Tropomyosin receptor kinase B

NTRK2
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesNTRK2, GP145-TrkB, TRKB, trk-B, neurotrophic receptor tyrosine kinase 2, OBHD, EIEE58
External IDsOMIM: 600456; MGI: 97384; HomoloGene: 4504; GeneCards: NTRK2; OMA:NTRK2 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

4915

18212

Ensembl

ENSG00000148053

ENSMUSG00000055254

UniProt

Q16620

P15209

RefSeq (mRNA)

NM_001025074
NM_008745
NM_001282961

RefSeq (protein)

NP_001020245
NP_001269890
NP_032771

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

Tropomyosin receptor kinase B (TrkB),[5][6][7] 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.[8] TrkB is a receptor for brain-derived neurotrophic factor (BDNF).[9][10] The standard pronunciation for this protein is "track bee".[citation needed]

Function

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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).[11][12] 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.[13] In addition to the role of the pathway in neuronal development, BDNF signaling is also necessary for proper astrocyte morphogenesis and maturation, via the astrocytic TrkB.T1 isoform.[14]

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

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 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

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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.

Role in cancer

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Although originally identified as an oncogenic fusion in 1982,[15] 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.[16]

Role in neurodegeneration

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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. [17][18] 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.[19] Both TrkB and BDNF are downregulated in the brain of early AD patients with mild cognitive impairments,[20][21] 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.[22] 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.[23] 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.[24] 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.[25] 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 sclerosis and stress-related disorders.[26][27][28](Notaras and van den Buuse, 2020; Pradhan et al., 2019; Tejeda and Díaz-Guerra, 2017).

As a drug target

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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.[29] 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).[30][31][28] Recent studies suggest that TrkB is the target of some antidepressants,[32] including psychedelics.[33]

Ligands

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Agonists

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Antagonists

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Positive allosteric modulators

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Others

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Interactions

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TrkB has been shown to interact with:

