Tropomyosin receptor kinase C (TrkC),
also known as NT-3 growth factor receptor, neurotrophic tyrosine kinase receptor type 3, or TrkC tyrosine kinase is a
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...
that in humans is encoded by the ''NTRK3''
gene
In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...
.
TrkC is the high affinity
catalytic receptor An enzyme-linked receptor, also known as a catalytic receptor, is a transmembrane receptor, where the binding of an extracellular ligand causes enzymatic activity on the intracellular side. Hence a catalytic receptor is an integral membrane protein ...
for the
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 factor ...
NT-3
Neurotrophin-3 is a protein that in humans is encoded by the ''NTF3'' gene.
The protein encoded by this gene, NT-3, is a neurotrophic factor in the NGF (Nerve Growth Factor) family of neurotrophins. It is a protein growth factor which has activi ...
(
neurotrophin-3
Neurotrophin-3 is a protein that in humans is encoded by the ''NTF3'' gene.
The protein encoded by this gene, NT-3, is a neurotrophic factor in the NGF (Nerve Growth Factor) family of neurotrophins. It is a protein growth factor which has activi ...
). As such, TrkC mediates the multiple effects of this
neurotrophic factor
Neurotrophic factors (NTFs) are a family of biomolecules – nearly all of which are peptides or small proteins – that support the growth, survival, and cell differentiation, differentiation of both developing and mature neurons. Most ...
, which includes neuronal differentiation and survival.
The TrkC receptor is part of the large family of
receptor tyrosine kinases
Receptor tyrosine kinases (RTKs) 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 ...
. A "tyrosine
kinase
In biochemistry, a kinase () is an enzyme that catalyzes the transfer of phosphate groups from high-energy, phosphate-donating molecules to specific substrates. This process is known as phosphorylation, where the high-energy ATP molecule don ...
" is an enzyme which is capable of adding a phosphate group to the certain tyrosines on target proteins, or "substrates". A
receptor tyrosine kinase
Receptor tyrosine kinases (RTKs) 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 ...
is a "tyrosine kinase" which is located at the cellular membrane, and is activated by binding of a
ligand
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 ...
via its extracellular domain. Other example of tyrosine kinase receptors include the
insulin receptor
The insulin receptor (IR) is a transmembrane receptor that is activated by insulin, IGF-I, IGF-II and belongs to the large class of receptor tyrosine kinase. Metabolically, the insulin receptor plays a key role in the regulation of glucose homeo ...
, the
IGF-1 receptor
The insulin-like growth factor 1 (IGF-1) receptor is a protein found on the surface of human cells. It is a transmembrane receptor that is activated by a hormone called insulin-like growth factor 1 ( IGF-1) and by a related hormone called IGF-2. ...
, the
MuSK protein
MuSK (for Muscle-Specific Kinase) is a receptor tyrosine kinase required for the formation and maintenance of the neuromuscular junction. It is activated by a nerve-derived proteoglycan called agrin, which is similarly also required for neuromuscu ...
receptor, the
vascular endothelial growth factor
Vascular endothelial growth factor (VEGF, ), originally known as vascular permeability factor (VPF), is a signal protein produced by many cells that stimulates the formation of blood vessels. To be specific, VEGF is a sub-family of growth factors, ...
(VEGF) receptor, etc. The "substrate" proteins which are phosphorylated by TrkC include
PI3 kinase
Phosphoinositide 3-kinases (PI3Ks), also called phosphatidylinositol 3-kinases, are a family of enzymes involved in cellular functions such as cell growth, proliferation, differentiation, motility, survival and intracellular trafficking, which i ...
.
Function
TrkC is the high affinity
catalytic receptor An enzyme-linked receptor, also known as a catalytic receptor, is a transmembrane receptor, where the binding of an extracellular ligand causes enzymatic activity on the intracellular side. Hence a catalytic receptor is an integral membrane protein ...
for the
neurotrophin-3
Neurotrophin-3 is a protein that in humans is encoded by the ''NTF3'' gene.
The protein encoded by this gene, NT-3, is a neurotrophic factor in the NGF (Nerve Growth Factor) family of neurotrophins. It is a protein growth factor which has activi ...
(also known as NTF3 or NT-3). Similar to other NTRK receptors and receptor tyrosine kinases in general, ligand binding induces receptor dimerization followed by trans-autophosphorylation on conserved tyrosine in the intracellular (cytoplasmic) domain of the receptor. These conserved tyrosine serve as docking sites for adaptor proteins that trigger downstream signaling cascades. Signaling through
PLCG1
Phospholipase C, gamma 1, also known as PLCG1,is a protein that in humans involved in cell growth, migration, apoptosis, and proliferation. It is encoded by the ''PLCG1'' gene and is part of the PLC superfamily.
