Biology:Tropomyosin receptor kinase C

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Short description: Protein-coding gene in the species Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example


Tropomyosin receptor kinase C (TrkC),[1] 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.[2]

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[3]

Moreover, TrkC has been identified as a novel synaptogenic adhesion molecule responsible for excitatory synapse development.[4]

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.[5] 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[6]

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.[7] 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.[8] 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.[9]

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.[10]

The reduction of TrkC expression has been observed in neurodegenerative diseases, including Alzheimer's (AD), Parkinson's (PD), and Huntington's diseases (HD).[11] 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[12]

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.[13]

Role in cancer

Although originally identified as an oncogenic fusion in 1982,[14] 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.[15] 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.[16] Increased NTRK3 expression has been demonstrated in neuroblastoma,[17] in medulloblastoma,[18] and in neuroectodermal brain tumors.[19]

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.[20] 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.[21] 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.[22]

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).[23]

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[24]

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.[36] 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.[37]

References

  1. ↑ "Chapter 8: Atypical neurotransmitters". Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. 2009. 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." 
  2. ↑ "Molecular cloning of the cDNA for human TrkC (NTRK3), chromosomal assignment, and evidence for a splice variant". Genomics 22 (2): 267–72. July 1994. doi:10.1006/geno.1994.1383. PMID 7806211. 
  3. ↑ Tsoulfas, P. (2018). "Signaling by NTRK3 (TRKC)". Reactome - A Curated Knowledgebase of Biological Pathways 65. doi:10.3180/R-HSA-9034015.1. https://reactome.org/PathwayBrowser/#/R-HSA-9034015. 
  4. ↑ "Postsynaptic TrkC and presynaptic PTPσ function as a bidirectional excitatory synaptic organizing complex". Neuron 69 (2): 287–303. January 2011. doi:10.1016/j.neuron.2010.12.024. PMID 21262467. 
  5. ↑ "TrkC isoforms with inserts in the kinase domain show impaired signaling responses". The Journal of Biological Chemistry 271 (10): 5691–7. March 1996. doi:10.1074/jbc.271.10.5691. PMID 8621434. 
  6. ↑ "Emerging roles of the neurotrophin receptor TrkC in synapse organization". Neuroscience Research 116 (2017): 10–17. March 2017. doi:10.1016/j.neures.2016.09.009. PMID 27697534. 
  7. ↑ "Efficacy of Larotrectinib in TRK Fusion-Positive Cancers in Adults and Children". The New England Journal of Medicine 378 (8): 731–739. February 2018. doi:10.1056/NEJMoa1714448. PMID 29466156. 
  8. ↑ "Origin and evolution of the Trk family of neurotrophic receptors". Molecular and Cellular Neurosciences 31 (2): 179–92. February 2006. doi:10.1016/j.mcn.2005.09.007. PMID 16253518. https://www.sciencedirect.com/science/article/abs/pii/S104474310500223X. 
  9. ↑ "Neurotrophin-3 production promotes human neuroblastoma cell survival by inhibiting TrkC-induced apoptosis". The Journal of Clinical Investigation 120 (3): 850–8. March 2010. doi:10.1172/jci41013. PMID 20160348. 
  10. ↑ "Neurotrophic factors and their receptors". Current Opinion in Cell Biology 7 (2): 148–55. April 1995. doi:10.1016/0955-0674(95)80022-0. PMID 7612265. 
  11. ↑ "Roles of TrkC Signaling in the Regulation of Tumorigenicity and Metastasis of Cancer". Cancers 12 (1): 147. January 2020. doi:10.3390/cancers12010147. PMID 31936239. .
  12. ↑ "Neuroprotection: Pro-survival and Anti-neurotoxic Mechanisms as Therapeutic Strategies in Neurodegeneration". Frontiers in Cellular Neuroscience 13 (231): 231. 31 January 2019. doi:10.3389/fncel.2019.00231. PMID 31244606. 
  13. ↑ "Tropomyosin Receptor Kinase C Targeted Delivery of a Peptidomimetic Ligand-Photosensitizer Conjugate Induces Antitumor Immune Responses Following Photodynamic Therapy". Scientific Reports 6 (37209): 37209. November 2016. doi:10.1038/srep37209. PMID 27853305. Bibcode: 2016NatSR...637209K. 
