Tropomyosin receptor kinase B

Last updated
NTRK2
Protein NTRK2 PDB 1hcf.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases NTRK2 , GP145-TrkB, TRKB, trk-B, neurotrophic receptor tyrosine kinase 2, OBHD, EIEE58
External IDs OMIM: 600456 MGI: 97384 HomoloGene: 4504 GeneCards: NTRK2
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_001025074
NM_008745
NM_001282961

RefSeq (protein)

NP_001020245
NP_001269890
NP_032771

Location (UCSC) Chr 9: 84.67 – 85.03 Mb Chr 13: 58.95 – 59.28 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Tropomyosin receptor kinase B (TrkB), [5] also known as tyrosine receptor kinase B, [5] 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. [5] [6] TrkB is a receptor for brain-derived neurotrophic factor (BDNF). Standard pronunciation is "track bee".

Function

Tropomyosin receptor kinase B is the high affinity catalytic receptor for several "neurotrophins", which are small protein growth factors that induce the survival and differentiation of distinct cell populations. The neurotrophins that activate TrkB are: BDNF (Brain Derived Neurotrophic Factor), neurotrophin-4 (NT-4), and neurotrophin-3 (NT-3). [5] As such, TrkB mediates the multiple effects of these neurotrophic factors, which includes neuronal differentiation and survival. Research has shown that activation of the TrkB receptor can lead to down regulation of the KCC2 chloride transporter in cells of the CNS. [7] Except for the role of the pathway in neuronal development, BDNF signalling is also necessary for proper astrocyte morphogenesis and maturation, via the astrocytic TrkB.T1 isoform. [8]

The TrkB receptor is part of the large family of receptor tyrosine kinases. A "tyrosine kinase" is an enzyme which is capable of adding a phosphate group to certain tyrosines on target proteins, 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 to the receptor's extracellular domain. Other examples of tyrosine kinase receptors include the insulin receptor, the IGF1 receptor, the MuSK protein receptor, the Vascular Endothelial Growth Factor (or VEGF) receptor, etc.

TrkB signaling TrkB-schema-eng.png
TrkB signaling

Currently, there are three TrkB isoforms in the mammalian CNS. The full-length isoform (TK+) is a typical tyrosine kinase receptor, and transduces the BDNF signal via Ras-ERK, PI3K, and PLCγ. In contrast, two truncated isoforms (TK-: T1 and T2) possess the same extracellular domain, transmembrane domain, and first 12 intracellular amino acid sequences as TK+. However, the C-terminal sequences are the isoform-specific (11 and 9 amino acids, respectively). T1 has the original signaling cascade that is involved in the regulation of cell morphology and calcium influx.

Family members

TrkB is part of a sub-family of protein kinases which includes also TrkA and TrkC. There are other neurotrophic factors structurally related to BDNF: NGF (for Nerve Growth Factor), NT-3 (for Neurotrophin-3) and NT-4 (for Neurotrophin-4). While TrkB mediates the effects of BDNF, NT-4 and NT-3, TrkA is bound and thereby activated only by NGF. Further, TrkC 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.

LNGFR

There is one other BDNF receptor besides TrkB, called the "LNGFR" (for "low-affinity nerve growth factor receptor"). Unlike TrkB, the LNGFR plays a somewhat less clear role in BDNF 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.

Role in cancer

Although originally identified as an oncogenic fusion in 1982, [9] 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 inhibitors are (in 2015) in clinical trials and have shown early promise in shrinking human tumors. [10]

Role in Neurodegeneration

TrkB and its ligand BDNF have been associated to both normal brain function and in the pathology and progression of Alzheimer’s disease (AD) and other neurodegenerative disorders. First of all, BDNF/TrkB signalling has been implicated in long-term memory formation, the regulation of long-term potentiation, as well as hippocampal synaptic plasticity. [11] [12] In particular, neuronal activity has been shown to lead to an increase in TrkB mRNA transcription, as well as changes in TrkB protein trafficking, including receptor endocytosis or translocation. [13] Both TrkB and BDNF are downregulated in the brain of early AD patients with mild cognitive impairments, [14] [15] while work in mice has shown that reducing TrkB levels in the brain of AD mouse models leads to a significant increase in memory deficits. [16] In addition, combining the induction of adult hippocampal neurogenesis and increasing BDNF levels lead to an improved cognition, mimicking exercise benefits in AD mouse models. [17] The effect of TrkB/BDNF signalling on AD pathology has been shown to be in part mediated by an increase in δ-secretase levels, via an upregulation of the JAK2/STAT3 pathway and C/EBPβ downstream of TrkB. [18] Additionally, TrkB has been shown to reduce amyloid-β production by APP binding and phosphorylation, while TrkB cleavage by δ-secretase blocks normal TrkB activity. [19] Dysregulation of the TrkB/BDNF pathway has been implicated in other neurological and neurodegenerative conditions, including stroke, Huntington’s Disease, Parkinson’s Disease, Amyotrophic lateral schlerosis and stress-related disorders. [20] [21] [22] (Notaras and van den Buuse, 2020; Pradhan et al., 2019; Tejeda and Díaz-Guerra, 2017).

