Biology:Tropomyosin receptor kinase B

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Short description: Protein and coding gene in humans


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

Tropomyosin receptor kinase B (TrkB),[1][2][3] 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.[4] TrkB is a receptor for brain-derived neurotrophic factor (BDNF).[5][6] The standard pronunciation for this protein is "track bee".[citation needed]

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).[7][8] 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.[9] 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.[10]

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

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

Although originally identified as an oncogenic fusion in 1982,[11] 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.[12]

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. [13][14] 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.[15] Both TrkB and BDNF are downregulated in the brain of early AD patients with mild cognitive impairments,[16][17] 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.[18] 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.[19] 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.[20] 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.[21] 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.[22][23][24](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.[25] 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).[26][27][24] Recent studies suggest that TrkB is the target of some antidepressants,[28] including psychedelics.[29]

Ligands

Agonists


Antagonists


Others

Interactions

TrkB has been shown to interact with:


See also

  • Trk receptor

References

  1. ↑ "trkB, a novel tyrosine protein kinase receptor expressed during mouse neural development". EMBO J 8 (12): 3701–3709. Dec 1989. doi:10.1002/j.1460-2075.1989.tb08545.x. PMID 2555172. 
  2. ↑ "Similarities and differences in the way neurotrophins interact with the Trk receptors in neuronal and nonneuronal cells". Neuron 10 (2): 137–149. Feb 1993. doi:10.1016/0896-6273(93)90306-c. PMID 7679912. 
  3. ↑ "Chapter 8: Atypical neurotransmitters". Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. 2009. 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." 
  4. ↑ "Cloning and chromosomal localization of the human TRK-B tyrosine kinase receptor gene (NTRK2)". Genomics 25 (2): 538–546. January 1995. doi:10.1016/0888-7543(95)80055-Q. PMID 7789988. 
  5. ↑ "trkB encodes a functional receptor for brain-derived neurotrophic factor and neurotrophin-3 but not nerve growth factor". Cell 65 (5): 885–893. May 1991. doi:10.1016/0092-8674(91)90395-f. PMID 1710174. 
  6. ↑ "TrkB mediates BDNF/NT-3-dependent survival and proliferation in fibroblasts lacking the low affinity NGF receptor". Cell 66 (2): 405–413. July 1991. doi:10.1016/0092-8674(91)90629-d. PMID 1649703. 
  7. ↑ "TrkB mediates BDNF/NT-3-dependent survival and proliferation in fibroblasts lacking the low affinity NGF receptor". Cell 66 (2): 405–413. July 1991. doi:10.1016/0092-8674(91)90629-d. PMID 1649703. 
  8. ↑ "Similarities and differences in the way neurotrophins interact with the Trk receptors in neuronal and nonneuronal cells". Neuron 10 (2): 137–149. Feb 1993. doi:10.1016/0896-6273(93)90306-c. PMID 7679912. 
  9. ↑ "BDNF-induced TrkB activation down-regulates the K+-Cl- cotransporter KCC2 and impairs neuronal Cl- extrusion.". 
  10. ↑ "Author response: Astrocyte morphogenesis is dependent on BDNF signaling via astrocytic TrkB.T1". eLife. 2019-07-21. doi:10.7554/elife.44667.019. 
