Tropomyosin receptor kinase C

Last updated
NTRK3
Protein NTRK3 PDB 1wwc.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases NTRK3 , GP145-TrkC, TRKC, gp145(trkC), neurotrophic receptor tyrosine kinase 3
External IDs OMIM: 191316 MGI: 97385 HomoloGene: 49183 GeneCards: NTRK3
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_008746
NM_182809

RefSeq (protein)

NP_032772
NP_877961

Location (UCSC) Chr 15: 87.86 – 88.26 Mb Chr 7: 78.18 – 78.74 Mb
PubMed search [3] [4]
Wikidata
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Tropomyosin receptor kinase C (TrkC), [5] 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. [6]

TrkC is the high affinity catalytic receptor for the neurotrophin NT-3 (neurotrophin-3). As such, TrkC mediates the multiple effects of this neurotrophic factor, which includes neuronal differentiation and survival.

The TrkC 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 the 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 via its extracellular domain. Other example of tyrosine kinase receptors include the insulin receptor, the IGF-1 receptor, the MuSK protein receptor, the vascular endothelial growth factor (VEGF) receptor, etc. The "substrate" proteins which are phosphorylated by TrkC include PI3 kinase.

Function

TrkC is the high affinity catalytic receptor for the neurotrophin-3 (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, PI3K and RAAS, downstream of activated NTRK3, regulates cell survival, proliferation and motility [7]

Moreover, TrkC has been identified as a novel synaptogenic adhesion molecule responsible for excitatory synapse development. [8]

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. [9] NT-3 activation of catalytic TrkC isoform promotes both proliferation of neural crest cells and neuronal differentiation. On the other hand, the binding of NT-3 to the non-catalytic TrkC isoform induces neuronal differentiation, but nor neuronal proliferation [10]

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, TrkB and TrkC (encoded by the genes NTRK1, NTRK2 and NTRK3 respectively) make up the Trk receptor family. [11] This family of receptors are all activated by neurotrophins, including NGF (for Nerve Growth Factor), BDNF (for Brain Derived Neurotrophic Factor), NT-4 (for Neurotrophin-4) and NT-3 (for Neurotrophin-3). While TrkA mediated 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. [12] 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 receptor family besides the Trks (TrkC & TrkB), called the "LNGFR" (for "low affinity nerve growth factor receptor"). As opposed to TrkC, the LNGFR plays a somewhat less clear role in NT-3 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 NT-3, however, the absence of the NT-3 will result in the induction of apoptosis by NTRK3. [13]

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 can be associated with different diseases.

One study have demonstrated that mice defective for either NT-3 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. [14]

The reduction of TrkC expression has been observed in neurodegenerative diseases, including Alzheimer's (AD), Parkinson's (PD), and Huntington's diseases (HD). [15] The role of NT-3 was also therapeutically studied in models of amyotrophic lateral sclerosis (ALS) with loss of spinal cord motor neurons that express TrkC [16]

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. [17]

Role in cancer

Although originally identified as an oncogenic fusion in 1982, [18] 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. [19] 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. [20] Increased NTRK3 expression has been demonstrated in neuroblastoma, [21] in medulloblastoma, [22] and in neuroectodermal brain tumors. [23]

NTRK3 methylation

The promoter region of NTRK3 contains a dense CpG island 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 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 formation. [24] 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 for molecular detection of CRC, specially in combination with other markers like SEPT9. [25] 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, FES, FLT3, SEPT5, SEPT9, SOX1, SOX17, and NTRK3) for prognostic prediction in ESCC (esophageal squamous cell carcinoma) patients. [26]

TrkC (NTRK3 gene) inhibitors in development

Entrectinib (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). [27]

Entrectinib 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 [28]

Interactions

TrkC has been shown to interact with:

Ligands

Small molecules peptidomimetics based on β-turn NT-3, with the rationale of targeting the extracellular domain of the TrkC receptor have shown to be agonist of TrkC. [40] Posterior studies, have shown that peptidomimetics with an organic backbone, and a pharmacophore based on β-turn NT-3 structure can also function as an antagonist of TrkC. [41]

Related Research Articles

Tyrosine kinase Class of enzymes that phosphorylate protein tyrosine residues

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.

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

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

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.

Tropomyosin receptor kinase B

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 receptor for brain-derived neurotrophic factor (BDNF). Standard pronunciation is "track bee".

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.

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.

Receptor tyrosine kinase Class of enzymes

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 proteins. Receptor tyrosine kinases have been shown not only to be key regulators of normal cellular processes but also to have a critical role in the development and progression of many types of cancer. Mutations in receptor tyrosine kinases lead to activation of a series of signalling cascades which have numerous effects on protein expression. Receptor tyrosine kinases are part of the larger family of protein tyrosine kinases, encompassing the receptor tyrosine kinase proteins which contain a transmembrane domain, as well as the non-receptor tyrosine kinases which do not possess transmembrane domains.

