival of certain target neurons . It also functions as a signaling molecule. It is perhaps the prototypical growth factor, in that it is one of the first to be described...
, or "NGF". As such, it mediates the multiple effects of NGF, which includes neuron
Neuron
A neuron is an electrically excitable cell that processes and transmits information by electrical and chemical signaling. Chemical signaling occurs via synapses, specialized connections with other cells. Neurons connect to each other to form networks. Neurons are the core components of the nervous...
al differentiation
Cellular differentiation
In developmental biology, cellular differentiation is the process by which a less specialized cell becomes a more specialized cell type. Differentiation occurs numerous times during the development of a multicellular organism as the organism changes from a simple zygote to a complex system of...
and survival.
The TrkA receptor is part of the large family of receptor tyrosine kinase
Receptor tyrosine kinase
Receptor tyrosine kinases s are the high-affinity cell surface receptors for many polypeptide growth factors, cytokines, and hormones. Of the 90 unique tyrosine kinase genes identified in the human genome, 58 encode receptor tyrosine kinase proteins....
s. A "tyrosine kinase
Tyrosine kinase
A tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to a protein in a cell. It functions as an "on" or "off" switch in many cellular functions....
" is an enzyme which is capable of adding a phosphate group to a/the certain tyrosine
Tyrosine
Tyrosine or 4-hydroxyphenylalanine, is one of the 22 amino acids that are used by cells to synthesize proteins. Its codons are UAC and UAU. It is a non-essential amino acid with a polar side group...
s on target protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
s, or "substrates
Substrate (biochemistry)
In biochemistry, a substrate is a molecule upon which an enzyme acts. Enzymes catalyze chemical reactions involving the substrate. In the case of a single substrate, the substrate binds with the enzyme active site, and an enzyme-substrate complex is formed. The substrate is transformed into one or...
". A receptor tyrosine kinase is a tyrosine kinase which is located at the cellular membrane, and is activated by binding of a ligand
Ligand (biochemistry)
In biochemistry and pharmacology, a ligand is a substance that forms a complex with a biomolecule to serve a biological purpose. In a narrower sense, it is a signal triggering molecule, binding to a site on a target protein.The binding occurs by intermolecular forces, such as ionic bonds, hydrogen...
via its extracellular
Extracellular
In cell biology, molecular biology and related fields, the word extracellular means "outside the cell". This space is usually taken to be outside the plasma membranes, and occupied by fluid...
domain. Other example of tyrosine kinase receptors include the insulin receptor
Insulin receptor
In molecular biology, the insulin receptor is a transmembrane receptor that is activated by insulin. It belongs to the large class of tyrosine kinase receptors....
, the Insulin-like growth factor 1 receptor, the MuSK receptor, the Vascular Endothelial Growth Factor (or VEGF) receptor, etc. The substrate proteins which are phosphorylated
Phosphorylation
Phosphorylation is the addition of a phosphate group to a protein or other organic molecule. Phosphorylation activates or deactivates many protein enzymes....
by TrkA include PI3 kinase.
Family members
TrkA is part of a sub-family of protein kinases which includes TrkBTrkB
TrkB receptor also known as TrkB tyrosine kinase 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.-Function:...
and TrkC
TrkC
NT-3 growth factor receptor also known as neurotrophic tyrosine kinase receptor type 3 or TrkC tyrosine kinase or Trk-C receptor is a protein that in humans is encoded by the NTRK3 gene....
. Also, there are other neurotrophic factors structurally related to NGF: BDNF (for Brain-Derived Neurotrophic Factor), NT-3 (for Neurotrophin-3) and NT-4 (for Neurotrophin-4). While TrkA mediates the effects of NGF, TrkB
TrkB
TrkB receptor also known as TrkB tyrosine kinase 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.-Function:...
is bound and activated by BDNF, NT-4, and NT-3. Further, TrkC
TrkC
NT-3 growth factor receptor also known as neurotrophic tyrosine kinase receptor type 3 or TrkC tyrosine kinase or Trk-C receptor is a protein that in humans is encoded by the NTRK3 gene....
binds and is activated by NT-3.