  11. ↑ "Oncogenes in solid human tumours". Nature 300 (5892): 539–542. December 1982. doi:10.1038/300539a0. PMID 7144906. Bibcode: 1982Natur.300..539P. 
  12. ↑ "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. October 2015. doi:10.1158/2159-8290.CD-15-0443. PMID 26216294. 
  13. ↑ "TrkB signalling pathways in LTP and learning". Nature Reviews. Neuroscience 10 (12): 850–860. December 2009. doi:10.1038/nrn2738. PMID 19927149. 
  14. ↑ "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. November 2004. doi:10.1016/j.arr.2004.07.002. PMID 15541709. https://zenodo.org/record/1258746. 
  15. ↑ "Activity-dependent modulation of the BDNF receptor TrkB: mechanisms and implications". Trends in Neurosciences 28 (9): 464–471. September 2005. doi:10.1016/j.tins.2005.07.003. PMID 16040136. 
  16. ↑ "Microarray analysis of hippocampal CA1 neurons implicates early endosomal dysfunction during Alzheimer's disease progression". Biological Psychiatry 68 (10): 885–893. November 2010. doi:10.1016/j.biopsych.2010.05.030. PMID 20655510. 
  17. ↑ "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. June 2005. doi:10.1111/j.1471-4159.2005.03135.x. PMID 15935057. 
  18. ↑ "TrkB reduction exacerbates Alzheimer's disease-like signaling aberrations and memory deficits without affecting β-amyloidosis in 5XFAD mice". Translational Psychiatry 5 (5): e562. May 2015. doi:10.1038/tp.2015.55. PMID 25942043. 
  19. ↑ "Combined adult neurogenesis and BDNF mimic exercise effects on cognition in an Alzheimer's mouse model". Science 361 (6406): eaan8821. September 2018. doi:10.1126/science.aan8821. PMID 30190379. 
  20. ↑ "Deficiency in BDNF/TrkB Neurotrophic Activity Stimulates δ-Secretase by Upregulating C/EBPβ in Alzheimer's Disease". Cell Reports 28 (3): 655–669.e5. July 2019. doi:10.1016/j.celrep.2019.06.054. PMID 31315045. 
  21. ↑ "TrkB receptor cleavage by delta-secretase abolishes its phosphorylation of APP, aggravating Alzheimer's disease pathologies". Molecular Psychiatry 26 (7): 2943–2963. July 2021. doi:10.1038/s41380-020-00863-8. PMID 32782380. 
  22. ↑ "Neurobiology of BDNF in fear memory, sensitivity to stress, and stress-related disorders". Molecular Psychiatry 25 (10): 2251–2274. October 2020. doi:10.1038/s41380-019-0639-2. PMID 31900428. 
  23. ↑ "The Role of Altered BDNF/TrkB Signaling in Amyotrophic Lateral Sclerosis". Frontiers in Cellular Neuroscience 13: 368. 2019-08-13. doi:10.3389/fncel.2019.00368. PMID 31456666. 
  24. ↑ 24.0 24.1 "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. January 2017. doi:10.3390/ijms18020268. PMID 28134845. 
  25. ↑ "Promising entrectinib clinical trial data". ScienceDaily. 18 April 2016. https://www.sciencedaily.com/releases/2016/04/160418092429.htm. 
  26. ↑ "Born to Protect: Leveraging BDNF Against Cognitive Deficit in Alzheimer's Disease". CNS Drugs 34 (3): 281–297. March 2020. doi:10.1007/s40263-020-00705-9. PMID 32052374. 
  27. ↑ "BDNF as a Promising Therapeutic Agent in Parkinson's Disease". International Journal of Molecular Sciences 21 (3): 1170. February 2020. doi:10.3390/ijms21031170. PMID 32050617. 
  28. ↑ "Antidepressant drugs act by directly binding to TRKB neurotrophin receptors". Cell 184 (5): 1299–1313.e19. March 2021. doi:10.1016/j.cell.2021.01.034. PMID 33606976. 
  29. ↑ "Psychedelics promote plasticity by directly binding to BDNF receptor TrkB". Nature Neuroscience 26 (6): 1032–1041. June 2023. doi:10.1038/s41593-023-01316-5. PMID 37280397. 
  30. ↑ "Amitriptyline is a TrkA and TrkB receptor agonist that promotes TrkA/TrkB heterodimerization and has potent neurotrophic activity". Chemistry & Biology 16 (6): 644–656. June 2009. doi:10.1016/j.chembiol.2009.05.010. PMID 19549602. 