Neurotrophin-3

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

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.

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.

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.

ROS1

Proto-oncogene tyrosine-protein kinase ROS is an enzyme that in humans is encoded by the ROS1 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.

In cellular biology, dependence receptors are proteins that mediate programmed cell death by monitoring the absence of certain trophic factors that otherwise serve as ligands (interactors) for the dependence receptors. A trophic ligand is a molecule whose protein binding stimulates cell growth, differentiation, and/or survival. Cells depend for their survival on stimulation that is mediated by various receptors and sensors, and integrated via signaling within the cell and between cells. The withdrawal of such trophic support leads to a form of cellular suicide.

Entrectinib TKI inhibitor used for cancer treatment

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 receptor kinases (TRK) A, B and C, C-ros oncogene 1 (ROS1) and anaplastic lymphoma kinase (ALK).

Mammary analogue secretory carcinoma (MASC) is a salivary gland neoplasm that shares a genetic mutation with certain types of breast cancer. MASCSG was first described by Skálová et al. in 2010. The authors of this report found a chromosome translocation in certain salivary gland tumors that was identical to the (12;15)(p13;q25) fusion gene mutation found previously in secretory carcinoma, a subtype of invasive ductal carcinoma of the breast.

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.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000140538 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000059146 - Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 8: Atypical neurotransmitters". In Sydor A, Brown RY (eds.). Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. ISBN   978-0-07-148127-4. Another common feature of neurotrophins is that they produce their physiologic effects by means of the tropomyosin receptor kinase (Trk) receptor family (also known as the tyrosine receptor kinase family). ... Try receptors. All neurotrophins bind to a class of highly homologous receptor tyrosine kinases known as Trk receptors, of which three types are known: TrkA, TrkB, and TrkC. These transmembrane receptors are glycoproteins whose molecular masses range from 140 to 145 kDa. Each type of Trk receptor tends to bind specific neurotrophins: TrkA is the receptor for NGF, TrkB the receptor for BDNF and NT-4, and TrkC the receptor for NT-3.However, some overlap in the specificity of these receptors has been noted.
  6. McGregor LM, Baylin SB, Griffin CA, Hawkins AL, Nelkin BD (July 1994). "Molecular cloning of the cDNA for human TrkC (NTRK3), chromosomal assignment, and evidence for a splice variant". Genomics. 22 (2): 267–72. doi:10.1006/geno.1994.1383. PMID   7806211.
  7. "Signaling by NTRK3 (TRKC)". Reactome.
  8. Takahashi H, Arstikaitis P, Prasad T, Bartlett TE, Wang YT, Murphy TH, Craig AM (January 2011). "Postsynaptic TrkC and presynaptic PTPσ function as a bidirectional excitatory synaptic organizing complex". Neuron. 69 (2): 287–303. doi:10.1016/j.neuron.2010.12.024. PMC   3056349 . PMID   21262467.
  9. Tsoulfas P, Stephens RM, Kaplan DR, Parada LF (March 1996). "TrkC isoforms with inserts in the kinase domain show impaired signaling responses". The Journal of Biological Chemistry. 271 (10): 5691–7. doi: 10.1074/jbc.271.10.5691 . PMID   8621434.
  10. Naito Y, Lee AK, Takahashi H (March 2017). "Emerging roles of the neurotrophin receptor TrkC in synapse organization". Neuroscience Research. 116 (2017): 10–17. doi:10.1016/j.neures.2016.09.009. PMID   27697534.
  11. Drilon A, Laetsch TW, Kummar S, DuBois SG, Lassen UN, Demetri GD, et al. (February 2018). "Efficacy of Larotrectinib in TRK Fusion-Positive Cancers in Adults and Children". The New England Journal of Medicine. 378 (8): 731–739. doi:10.1056/NEJMoa1714448. PMC   5857389 . PMID   29466156.