See also

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References

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000148053 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000055254 – 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. ^ Klein R, Parada LF, Coulier F, Barbacid M (December 1989). "trkB, a novel tyrosine protein kinase receptor expressed during mouse neural development". EMBO J. 8 (12): 3701–3709. doi:10.1002/j.1460-2075.1989.tb08545.x. PMC 402053. PMID 2555172.
  6. ^ Ip NY, Stitt TN, Tapley P, Klein R, Glass DJ, Fandl J, Greene LA, Barbacid M, Yancopoulos GD (February 1993). "Similarities and differences in the way neurotrophins interact with the Trk receptors in neuronal and nonneuronal cells". Neuron. 10 (2): 137–149. doi:10.1016/0896-6273(93)90306-c. PMID 7679912. S2CID 46072027.
  7. ^ 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 9780071481274. 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). ...Trk 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.
  8. ^ Nakagawara A, Liu XG, Ikegaki N, White PS, Yamashiro DJ, Nycum LM, et al. (January 1995). "Cloning and chromosomal localization of the human TRK-B tyrosine kinase receptor gene (NTRK2)". Genomics. 25 (2): 538–546. doi:10.1016/0888-7543(95)80055-Q. PMID 7789988.
  9. ^ Squinto SP, Stitt TN, Aldrich TH, Valenzuela DM, DiStefano PS, Yancopoulos GD (May 1991). "trkB encodes a functional receptor for brain-derived neurotrophic factor and neurotrophin-3 but not nerve growth factor". Cell. 65 (5): 885–893. doi:10.1016/0092-8674(91)90395-f. PMID 1710174. S2CID 28853455.
  10. ^ Glass DJ, Nye SH, Hantzopoulos P, Macchi MJ, Squinto SP, Goldfarb M, Yancopoulos GD (July 1991). "TrkB mediates BDNF/NT-3-dependent survival and proliferation in fibroblasts lacking the low affinity NGF receptor". Cell. 66 (2): 405–413. doi:10.1016/0092-8674(91)90629-d. PMID 1649703. S2CID 43626580.
  11. ^ Glass DJ, Nye SH, Hantzopoulos P, Macchi MJ, Squinto SP, Goldfarb M, Yancopoulos GD (July 1991). "TrkB mediates BDNF/NT-3-dependent survival and proliferation in fibroblasts lacking the low affinity NGF receptor". Cell. 66 (2): 405–413. doi:10.1016/0092-8674(91)90629-d. PMID 1649703. S2CID 43626580.
  12. ^ Ip NY, Stitt TN, Tapley P, Klein R, Glass DJ, Fandl J, Greene LA, Barbacid M, Yancopoulos GD (February 1993). "Similarities and differences in the way neurotrophins interact with the Trk receptors in neuronal and nonneuronal cells". Neuron. 10 (2): 137–149. doi:10.1016/0896-6273(93)90306-c. PMID 7679912. S2CID 46072027.
  13. ^ "BDNF-induced TrkB activation down-regulates the K+-Cl- cotransporter KCC2 and impairs neuronal Cl- extrusion". PMC 2173387.
  14. ^ Holt LM, Hernandez RD, Pacheco NL, Ceja BT, Hossain M, Olsen ML (21 July 2019). "Author response: Astrocyte morphogenesis is dependent on BDNF signaling via astrocytic TrkB.T1". eLife. doi:10.7554/elife.44667.019. S2CID 209561191.
  15. ^ Pulciani S, Santos E, Lauver AV, Long LK, Aaronson SA, Barbacid M (December 1982). "Oncogenes in solid human tumours". Nature. 300 (5892): 539–542. Bibcode:1982Natur.300..539P. doi:10.1038/300539a0. PMID 7144906. S2CID 30179526.
  16. ^ 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): 1049–1057. doi:10.1158/2159-8290.CD-15-0443. PMC 4635026. PMID 26216294.
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  18. ^ Pang PT, Lu B (November 2004). "Regulation of late-phase LTP and long-term memory in normal and aging hippocampus: role of secreted proteins tPA and BDNF". Ageing Research Reviews. Synaptic Function and Behavior During Normal Ageing. 3 (4): 407–430. doi:10.1016/j.arr.2004.07.002. PMID 15541709. S2CID 25174502.
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  21. ^ Peng S, Wuu J, Mufson EJ, Fahnestock M (June 2005). "Precursor form of brain-derived neurotrophic factor and mature brain-derived neurotrophic factor are decreased in the pre-clinical stages of Alzheimer's disease". Journal of Neurochemistry. 93 (6): 1412–1421. doi:10.1111/j.1471-4159.2005.03135.x. PMID 15935057. S2CID 770223.
  22. ^ Devi L, Ohno M (May 2015). "TrkB reduction exacerbates Alzheimer's disease-like signaling aberrations and memory deficits without affecting β-amyloidosis in 5XFAD mice". Translational Psychiatry. 5 (5): e562. doi:10.1038/tp.2015.55. PMC 4471286. PMID 25942043.
  23. ^ Choi SH, Bylykbashi E, Chatila ZK, Lee SW, Pulli B, Clemenson GD, et al. (September 2018). "Combined adult neurogenesis and BDNF mimic exercise effects on cognition in an Alzheimer's mouse model". Science. 361 (6406): eaan8821. doi:10.1126/science.aan8821. PMC 6149542. PMID 30190379.
  24. ^ Wang ZH, Xiang J, Liu X, Yu SP, Manfredsson FP, Sandoval IM, et al. (July 2019). "Deficiency in BDNF/TrkB Neurotrophic Activity Stimulates δ-Secretase by Upregulating C/EBPβ in Alzheimer's Disease". Cell Reports. 28 (3): 655–669.e5. doi:10.1016/j.celrep.2019.06.054. PMC 6684282. PMID 31315045.
  25. ^ Xia Y, Wang ZH, Liu P, Edgington-Mitchell L, Liu X, Wang XC, Ye K (July 2021). "TrkB receptor cleavage by delta-secretase abolishes its phosphorylation of APP, aggravating Alzheimer's disease pathologies". Molecular Psychiatry. 26 (7): 2943–2963. doi:10.1038/s41380-020-00863-8. PMID 32782380. S2CID 221109220.