Function
PLCγ1 is a cell grow ...
,
PI3K
Phosphoinositide 3-kinases (PI3Ks), also called phosphatidylinositol 3-kinases, are a family of enzymes involved in cellular functions such as cell growth, proliferation, differentiation, motility, survival and intracellular trafficking, which i ...
and
RAAS, downstream of activated NTRK3, regulates cell survival, proliferation and motility
Moreover, TrkC has been identified as a novel synaptogenic adhesion molecule responsible for excitatory synapse development.
The TrkC locus encodes at least eight isoforms including forms without the kinase domain or with kinase insertions adjacent to the major autophosphorylation site. These forms arise by alternative splicing events and are expressed in different tissues and cell types.
NT-3
Neurotrophin-3 is a protein that in humans is encoded by the ''NTF3'' gene.
The protein encoded by this gene, NT-3, is a neurotrophic factor in the NGF (Nerve Growth Factor) family of neurotrophins. It is a protein growth factor which has activi ...
activation of catalytic TrkC isoform promotes both proliferation of neural crest cells and neuronal differentiation. On the other hand, the binding of
NT-3
Neurotrophin-3 is a protein that in humans is encoded by the ''NTF3'' gene.
The protein encoded by this gene, NT-3, is a neurotrophic factor in the NGF (Nerve Growth Factor) family of neurotrophins. It is a protein growth factor which has activi ...
to the non-catalytic TrkC isoform induces neuronal differentiation, but nor neuronal proliferation
Family members
Tropomyosin receptor kinases, also known as neurotrophic tyrosine kinase receptors (Trk) play an essential role in the biology of neurons by mediating Neurotrophin-activated signaling. There are three transmembrane receptors
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
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 recepto ...
and TrkC (encoded by the genes NTRK1, NTRK2 and NTRK3 respectively) make up the Trk receptor family. This family of receptors are all activated by neurotrophins, including NGF (for
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 on ...
), BDNF (for
Brain Derived Neurotrophic Factor
Brain-derived neurotrophic factor (BDNF), or abrineurin, is a protein found in the and the periphery. that, in humans, is encoded by the ''BDNF'' gene. BDNF is a member of the neurotrophin family of growth factors, which are related to the canon ...
), NT-4 (for
Neurotrophin-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 kinase ...
) and
NT-3
Neurotrophin-3 is a protein that in humans is encoded by the ''NTF3'' gene.
The protein encoded by this gene, NT-3, is a neurotrophic factor in the NGF (Nerve Growth Factor) family of neurotrophins. It is a protein growth factor which has activi ...
(for Neurotrophin-3).
While TrkA mediated the effects of NGF,
TrkB
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 recepto ...
is bound and activated by
BDNF
Brain-derived neurotrophic factor (BDNF), or abrineurin, is a protein found in the and the periphery. that, in humans, is encoded by the ''BDNF'' gene. BDNF is a member of the neurotrophin family of growth factors, which are related to the cano ...
, NT-4 and NT-3. Further,
TrkC
Tropomyosin receptor kinase C (TrkC), also known as NT-3 growth factor receptor, neurotrophic tyrosine kinase receptor type 3, or TrkC tyrosine kinase is a protein that in humans is encoded by the ''NTRK3'' gene.
TrkC is the high affinity catalyt ...
binds and is activated by NT-3. TrkB binds BDNF and NT-4 more strongly than it binds NT-3. TrkC binds NT-3 more strongly than TrkB does.
There is one other
NT-3
Neurotrophin-3 is a protein that in humans is encoded by the ''NTF3'' gene.
The protein encoded by this gene, NT-3, is a neurotrophic factor in the NGF (Nerve Growth Factor) family of neurotrophins. It is a protein growth factor which has activi ...
receptor family besides the Trks (TrkC & TrkB), called the "
LNGFR
The p75 neurotrophin receptor (p75NTR) was first identified in 1973 as the low-affinity nerve growth factor receptor (LNGFR) before discovery that p75NTR bound other neurotrophins equally well as nerve growth factor. p75NTR is a neurotrophic fact ...
" (for "
low affinity nerve growth factor receptor
The p75 neurotrophin receptor (p75NTR) was first identified in 1973 as the low-affinity nerve growth factor receptor (LNGFR) before discovery that p75NTR bound other neurotrophins equally well as nerve growth factor. p75NTR is a neurotrophic facto ...
"). As opposed to TrkC, the LNGFR plays a somewhat less clear role in
NT-3
Neurotrophin-3 is a protein that in humans is encoded by the ''NTF3'' gene.