As a drug target

Entrectinib (formerly RXDX-101) is an investigational drug developed by Ignyta, Inc., which has potential antitumor activity. It is a selective pan-trk receptor tyrosine kinase inhibitor (TKI) targeting gene fusions in trkA, trkB (this gene), and trkC (respectively, coded by NTRK1, NTRK2, and NTRK3 genes) that is currently in phase 2 clinical testing. [23] In addition, TrkB/BDNF signalling has been the target for developing novel drugs for Alzheimer’s Disease, Parkinson’s Disease or other neurodegenerative and psychiatric disorders, aiming at either pharmacological modulation of the pathway (e.g. small molecule mimetics) or other means (e.g. exercise induced changes in TrkB signalling). [24] [25] [22]

Ligands

Agonists

Antagonists

Others

Interactions

TrkB has been shown to interact with:

See also

Related Research Articles

Brain-derived neurotrophic factor Protein

Brain-derived neurotrophic factor (BDNF), or abrineurin, is a protein 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 canonical nerve growth factor. Neurotrophic factors are found in the brain and the periphery. BDNF was first isolated from pig brain in 1982 by Yves-Alain Barde and Hans Thoenen.

Neurotrophin

Neurotrophins are a family of proteins that induce the survival, development, and function of neurons.

Nerve growth factor Mammalian protein found in Homo sapiens

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 one of the first to be described. Since it was first isolated by Nobel Laureates Rita Levi-Montalcini and Stanley Cohen in 1956, numerous biological processes involving NGF have been identified, two of them being the survival of pancreatic beta cells and the regulation of the immune system.

Tropomyosin receptor kinase A Protein-coding gene in the species Homo sapiens

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 gene.

Low-affinity nerve growth factor receptor Human protein-coding gene

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 factor receptor. Neurotrophic factor receptors bind Neurotrophins including Nerve growth factor, Neurotrophin-3, Brain-derived neurotrophic factor, and Neurotrophin-4. All neurotrophins bind to p75NTR. This also includes the immature pro-neurotrophin forms. Neurotrophic factor receptors, including p75NTR, are responsible for ensuring a proper density to target ratio of developing neurons, refining broader maps in development into precise connections. p75NTR is involved in pathways that promote neuronal survival and neuronal death.

Tropomyosin receptor kinase C

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.

Neurotrophic factors (NTFs) are a family of biomolecules – nearly all of which are peptides or small proteins – that support the growth, survival, and differentiation of both developing and mature neurons. Most NTFs exert their trophic effects on neurons by signaling through tyrosine kinases, usually a receptor tyrosine kinase. In the mature nervous system, they promote neuronal survival, induce synaptic plasticity, and modulate the formation of long-term memories. Neurotrophic factors also promote the initial growth and development of neurons in the central nervous system and peripheral nervous system, and they are capable of regrowing damaged neurons in test tubes and animal models. Some neurotrophic factors are also released by the target tissue in order to guide the growth of developing axons. Most neurotrophic factors belong to one of three families: (1) neurotrophins, (2) glial cell-line derived neurotrophic factor family ligands (GFLs), and (3) neuropoietic cytokines. Each family has its own distinct cell signaling mechanisms, although the cellular responses elicited often do overlap.

Neurotrophin-3

Neurotrophin-3 is a protein that in humans is encoded by the NTF3 gene.

Neurotrophin-4 Protein-coding gene in the species Homo sapiens

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.

FRS2

Fibroblast growth factor receptor substrate 2 is a protein that in humans is encoded by the FRS2 gene.

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 of these receptors also has significant effects on functional properties of neurons.

DDR1

Discoidin domain receptor family, member 1, also known as DDR1 or CD167a, is a human gene.

SHC3 Protein-coding gene in the species Homo sapiens

SHC-transforming protein 3 is a protein that in humans is encoded by the SHC3 gene.

Neurotrophic factor receptors or neurotrophin receptors are a group of growth factor receptors which specifically bind to neurotrophins.