The Low Affinity Nerve Growth Factor Receptor
There is one other NGF receptor besides TrkA, called the "LNGFR" (for "Low Affinity Nerve Growth Factor ReceptorLow Affinity Nerve Growth Factor Receptor
The Low-Affinity Nerve Growth Factor Receptor is one of the two receptor types for the neurotrophins, a family of protein growth factors that stimulate neuronal cells to survive and differentiate...
"). As opposed to TrkA, the LNGFR plays a somewhat less clear role in NGF biology. Some researchers have shown the LNGFR binds and serves as a "sink" for neurotrophins. Cells which express both the LNGFR and the Trk receptors might therefore have a greater activity - since they have a higher "microconcentration" of the neurotrophin. It has also been shown, however, that in the absence of a co-expressed TrkA, the LNGFR may signal a cell to die via apoptosis - so therefore cells expressing the LNGFR in the absence of Trk receptors may die rather than live in the presence of a neurotrophin.
Role in disease
TrkA was originally cloned from a colon tumor; the cancer occurred via a translocation, which resulted in the activation of the TrkA kinase domain. However, TrkA itself does not appear to be an oncogeneOncogene
An oncogene is a gene that has the potential to cause cancer. In tumor cells, they are often mutated or expressed at high levels.An oncogene is a gene found in the chromosomes of tumor cells whose activation is associated with the initial and continuing conversion of normal cells into cancer...
.
In one study, a total absence of TrkA receptor was found in keratoconus
Keratoconus
Keratoconus , is a degenerative disorder of the eye in which structural changes within the cornea cause it to thin and change to a more conical shape than its normal gradual curve....
-affected corneas, along with an increased level of repressor isoform of Sp3 transcription factor
Sp3 transcription factor
Sp3 transcription factor, also known as SP3, refers to both a protein and the gene it is encoded by.This gene belongs to a family of Sp1 related genes that encode transcription factors that regulate transcription by binding to consensus GC- and GT-box regulatory elements in target genes...
.
Regulation of TrkA
The levels of distinct proteins can be regulated by the "ubiquitinUbiquitin
Ubiquitin is a small regulatory protein that has been found in almost all tissues of eukaryotic organisms. Among other functions, it directs protein recycling.Ubiquitin can be attached to proteins and label them for destruction...
/proteasome
Proteasome
Proteasomes are very large protein complexes inside all eukaryotes and archaea, and in some bacteria. In eukaryotes, they are located in the nucleus and the cytoplasm. The main function of the proteasome is to degrade unneeded or damaged proteins by proteolysis, a chemical reaction that breaks...
" system. In this system, a small (7-8 kd)protein called "ubiquitin
Ubiquitin
Ubiquitin is a small regulatory protein that has been found in almost all tissues of eukaryotic organisms. Among other functions, it directs protein recycling.Ubiquitin can be attached to proteins and label them for destruction...
" is affixed to a target protein, and is thereby targeted for destruction by a structure called the "proteasome
Proteasome
Proteasomes are very large protein complexes inside all eukaryotes and archaea, and in some bacteria. In eukaryotes, they are located in the nucleus and the cytoplasm. The main function of the proteasome is to degrade unneeded or damaged proteins by proteolysis, a chemical reaction that breaks...
". TrkA is targeted for proteasome-mediated destruction by an "E3 ubiquitin ligase
Ubiquitin ligase
A ubiquitin ligase is a protein that in combination with an E2 ubiquitin-conjugating enzyme causes the attachment of ubiquitin to a lysine on a target protein via an isopeptide bond; the E3 ubiquitin ligase targets specific protein substrates for degradation by the proteasome...
" called NEDD-4. This mechanism may be a distinct way to control the survival of a neuron. The extent and maybe type of TrkA ubiquitiniation can be regulated by the other, unrelated receptor for NGF, p75NTR [5].
Interactions
TrkA has been shown to interactProtein-protein interaction
Protein–protein interactions occur when two or more proteins bind together, often to carry out their biological function. Many of the most important molecular processes in the cell such as DNA replication are carried out by large molecular machines that are built from a large number of protein...
with:
- Abl geneAbl geneV-abl Abelson murine leukemia viral oncogene homolog 1 also known as ABL1 is a protein that, in humans, is encoded by the ABL1 gene located on chromosome 9.- Function :...