  12. Benito-Gutiérrez E, Garcia-Fernàndez J, Comella JX (February 2006). "Origin and evolution of the Trk family of neurotrophic receptors". Molecular and Cellular Neurosciences. 31 (2): 179–92. doi:10.1016/j.mcn.2005.09.007. PMID   16253518.
  13. Bouzas-Rodriguez J, Cabrera JR, Delloye-Bourgeois C, Ichim G, Delcros JG, Raquin MA, et al. (March 2010). "Neurotrophin-3 production promotes human neuroblastoma cell survival by inhibiting TrkC-induced apoptosis". The Journal of Clinical Investigation. 120 (3): 850–8. doi:10.1172/jci41013. PMC   2827960 . PMID   20160348.
  14. Barbacid M (April 1995). "Neurotrophic factors and their receptors". Current Opinion in Cell Biology. 7 (2): 148–55. doi:10.1016/0955-0674(95)80022-0. PMID   7612265.
  15. Jin W (January 2020). "Roles of TrkC Signaling in the Regulation of Tumorigenicity and Metastasis of Cancer". Cancers. 12 (1). doi: 10.3390/cancers12010147 . PMC   7016819 . PMID   31936239..
  16. Saragovi HU, Galan A, Levin LA (31 January 2019). "Neuroprotection: Pro-survival and Anti-neurotoxic Mechanisms as Therapeutic Strategies in Neurodegeneration". Frontiers in Cellular Neuroscience. 13 (231): 231. doi: 10.3389/fncel.2019.00231 . PMC   6563757 . PMID   31244606.
  17. Kue CS, Kamkaew A, Voon SH, Kiew LV, Chung LY, Burgess K, Lee HB (November 2016). "Tropomyosin Receptor Kinase C Targeted Delivery of a Peptidomimetic Ligand-Photosensitizer Conjugate Induces Antitumor Immune Responses Following Photodynamic Therapy". Scientific Reports. 6 (37209): 37209. doi: 10.1038/srep37209 . PMID   27853305.
  18. Pulciani S, Santos E, Lauver AV, Long LK, Aaronson SA, Barbacid M (December 1982). "Oncogenes in solid human tumours". Nature. 300 (5892): 539–42. Bibcode:1982Natur.300..539P. doi:10.1038/300539a0. PMID   7144906.
  19. Doebele RC, Davis LE, Vaishnavi A, Le AT, Estrada-Bernal A, Keysar S, et al. (October 2015). "An Oncogenic NTRK Fusion in a Patient with Soft-Tissue Sarcoma with Response to the Tropomyosin-Related Kinase Inhibitor LOXO-101". Cancer Discovery. 5 (10): 1049–57. doi:10.1158/2159-8290.CD-15-0443. PMC   4635026 . PMID   26216294.
  20. Jin W, Kim GM, Kim MS, Lim MH, Yun C, Jeong J, et al. (November 2010). "TrkC plays an essential role in breast tumor growth and metastasis". Carcinogenesis. 31 (11): 1939–47. doi: 10.1093/carcin/bgq180 . PMID   20802235.
  21. Brodeur GM, Minturn JE, Ho R, Simpson AM, Iyer R, Varela CR, et al. (May 2009). "Trk receptor expression and inhibition in neuroblastomas". Clinical Cancer Research. 15 (10): 3244–50. doi:10.1158/1078-0432.ccr-08-1815. PMC   4238907 . PMID   19417027.
  22. Huong LD, Shin JA, Choi ES, Cho NP, Kim HM, Leem DH, Cho SD (July 2012). "β-Phenethyl isothiocyanate induces death receptor 5 to induce apoptosis in human oral cancer cells via p38". Oral Diseases. 18 (5): 513–9. doi:10.1111/j.1601-0825.2012.01905.x. PMID   22309674.
  23. Grotzer MA, Janss AJ, Fung K, Biegel JA, Sutton LN, Rorke LB, et al. (March 2000). "TrkC expression predicts good clinical outcome in primitive neuroectodermal brain tumors". Journal of Clinical Oncology. 18 (5): 1027–35. doi:10.1200/jco.2000.18.5.1027. PMID   10694553.
  24. Luo Y, Kaz AM, Kanngurn S, Welsch P, Morris SM, Wang J, et al. (2013-07-11). "NTRK3 is a potential tumor suppressor gene commonly inactivated by epigenetic mechanisms in colorectal cancer". PLoS Genetics. 9 (7): e1003552. doi:10.1371/journal.pgen.1003552. PMC   3708790 . PMID   23874207.
  25. Behrouz Sharif S, Hashemzadeh S, Mousavi Ardehaie R, Eftekharsadat A, Ghojazadeh M, Mehrtash AH, et al. (December 2016). "Detection of aberrant methylated SEPT9 and NTRK3 genes in sporadic colorectal cancer patients as a potential diagnostic biomarker". Oncology Letters. 12 (6): 5335–5343. doi:10.3892/ol.2016.5327. PMC   5228494 . PMID   28105243.
  26. Kuo IY, Chang JM, Jiang SS, Chen CH, Chang IS, Sheu BS, et al. (2014). "Prognostic CpG methylation biomarkers identified by methylation array in esophageal squamous cell carcinoma patients". International Journal of Medical Sciences. 11 (8): 779–87. doi:10.7150/ijms.7405. PMC   4057483 . PMID   24936140.