  31. ↑ "Neurosteroid dehydroepiandrosterone interacts with nerve growth factor (NGF) receptors, preventing neuronal apoptosis". PLOS Biology 9 (4): e1001051. April 2011. doi:10.1371/journal.pbio.1001051. PMID 21541365. 
  32. ↑ "Deoxygedunin, a natural product with potent neurotrophic activity in mice". PLOS ONE 5 (7): e11528. July 2010. doi:10.1371/journal.pone.0011528. PMID 20644624. Bibcode: 2010PLoSO...511528J. 
  33. ↑ "A synthetic 7,8-dihydroxyflavone derivative promotes neurogenesis and exhibits potent antidepressant effect". Journal of Medicinal Chemistry 53 (23): 8274–8286. December 2010. doi:10.1021/jm101206p. PMID 21073191. 
  34. ↑ "7,8-dihydroxyflavone, a small molecular TrkB agonist, is useful for treating various BDNF-implicated human disorders". Translational Neurodegeneration 5: 2. 2016. doi:10.1186/s40035-015-0048-7. PMID 26740873. 
  35. ↑ "The prodrug of 7,8-dihydroxyflavone development and therapeutic efficacy for treating Alzheimer's disease". Proceedings of the National Academy of Sciences of the United States of America 115 (3): 578–583. January 2018. doi:10.1073/pnas.1718683115. PMID 29295929. Bibcode: 2018PNAS..115..578C. 
  36. ↑ "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. October 2015. doi:10.1016/j.jpsychires.2015.08.002. PMID 26343602. 
  37. ↑ "Novel mechanisms for DHEA action". Journal of Molecular Endocrinology 56 (3): R139–R155. April 2016. doi:10.1530/JME-16-0013. PMID 26908835. 
  38. ↑ "Dehydroepiandrosterone: an ancestral ligand of neurotrophin receptors". Endocrinology 156 (1): 16–23. January 2015. doi:10.1210/en.2014-1596. PMID 25330101. 
  39. ↑ 39.0 39.1 39.2 39.3 "Antidepressant drugs act by directly binding to TRKB neurotrophin receptors". Cell 184 (5): 1299–1313.e19. March 2021. doi:10.1016/j.cell.2021.01.034. PMID 33606976. 
  40. ↑ 40.0 40.1 "Psychedelics promote plasticity by directly binding to BDNF receptor TrkB". Nature Neuroscience 26 (6): 1032–1041. June 2023. doi:10.1038/s41593-023-01316-5. PMID 37280397. 
  41. ↑ "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. October 1997. doi:10.1074/jbc.272.40.25296. PMID 9312147. 
  42. ↑ "A discrete domain of the human TrkB receptor defines the binding sites for BDNF and NT-4". Biochemical and Biophysical Research Communications 291 (3): 501–507. March 2002. doi:10.1006/bbrc.2002.6468. PMID 11855816. 
  43. ↑ "Association of the Src family tyrosine kinase Fyn with TrkB". Journal of Neurochemistry 71 (1): 106–111. July 1998. doi:10.1046/j.1471-4159.1998.71010106.x. PMID 9648856. 
  44. ↑ 44.0 44.1 44.2 "Brain-derived neurotrophic factor promotes interaction of the Nck2 adaptor protein with the TrkB tyrosine kinase receptor". Biochemical and Biophysical Research Communications 294 (5): 1087–1092. June 2002. doi:10.1016/S0006-291X(02)00606-X. PMID 12074588. 
  45. ↑ "The signaling adapter FRS-2 competes with Shc for binding to the nerve growth factor receptor TrkA. A model for discriminating proliferation and differentiation". The Journal of Biological Chemistry 274 (14): 9861–9870. April 1999. doi:10.1074/jbc.274.14.9861. PMID 10092678. 
  46. ↑ "Association of the atypical protein kinase C-interacting protein p62/ZIP with nerve growth factor receptor TrkA regulates receptor trafficking and Erk5 signaling". The Journal of Biological Chemistry 278 (7): 4730–4739. February 2003. doi:10.1074/jbc.M208468200. PMID 12471037. 
  47. ↑ "N-Shc and Sck, two neuronally expressed Shc adapter homologs. Their differential regional expression in the brain and roles in neurotrophin and Src signaling". The Journal of Biological Chemistry 273 (12): 6960–6967. March 1998. doi:10.1074/jbc.273.12.6960. PMID 9507002. 

Further reading

External links



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