. - FRS2FRS2Fibroblast growth factor receptor substrate 2 is a protein that in humans is encoded by the FRS2 gene.-Interactions:FRS2 has been shown to interact with PRKCI, Grb2, PTPN11, Fibroblast growth factor receptor 1, TrkA, Cbl gene and SOS1....
, - Grb2Grb2Growth factor receptor-bound protein 2 also known as Grb2 is an adaptor protein involved in signal transduction/cell communication. In humans, the GRB2 protein is encoded by the GRB2 gene....
, - MATKMegakaryocyte-associated tyrosine kinaseMegakaryocyte-associated tyrosine-protein kinase is an enzyme that in humans is encoded by the MATK gene.-Interactions:Megakaryocyte-associated tyrosine kinase has been shown to interact with CD117 and TrkA.-Further reading:...
, - NGFBNerve growth factorNerve growth factor is a small secreted protein that is important for the growth, maintenance, and survival of certain target neurons . It also functions as a signaling molecule. It is perhaps the prototypical growth factor, in that it is one of the first to be described...
, - PLCG1PLCG1Phospholipase C, gamma 1, also known as PLCG1, is a protein that in humans is encoded by the PLCG1 gene.-Function:The protein encoded by this gene catalyzes the formation of inositol 1,4,5-trisphosphate and diacylglycerol from phosphatidylinositol 4,5-bisphosphate...
, - RICSRICS (gene)Rho GTPase-activating protein 32 is a protein that in humans is encoded by the RICS gene. RICS has two known isoforms, RICS that are expressed primarily at neurite growth cones, and at the post synaptic membranes, and PX-RICS which is more widely expressed in the endoplasmic reticulum, Golgi...
, - SQSTM1Sequestosome 1Sequestosome-1 is a protein that in humans is encoded by the SQSTM1 gene.-Interactions:Sequestosome 1 has been shown to interact with RAD23A, TrkA, TrkB, PRKCI, RIPK1, TRAF6 and MAP1LC3A.-Further reading:...
, - SH2B1SH2B1SH2B adapter protein 1 is a protein that in humans is encoded by the SH2B1 gene.-Interactions:SH2B1 has been shown to interact with Insulin receptor, Grb2, TrkA and Janus kinase 2.- Clinical significance :...
, - SH2B2SH2B2SH2B adapter protein 2 is a protein that in humans is encoded by the SH2B2 gene.-Interactions:SH2B2 has been shown to interact with TrkA and Cbl gene.-Further reading:...
, and - SHC1SHC1SHC-transforming protein 1 is a protein that in humans is encoded by the SHC1 gene. SHC has been found to be important in the regulation of apoptosis and drug resistance in mammalian cells....
.
Small molecules such as amitriptyline
Amitriptyline
Amitriptyline is a tricyclic antidepressant . It is the most widely used TCA and has at least equal efficacy against depression as the newer class of SSRIs...
and gambogic acid
Gambogic acid
Gambogic acid is a xanthonoid that is derived from the brownish or orange resin from Garcinia hanburyi. This natural chemical has shown promising antitumor activity in clinical trials with mice. Garcinia hanburyi is a small to medium sized evergreen tree with smooth grey bark...
derivatives have been claimed to activate TrkA. Amitriptyline activates TrkA and facilitate the heterodimerisation of TrkA and TrkB
TrkB
TrkB receptor also known as TrkB tyrosine kinase 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.-Function:...
in the absence of NGF. Binding of Amitriptyline to TrkA occurs to the Leucine Rich Region (LRR) of the extracellular domain of the receptor, which is distinct from the NGF binding site. Amitryptiline possess neurotrophic activity both in-vitro and in-vivo (mouse model). Gambogic Amide, a derivative of Gambogic acid, selectively activates TrkA (but not TrkB
TrkB
TrkB receptor also known as TrkB tyrosine kinase 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.-Function:...
and TrkC
TrkC
NT-3 growth factor receptor also known as neurotrophic tyrosine kinase receptor type 3 or TrkC tyrosine kinase or Trk-C receptor is a protein that in humans is encoded by the NTRK3 gene....
) both in-vitro and in-vivo by interacting with the cytoplasmic juxtamembrane domain of TrkA.