  26. ^ Notaras M, van den Buuse M (October 2020). "Neurobiology of BDNF in fear memory, sensitivity to stress, and stress-related disorders". Molecular Psychiatry. 25 (10): 2251–2274. doi:10.1038/s41380-019-0639-2. PMID 31900428. S2CID 209540967.
  27. ^ Pradhan J, Noakes PG, Bellingham MC (13 August 2019). "The Role of Altered BDNF/TrkB Signaling in Amyotrophic Lateral Sclerosis". Frontiers in Cellular Neuroscience. 13: 368. doi:10.3389/fncel.2019.00368. PMC 6700252. PMID 31456666.
  28. ^ a b Tejeda GS, Díaz-Guerra M (January 2017). "Integral Characterization of Defective BDNF/TrkB Signalling in Neurological and Psychiatric Disorders Leads the Way to New Therapies". International Journal of Molecular Sciences. 18 (2): 268. doi:10.3390/ijms18020268. PMC 5343804. PMID 28134845.
  29. ^ "Promising entrectinib clinical trial data". ScienceDaily. 18 April 2016.
  30. ^ Caffino L, Mottarlini F, Fumagalli F (March 2020). "Born to Protect: Leveraging BDNF Against Cognitive Deficit in Alzheimer's Disease". CNS Drugs. 34 (3): 281–297. doi:10.1007/s40263-020-00705-9. hdl:2434/731220. PMID 32052374. S2CID 211081340.
  31. ^ Palasz E, Wysocka A, Gasiorowska A, Chalimoniuk M, Niewiadomski W, Niewiadomska G (February 2020). "BDNF as a Promising Therapeutic Agent in Parkinson's Disease". International Journal of Molecular Sciences. 21 (3): 1170. doi:10.3390/ijms21031170. PMC 7037114. PMID 32050617.
  32. ^ Casarotto PC, Girych M, Fred SM, Kovaleva V, Moliner R, Enkavi G, et al. (March 2021). "Antidepressant drugs act by directly binding to TRKB neurotrophin receptors". Cell. 184 (5): 1299–1313.e19. doi:10.1016/j.cell.2021.01.034. PMC 7938888. PMID 33606976.
  33. ^ Moliner R, Girych M, Brunello CA, Kovaleva V, Biojone C, Enkavi G, et al. (June 2023). "Psychedelics promote plasticity by directly binding to BDNF receptor TrkB". Nature Neuroscience. 26 (6): 1032–1041. doi:10.1038/s41593-023-01316-5. PMC 10244169. PMID 37280397.
  34. ^ Jang SW, Liu X, Chan CB, Weinshenker D, Hall RA, Xiao G, Ye K (June 2009). "Amitriptyline is a TrkA and TrkB receptor agonist that promotes TrkA/TrkB heterodimerization and has potent neurotrophic activity". Chemistry & Biology. 16 (6): 644–656. doi:10.1016/j.chembiol.2009.05.010. PMC 2844702. PMID 19549602.
  35. ^ Lazaridis I, Charalampopoulos I, Alexaki VI, Avlonitis N, Pediaditakis I, Efstathopoulos P, et al. (April 2011). "Neurosteroid dehydroepiandrosterone interacts with nerve growth factor (NGF) receptors, preventing neuronal apoptosis". PLOS Biology. 9 (4): e1001051. doi:10.1371/journal.pbio.1001051. PMC 3082517. PMID 21541365.
  36. ^ Jang SW, Liu X, Chan CB, France SA, Sayeed I, Tang W, et al. (July 2010). "Deoxygedunin, a natural product with potent neurotrophic activity in mice". PLOS ONE. 5 (7): e11528. Bibcode:2010PLoSO...511528J. doi:10.1371/journal.pone.0011528. PMC 2903477. PMID 20644624.
  37. ^ Liu X, Chan CB, Jang SW, Pradoldej S, Huang J, He K, et al. (December 2010). "A synthetic 7,8-dihydroxyflavone derivative promotes neurogenesis and exhibits potent antidepressant effect". Journal of Medicinal Chemistry. 53 (23): 8274–8286. doi:10.1021/jm101206p. PMC 3150605. PMID 21073191.
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  40. ^ Feng P, Akladious AA, Hu Y, Raslan Y, Feng J, Smith PJ (October 2015). "7,8-Dihydroxyflavone reduces sleep during dark phase and suppresses orexin A but not orexin B in mice". Journal of Psychiatric Research. 69: 110–119. doi:10.1016/j.jpsychires.2015.08.002. PMID 26343602.
  41. ^ a b c Casarotto PC, Girych M, Fred SM, Kovaleva V, Moliner R, Enkavi G, et al. (March 2021). "Antidepressant drugs act by directly binding to TRKB neurotrophin receptors". Cell. 184 (5): 1299–1313.e19. doi:10.1016/j.cell.2021.01.034. PMC 7938888. PMID 33606976.
  42. ^ a b c d e Moliner R, Girych M, Brunello CA, Kovaleva V, Biojone C, Enkavi G, et al. (June 2023). "Psychedelics promote plasticity by directly binding to BDNF receptor TrkB". Nature Neuroscience. 26 (6): 1032–1041. doi:10.1038/s41593-023-01316-5. PMC 10244169. PMID 37280397.
  43. ^ a b Dahlström M, Madjid N, Nordvall G, Halldin MM, Vazquez-Juarez E, Lindskog M, Sandin J, Winblad B, Eriksdotter M, Forsell P (July 2021). "Identification of Novel Positive Allosteric Modulators of Neurotrophin Receptors for the Treatment of Cognitive Dysfunction". Cells. 10 (8): 1871. doi:10.3390/cells10081871. PMC 8391421. PMID 34440640.
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  46. ^ Haniu M, Montestruque S, Bures EJ, Talvenheimo J, Toso R, Lewis-Sandy S, et al. (October 1997). "Interactions between brain-derived neurotrophic factor and the TRKB receptor. Identification of two ligand binding domains in soluble TRKB by affinity separation and chemical cross-linking". The Journal of Biological Chemistry. 272 (40): 25296–25303. doi:10.1074/jbc.272.40.25296. PMID 9312147.
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  48. ^ Iwasaki Y, Gay B, Wada K, Koizumi S (July 1998). "Association of the Src family tyrosine kinase Fyn with TrkB". Journal of Neurochemistry. 71 (1): 106–111. doi:10.1046/j.1471-4159.1998.71010106.x. PMID 9648856. S2CID 9012343.
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Further reading

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