“Tropomyosin receptor kinase C”的意思、由来-开放百科全书

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 (or VEGF) receptor, etc. The "substrate" proteins which are phosphorylated by TrkC include PI3 kinase.

Family members

TrkC is part of a sub-family of protein kinases which includes TrkA and TrkB. Also, there are other neurotrophic factors structurally related to NT-3: NGF (for Nerve Growth Factor), BDNF (for Brain Derived Neurotrophic Factor) 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 only 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.

Receptor

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.

Role in cancer

Although originally identified as an oncogenic fusion in 1982,^[3] 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.^[4]

TrkC (NTRK3 gene) inhibitors in development

References

1. ^{{cite book | vauthors = Malenka RC, Nestler EJ, Hyman SE | veditors = Sydor A, Brown RY | title = Molecular Neuropharmacology: A Foundation for Clinical Neuroscience | year = 2009 | publisher = McGraw-Hill Medical | location = New York | isbn = 978-0-07-148127-4 | pages = | edition = 2nd | chapter = Chapter 8: Atypical neurotransmitters | quote = 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. ^{{cite journal | vauthors = McGregor LM, Baylin SB, Griffin CA, Hawkins AL, Nelkin BD | title = Molecular cloning of the cDNA for human TrkC (NTRK3), chromosomal assignment, and evidence for a splice variant | journal = Genomics | volume = 22 | issue = 2 | pages = 267–72 | date = July 1994 | pmid = 7806211 | doi = 10.1006/geno.1994.1383 }}
3. ^{{cite journal | vauthors = Pulciani S, Santos E, Lauver AV, Long LK, Aaronson SA, Barbacid M | title = Oncogenes in solid human tumours | language = en | journal = Nature | volume = 300 | issue = 5892 | pages = 539–42 | date = December 1982 | pmid = 7144906 | doi = 10.1038/300539a0 | url = http://www.nature.com/nature/journal/v300/n5892/abs/300539a0.html }}
4. ^{{cite journal | vauthors = Doebele RC, Davis LE, Vaishnavi A, Le AT, Estrada-Bernal A, Keysar S, Jimeno A, Varella-Garcia M, Aisner DL, Li Y, Stephens PJ, Morosini D, Tuch BB, Fernandes M, Nanda N, Low JA | title = An Oncogenic NTRK Fusion in a Patient with Soft-Tissue Sarcoma with Response to the Tropomyosin-Related Kinase Inhibitor LOXO-101 | language = en | journal = Cancer Discovery | volume = 5 | issue = 10 | pages = 1049–57 | date = October 2015 | pmid = 26216294 | pmc = 4635026 | doi = 10.1158/2159-8290.CD-15-0443 }}
5. ^{{cite web | url = https://www.sciencedaily.com/releases/2016/04/160418092429.htm | title = Promising entrectinib clinical trial data | work = ScienceDaily | date = 18 April 2016}}

Family members

Receptor

Role in cancer

TrkC (NTRK3 gene) inhibitors in development

References

Further reading