The protein encoded by this gene, NT-3, is a neurotrophic factor in the NGF (Nerve Growth Factor) family of neurotrophins. It is a protein growth factor which has activi ...
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 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.
It has been demonstrated that NTRK3 is a dependence receptor, meaning that it can be capable of inducing
proliferation when it binds to its
ligand
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 ...
NT-3, however, the absence of the NT-3 will result in the induction of
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 incl ...
by NTRK3.
Role in disease
With the past of the years, lot of studies have shown that the lack or deregulation of TrkC or the complex TrkC:
NT-3
Neurotrophin-3 is a protein that in humans is encoded by the ''NTF3'' gene.
The protein encoded by this gene, NT-3, is a neurotrophic factor in the NGF (Nerve Growth Factor) family of neurotrophins. It is a protein growth factor which has activi ...
can be associated with different diseases.
One study have demonstrated that mice defective for either
NT-3
Neurotrophin-3 is a protein that in humans is encoded by the ''NTF3'' gene.
The protein encoded by this gene, NT-3, is a neurotrophic factor in the NGF (Nerve Growth Factor) family of neurotrophins. It is a protein growth factor which has activi ...
or TrkC display severe sensory defects. These mice have normal nociception, but they are defective in proprioception, the sensory activity responsible for localizing the limbs in space.
The reduction of TrkC expression has been observed in neurodegenerative diseases, including Alzheimer's (AD), Parkinson's (PD), and Huntington's diseases (HD).
The role of NT-3 was also therapeutically studied in models of amyotrophic lateral sclerosis (
ALS
Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND) or Lou Gehrig's disease, is a neurodegenerative disease that results in the progressive loss of motor neurons that control voluntary muscles. ALS is the most com ...
) with loss of spinal cord motor neurons that express TrkC
Moreover, it has been shown that TrkC plays a role in cancer. The expression and function of Trk subtypes are dependent on the tumor type. For example, in neuroblastoma, TrkC expression correlates with a good prognosis, but in breast, prostate and pancreatic cancers, the expression of the same TrkC subtype is associated with cancer progression and metastasis.
Role 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. A number of
Trk inhibitor
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 signaling cascades. However, the activation ...
s are (in 2015) in clinical trials and have shown early promise in shrinking human tumors. Family of neurotrophin receptors including NTRK3 have been shown to induce a variety of
pleiotorpic response in malignant cells, including enhanced tumor cell invasiveness and
chemotoxis. Increased NTRK3 expression has been demonstrated in
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 the ...
, in
medulloblastoma
Medulloblastoma is a common type of primary brain cancer in children. It originates in the part of the brain that is towards the back and the bottom, on the floor of the skull, in the cerebellum, or posterior fossa.
The brain is divided into two ...
, and in
neuroectodermal brain tumors.
NTRK3 methylation
The promoter region of NTRK3 contains a dense
CpG island
The CpG sites or CG sites are regions of DNA where a cytosine nucleotide is followed by a guanine nucleotide in the linear sequence of bases along its 5' → 3' direction. CpG sites occur with high frequency in genomic regions called CpG isl ...
located relatively adjacent to the
transcription start site (TSS). Using
HumanMethylation450 arrays,
quantitative methylation-specific PCR (qMSP), and
Methylight assays, it has been indicated that NTRK3 is methylated in all
CRC cell lines and non of the normal
epithelium
Epithelium or epithelial tissue is one of the four basic types of animal tissue, along with connective tissue, muscle tissue and nervous tissue. It is a thin, continuous, protective layer of compactly packed cells with a little intercellul ...
samples. In light of its preferential methylation in CRCs and because of its role as a neurotrophin receptor, it has been suggested to have a functional role in
colorectal cancer
Colorectal cancer (CRC), also known as bowel cancer, colon cancer, or rectal cancer, is the development of cancer from the colon or rectum (parts of the large intestine). Signs and symptoms may include blood in the stool, a change in bowel m ...
formation. It has also been suggested that methylation status of NTRK3 promoter is capable of discriminating CRC tumor samples from normal adjacent tumor-free tissue. Hence it can be considered as a
biomarker
In biomedical contexts, a biomarker, or biological marker, is a measurable indicator of some biological state or condition. Biomarkers are often measured and evaluated using blood, urine, or soft tissues to examine normal biological processes, ...
for molecular detection of CRC, specially in combination with other markers like
SEPT9
Septin-9 is a protein that in humans is encoded by the ''SEPT9'' gene.
Interactions
SEPT9 has been shown to interact with SEPT2 and SEPT7.
Function
Along with AHNAK, eIF4E and S100A11, SEPT9 has been shown to be essential for pseudopod pr ...