  27. Lee J, Park S, Jung HA, Sun JM, Lee SH, Ahn JS, et al. (November 2020). "Evaluating entrectinib as a treatment option for non-small cell lung cancer". Expert Opinion on Pharmacotherapy. 21 (16): 1935–1942. doi:10.1080/14656566.2020.1798932. PMID   32736487.
  28. Marcus L, Donoghue M, Aungst S, Myers CE, Helms WS, Shen G, et al. (February 2021). "FDA Approval Summary: Entrectinib for the Treatment of NTRK gene Fusion Solid Tumors". Clinical Cancer Research. 27 (4): 928–932. doi:10.1158/1078-0432.CCR-20-2771. PMID   32967940.
  29. Coles CH, Mitakidis N, Zhang P, Elegheert J, Lu W, Stoker AW, et al. (November 2014). "Structural basis for extracellular cis and trans RPTPσ signal competition in synaptogenesis". Nature Communications. 5 (5209): 5209. doi: 10.1038/ncomms6209 . PMC   4239663 . PMID   25385546.
  30. Lamballe, L; Klein, R; Barbecid, M (6 September 1991). "TrkC, a new member of the TrkC family of tyrosine protein kinases, is a receptor for Neurotrophin-3". Cell. 66 (5): 967-979. doi:10.1016/0092-8674(91)90442-2.
  31. Philo, J; Talvenheimo, J; Wen, J; Rosenfeld, R; Welcher, A; Arakawa, T (11 November 1994). "Interactions of Neurotrophin-3 (NT-3), brain-derived neurotrophic factor (BDNF), and the NT-3. BDNF heterodimer with the extracellular domains of the TrkB and TrkC receptors". Journal of Biological Chemistry. 269 (45): 27840-27846.
  32. Tsoulfas P, Stephens RM, Kaplan DR, Parada LF (March 1996). "TrkC isoforms with inserts in the kinase domain show impaired signaling responses". The Journal of Biological Chemistry. 271 (10): 5691–7. doi: 10.1074/jbc.271.10.5691 . PMID   8621434.
  33. Huang EJ, Reichardt LF (March 2001). "Neurotrophins: roles in neuronal development and function". Annual Review of Neuroscience. 24: 677–736. doi:10.1146/annurev.neuro.24.1.677. PMC   2758233 . PMID   11520916.
  34. Werner P, Paluru P, Simpson AM, Latney B, Iyer R, Brodeur GM, Goldmuntz E (December 2014). "Mutations in NTRK3 suggest a novel signaling pathway in human congenital heart disease". Human Mutation. 35 (12): 1459–68. doi:10.1002/humu.22688. PMC   4247247 . PMID   25196463.
  35. Jin W, Yun C, Kwak MK, Kim TA, Kim SJ (December 2007). "TrkC binds to the type II TGF-beta receptor to suppress TGF-beta signaling". Oncogene. 26 (55): 7684–91. doi: 10.1038/sj.onc.1210571 . PMID   17546043.
  36. Shi L, Yue J, You Y, Yin B, Gong Y, Xu C, et al. (November 2006). "Dok5 is substrate of TrkB and TrkC receptors and involved in neurotrophin induced MAPK activation". Cellular Signalling. 18 (11): 1995–2003. doi:10.1016/j.cellsig.2006.03.007. PMID   16647839.
  37. Jin W, Yun C, Kim HS, Kim SJ (October 2007). "TrkC binds to the bone morphogenetic protein type II receptor to suppress bone morphogenetic protein signaling". Cancer Research. 67 (20): 9869–77. doi: 10.1158/0008-5472.CAN-07-0436 . PMID   17942918.
  38. Marsh HN, Palfrey HC (September 1996). "Neurotrophin-3 and brain-derived neurotrophic factor activate multiple signal transduction events but are not survival factors for hippocampal pyramidal neurons". Journal of Neurochemistry. 67 (3): 952–63. doi:10.1046/j.1471-4159.1996.67030952.x. PMID   8752100.
  39. Yuen EC, Mobley WC (September 1999). "Early BDNF, NT-3, and NT-4 signaling events". Experimental Neurology. 159 (1): 297–308. doi:10.1006/exnr.1999.7148. PMID   10486198.
  40. Zaccaro MC, Lee HB, Pattarawarapan M, Xia Z, Caron A, L'Heureux PJ, et al. (September 2005). "Selective small molecule peptidomimetic ligands of TrkC and TrkA receptors afford discrete or complete neurotrophic activities". Chemistry & Biology. 12 (9): 1015–28. doi: 10.1016/j.chembiol.2005.06.015 . PMID   16183026.
  41. Brahimi F, Malakhov A, Lee HB, Pattarawarapan M, Ivanisevic L, Burgess K, Saragovi HU (October 2009). "A peptidomimetic of NT-3 acts as a TrkC antagonist". Peptides. 30 (10): 1833–9. doi:10.1016/j.peptides.2009.07.015. PMC   2755609 . PMID   19647025.

Further reading