ETV6-NTRK3 gene fusion is the translocation of genetic material between the ETV6 gene located on the short arm of chromosome 12 at position p13.2 and the NTRK3 gene located on the long arm of chromosome 15 at position q25.3 to create the (12;15)(p13;q25) fusion gene, ETV6-NTRK3. This new gene consists of the 5' end of ETV6 fused to the 3' end of NTRK3. ETV6-NTRK3 therefore codes for a chimeric oncoprotein consisting of the helix-loop-helix (HLH) protein dimerization domain of the ETV6 protein fused to the tyrosine kinase domain of the NTRK3 protein. The ETV6 gene codes for the transcription factor protein, ETV6, which suppresses the expression of, and thereby regulates, various genes that in mice are required for normal hematopoiesis as well as the development and maintenance of the vascular network. NTRK3 codes for Tropomyosin receptor kinase C a NT-3 growth factor receptor cell surface protein that when bound to its growth factor ligand, neurotrophin-3, becomes an active tyrosine kinase that phosphorylates tyrosine residues on, and thereby stimulates, signaling proteins that promote the growth, survival, and proliferation of their parent cells. The tyrosine kinase of the ETV6-NTRK3 fusion protein is dysfunctional in that it is continuously active in phosphorylating tyrosine residues on, and thereby continuously stimulating, proteins that promote the growth, survival, and proliferation of their parent cells. In consequence, these cells take on malignant characteristics and are on the pathway of becoming cancerous. Indeed, the ETV6-NTRK3 fusion gene appears to be a critical driver of several types of cancers. It was originally identified in congenital fibrosarcoma and subsequently found in secretory breast cancer, Mammary analogue secretory carcinoma of salivary glands, congenital fibrosarcoma, congenital mesoblastic nephroma, rare cases of acute myelogenous leukemia, ALK-negative Inflammatory myofibroblastic tumour, cholangiocarcinoma, and radiation-induced papillary thyroid carcinoma.

Tropoflavin Chemical with possible medical uses

Tropoflavin, also known as 7,8-dihydroxyflavone, is a naturally occurring flavone found in Godmania aesculifolia, Tridax procumbens, and primula tree leaves. It has been found to act as a potent and selective small-molecule agonist of the tropomyosin receptor kinase B (TrkB), the main signaling receptor of the neurotrophin brain-derived neurotrophic factor (BDNF). Tropoflavin is both orally bioavailable and able to penetrate the blood–brain barrier. A prodrug of tropoflavin with greatly improved potency and pharmacokinetics, R13, is under development for the treatment of Alzheimer's disease.

ANA-12

ANA-12 is a selective, small-molecule non-competitive antagonist of TrkB, the main receptor of brain-derived neurotrophic factor (BDNF). The compound crosses the blood-brain-barrier and exerts central TrkB blockade, producing effects as early as 30 minutes and as long as 6 hours following intraperitoneal injection in mice. It blocks the neurotrophic actions of BDNF without compromising neuron survival.

Cyclotraxin B

Cyclotraxin B (CTX-B) is a small (1200 Da) cyclic peptide and highly potent, selective, non-competitive antagonist or negative allosteric modulator of TrkB (IC50  = 0.30 nM), the main receptor of brain-derived neurotrophic factor (BDNF), which itself was derived from BDNF. It crosses the blood-brain-barrier with systemic administration and produces anxiolytic-like effects in animals, though notably not antidepressant-like effects. The compound has also been found to produce analgesic effects in animal models of neuropathic pain. In addition to TrkB, CTX-B has been found to be an allosteric modulator of VEGFR2, one of the receptors of vascular endothelial growth factor (VEGF).

BNN-20

BNN-20, also known as 17β-spiro-(androst-5-en-17,2'-oxiran)-3β-ol, is a synthetic neurosteroid, "microneurotrophin", and analogue of the endogenous neurosteroid dehydroepiandrosterone (DHEA). It acts as a selective, high-affinity, centrally active agonist of the TrkA, TrkB, and p75NTR, receptors for the neurotrophins nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), as well as for DHEA and DHEA sulfate (DHEA-S). The drug has been suggested as a potential novel treatment for Parkinson's disease and other conditions.

Lipofibromatosis-like neural tumor (LPF-NT) is an extremely rare soft tissue tumor first described by Agaram et al in 2016. As of mid-2021, at least 39 cases of LPF-NT have been reported in the literature. LPF-NT tumors have several features that resemble lipofibromatosis (LPF) tumors, malignant peripheral nerve sheath tumors, spindle cell sarcomas, low-grade neural tumors, peripheral nerve sheath tumors, and other less clearly defined tumors; Prior to the Agaram at al report, LPF-NTs were likely diagnosed as variants or atypical forms of these tumors. The analyses of Agaram at al and subsequent studies uncovered critical differences between LPF-NT and the other tumor forms which suggest that it is a distinct tumor entity differing not only from lipofibromatosis but also the other tumor forms.

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Further reading