. NTRK3 has also been indicated as one of the genes in the panel of nine CpG methylation probes located at promoter or exon 1 region of eight genes (including
DDIT3
DNA damage-inducible transcript 3, also known as C/EBP homologous protein (CHOP), is a pro-apoptotic transcription factor that is encoded by the ''DDIT3'' gene. It is a member of the CCAAT/enhancer-binding protein (C/EBP) family of DNA-binding ...
,
FES
Fez or Fes (; ar, فاس, fās; zgh, ⴼⵉⵣⴰⵣ, fizaz; french: Fès) is a city in northern inland Morocco and the capital of the Fès-Meknès administrative region. It is the second largest city in Morocco, with a population of 1.11 mi ...
,
FLT3
Cluster of differentiation antigen 135 (CD135) also known as fms like tyrosine kinase 3 (FLT-3), receptor-type tyrosine-protein kinase FLT3, or fetal liver kinase-2 (Flk2) is a protein that in humans is encoded by the ''FLT3'' gene. FLT3 is a cyto ...
,
SEPT5
Septin-5 is a protein that in humans is encoded by the ''SEPT5'' gene.
Function
This gene is a member of the septin gene family of nucleotide binding proteins, originally described in yeast as cell division cycle regulatory proteins. Septins a ...
, SEPT9,
SOX1
SOX1 is a gene that encodes a transcription factor with a HMG-box (high mobility group) DNA-binding domain and functions primarily in neurogenesis. SOX1, SOX2 and SOX3, members of the SOX gene family (specifically the SOXB1 group), contain trans ...
,
SOX17
SRY-box 17 is a protein that in humans is encoded by the SOX17 gene.
Regulation at the human ''SOX17'' locus
The gene encodes a member of the SOX (SRY-related HMG-box) family of transcription factors, located on Chromosome 8 q11.23. It's ge ...
, and NTRK3) for prognostic prediction in
ESCC (esophageal squamous cell carcinoma) patients.
TrkC (NTRK3 gene) inhibitors in development
Entrectinib
Entrectinib, sold under the brand name Rozlytrek, is an anti-cancer medication used to treat ROS1-positive non-small cell lung cancer and NTRK fusion-positive solid tumors. It is a selective tyrosine kinase inhibitor (TKI), of the tropomyosin r ...
(formerly RXDX-101) is an investigational drug developed by Ignyta, Inc., which has potential antitumor activity. It is an oral pan-TRK, ALK and ROS1 inhibitor that has demonstrated its anti tumor activity in murine, human tumor cell lines, and patient-derived xenograft tumor models. In vitro, entrectinib inhibits the Trk family members TrkA, TrkB and TrkC at low nano molar concentrations. It is highly bound to plasma proteins (99,5%), and can readily diffuse across the blood-brain barrier (BBB).
Entrectinib
Entrectinib, sold under the brand name Rozlytrek, is an anti-cancer medication used to treat ROS1-positive non-small cell lung cancer and NTRK fusion-positive solid tumors. It is a selective tyrosine kinase inhibitor (TKI), of the tropomyosin r ...
has been approved by the FDA on August 15, 2019 for the treatment of adult and pediatric patients 12 years of age and older with solid tumors that have a neurotrophic tyrosine kinase receptor gene fusion
Interactions
TrkC has been shown to interact with:
* SH2B2
* SQSTM1
* KIDINS220
* PTPRS
* MAPK8IP3/JIP3
*
Neurotrophin-3
Neurotrophin-3 is a protein that in humans is encoded by the ''NTF3'' gene.
The protein encoded by this gene, NT-3, is a neurotrophic factor in the NGF (Nerve Growth Factor) family of neurotrophins. It is a protein growth factor which has activi ...
* TβRII
*DOK5
* BMPRII
* PLCG1
Ligands
Small molecules peptidomimetics based on β-turn
NT-3
Neurotrophin-3 is a protein that in humans is encoded by the ''NTF3'' gene.
The protein encoded by this gene, NT-3, is a neurotrophic factor in the NGF (Nerve Growth Factor) family of neurotrophins. It is a protein growth factor which has activi ...
, with the rationale of targeting the extracellular domain of the TrkC receptor have shown to be agonist of TrkC. Posterior studies, have shown that peptidomimetics with an organic backbone, and a pharmacophore based on β-turn
NT-3
Neurotrophin-3 is a protein that in humans is encoded by the ''NTF3'' gene.
The protein encoded by this gene, NT-3, is a neurotrophic factor in the NGF (Nerve Growth Factor) family of neurotrophins. It is a protein growth factor which has activi ...
structure can also function as an antagonist of TrkC.
References
Further reading
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{{Portal bar, Biology, border=no
Developmental neuroscience
Programmed cell death
Tyrosine kinase receptors