- TrkA
Neurotrophic tyrosine kinase, receptor, type 1, also known as NTRK1, is a human
gene .PBB_Summary
section_title =
summary_text = This gene encodes a member of the neurotrophic tyrosine kinase receptor (NTKR) family. This kinase is a membrane-bound receptor that, upon neurotrophin binding, phosphorylates itself and members of the MAPK pathway. The presence of this kinase leads to cell differentiation and may play a role in specifying sensory neuron subtypes. Mutations in this gene have been associated with congenital insensitivity to pain, anhidrosis, self-mutilating behavior, mental retardation and cancer. Alternate transcriptional splice variants of this gene have been found, but only three have been characterized to date. [cite web | title = Entrez Gene: NTRK1 neurotrophic tyrosine kinase, receptor, type 1| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=4914| accessdate = ]Function
TrkA is the high affinity
catalytic receptor for theneurotrophin ,Nerve Growth Factor , or "NGF". As such, it mediates the multiple effects of NGF, which includesneuron al differentiation and survival.The TrkA receptor is part of the large family of
receptor tyrosine kinase s. A "tyrosine kinase " is an enzyme which is capable of adding a phosphate group to a/the certaintyrosine s on targetprotein s, or "substrates". A receptor tyrosine kinase is a tyrosine kinase which is located at thecellular membrane , and is activated by binding of a ligand via itsextracellular domain. Other example of tyrosine kinase receptors include theinsulin receptor , theInsulin-like growth factor 1 receptor , theMuSK receptor , the Vascular Endothelial Growth Factor (or VEGF) receptor, etc. The substrate proteins which are phosphorylated by TrkA includePI3 kinase . Despite the mistake being abundant in the scientific literature, TrkA stands for Tropomyosin-Related Kinase A and "not" Tyrosine Kinase A or Tyrosine Receptor Kinase A. Similarly for TrkB and TrkC, the abbreviated name has frequently been assumed to be something that it is not.Family members
TrkA is part of a sub-family of protein kinases which includes
TrkB andTrkC . Also, there are other neurotrophic factors structurally related to NGF:BDNF (for Brain-Derived Neurotrophic Factor), NT-3 (for Neurotrophin-3) and NT-4 (for Neurotrophin-4). While TrkA mediates the effects of NGF,TrkB is bound and activated byBDNF , NT-4, and NT-3. Further,TrkC binds and is activated by NT-3. [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16253518&query_hl=9&itool=pubmed_docsum]The Low Affinity Nerve Growth Factor Receptor
There is one other NGF receptor besides TrkA, called the "
LNGFR " (for "Low Affinity Nerve Growth Factor Receptor "). As opposed to TrkA, the LNGFR plays a somewhat less clear role in NGF 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 in the absence of a co-expressed TrkA, 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 disease
TrkA was originally cloned from a colon tumor; the cancer occurred via a translocation, which resulted in the activation of the TrkA kinase domain. However, TrkA itself does not appear to be an oncogene.
Regulation of TrkA
The levels of distinct proteins can be regulated by the "
ubiquitin /proteasome " system. In this system, a small (7-8 kd)protein called "ubiquitin " is affixed to a target protein, and is thereby targeted for destruction by a structure called the "proteasome ". TrkA is targeted for proteasome-mediated destruction by an "E3ubiquitin ligase " calledNEDD-4 . This mechanism may be a distinct way to control the survival of a neuron. The extent and maybe type of TrkA ubiquitiniation can be regulated by the other, unrelated receptor for NGF, p75NTR [5] .References
Further reading
PBB_Further_reading
citations =
*cite journal | author=Indo Y |title=Genetics of congenital insensitivity to pain with anhidrosis (CIPA) or hereditary sensory and autonomic neuropathy type IV. Clinical, biological and molecular aspects of mutations in TRKA(NTRK1) gene encoding the receptor tyrosine kinase for nerve growth factor. |journal=Clin. Auton. Res. |volume=12 Suppl 1 |issue= |pages= I20–32 |year= 2002 |pmid= 12102460 |doi=
*cite journal | author=Micera A, Lambiase A, Stampachiacchiere B, "et al." |title=Nerve growth factor and tissue repair remodeling: trkA(NGFR) and p75(NTR), two receptors one fate. |journal=Cytokine Growth Factor Rev. |volume=18 |issue= 3-4 |pages= 245–56 |year= 2007 |pmid= 17531524 |doi= 10.1016/j.cytogfr.2007.04.004PBB_Controls
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