  14. ↑ "Oncogenes in solid human tumours". Nature 300 (5892): 539–42. December 1982. doi:10.1038/300539a0. PMID 7144906. Bibcode: 1982Natur.300..539P. 
  15. ↑ "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. October 2015. doi:10.1158/2159-8290.CD-15-0443. PMID 26216294. 
  16. ↑ "TrkC plays an essential role in breast tumor growth and metastasis". Carcinogenesis 31 (11): 1939–47. November 2010. doi:10.1093/carcin/bgq180. PMID 20802235. 
  17. ↑ "Trk receptor expression and inhibition in neuroblastomas". Clinical Cancer Research 15 (10): 3244–50. May 2009. doi:10.1158/1078-0432.ccr-08-1815. PMID 19417027. 
  18. ↑ "β-Phenethyl isothiocyanate induces death receptor 5 to induce apoptosis in human oral cancer cells via p38". Oral Diseases 18 (5): 513–9. July 2012. doi:10.1111/j.1601-0825.2012.01905.x. PMID 22309674. 
  19. ↑ "TrkC expression predicts good clinical outcome in primitive neuroectodermal brain tumors". Journal of Clinical Oncology 18 (5): 1027–35. March 2000. doi:10.1200/jco.2000.18.5.1027. PMID 10694553. 
  20. ↑ "NTRK3 is a potential tumor suppressor gene commonly inactivated by epigenetic mechanisms in colorectal cancer". PLOS Genetics 9 (7): e1003552. 2013-07-11. doi:10.1371/journal.pgen.1003552. PMID 23874207. 
  21. ↑ "Detection of aberrant methylated SEPT9 and NTRK3 genes in sporadic colorectal cancer patients as a potential diagnostic biomarker". Oncology Letters 12 (6): 5335–5343. December 2016. doi:10.3892/ol.2016.5327. PMID 28105243. 
  22. ↑ "Prognostic CpG methylation biomarkers identified by methylation array in esophageal squamous cell carcinoma patients". International Journal of Medical Sciences 11 (8): 779–87. 2014. doi:10.7150/ijms.7405. PMID 24936140. 
  23. ↑ "Evaluating entrectinib as a treatment option for non-small cell lung cancer". Expert Opinion on Pharmacotherapy 21 (16): 1935–1942. November 2020. doi:10.1080/14656566.2020.1798932. PMID 32736487. 
  24. ↑ "FDA Approval Summary: Entrectinib for the Treatment of NTRK gene Fusion Solid Tumors". Clinical Cancer Research 27 (4): 928–932. February 2021. doi:10.1158/1078-0432.CCR-20-2771. PMID 32967940. 
  25. ↑ "Structural basis for extracellular cis and trans RPTPσ signal competition in synaptogenesis". Nature Communications 5 (5209): 5209. November 2014. doi:10.1038/ncomms6209. PMID 25385546. Bibcode: 2014NatCo...5.5209C. 
  26. ↑ 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. PMID 1653651. 
  27. ↑ 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. doi:10.1016/S0021-9258(18)46863-9. PMID 7961713. 
  28. ↑ "TrkC isoforms with inserts in the kinase domain show impaired signaling responses". The Journal of Biological Chemistry 271 (10): 5691–7. March 1996. doi:10.1074/jbc.271.10.5691. PMID 8621434. 
  29. ↑ "Neurotrophins: roles in neuronal development and function". Annual Review of Neuroscience 24: 677–736. March 2001. doi:10.1146/annurev.neuro.24.1.677. PMID 11520916. 
  30. ↑ "Mutations in NTRK3 suggest a novel signaling pathway in human congenital heart disease". Human Mutation 35 (12): 1459–68. December 2014. doi:10.1002/humu.22688. PMID 25196463. 
  31. ↑ "TrkC binds to the type II TGF-beta receptor to suppress TGF-beta signaling". Oncogene 26 (55): 7684–91. December 2007. doi:10.1038/sj.onc.1210571. PMID 17546043. 
  32. ↑ "Dok5 is substrate of TrkB and TrkC receptors and involved in neurotrophin induced MAPK activation". Cellular Signalling 18 (11): 1995–2003. November 2006. doi:10.1016/j.cellsig.2006.03.007. PMID 16647839. 
  33. ↑ "TrkC binds to the bone morphogenetic protein type II receptor to suppress bone morphogenetic protein signaling". Cancer Research 67 (20): 9869–77. October 2007. doi:10.1158/0008-5472.CAN-07-0436. PMID 17942918. 
  34. ↑ "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. September 1996. doi:10.1046/j.1471-4159.1996.67030952.x. PMID 8752100. 
  35. ↑ "Early BDNF, NT-3, and NT-4 signaling events". Experimental Neurology 159 (1): 297–308. September 1999. doi:10.1006/exnr.1999.7148. PMID 10486198. 
  36. ↑ "Selective small molecule peptidomimetic ligands of TrkC and TrkA receptors afford discrete or complete neurotrophic activities". Chemistry & Biology 12 (9): 1015–28. September 2005. doi:10.1016/j.chembiol.2005.06.015. PMID 16183026. 
  37. ↑ "A peptidomimetic of NT-3 acts as a TrkC antagonist". Peptides 30 (10): 1833–9. October 2009. doi:10.1016/j.peptides.2009.07.015. PMID 19647025. 

Further reading



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