TrkA
From Wikipedia, the free encyclopedia
Neurotrophic tyrosine kinase, receptor, type 1, also known as NTRK1, is a human gene.
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.[1]
Contents |
[edit] Function
TrkA is the high affinity catalytic receptor for the neurotrophin, Nerve Growth Factor, or "NGF". As such, it mediates the multiple effects of NGF, which includes neuronal differentiation and survival.
The TrkA 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 a/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 Insulin-like growth factor 1 receptor, the MuSK receptor, the Vascular Endothelial Growth Factor (or VEGF) receptor, etc. The substrate proteins which are phosphorylated by TrkA include PI3 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.
[edit] Family members
TrkA is part of a sub-family of protein kinases which includes TrkB and TrkC. 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 by BDNF, NT-4, and NT-3. Further, TrkC binds and is activated by NT-3.[3]
[edit] 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.
[edit] 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.
[edit] 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 "E3 ubiquitin ligase" called NEDD-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].
[edit] References
[edit] Further reading
- Indo Y (2002). "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.". Clin. Auton. Res. 12 Suppl 1: I20–32. PMID 12102460.
- Micera A, Lambiase A, Stampachiacchiere B, et al. (2007). "Nerve growth factor and tissue repair remodeling: trkA(NGFR) and p75(NTR), two receptors one fate.". Cytokine Growth Factor Rev. 18 (3-4): 245–56. doi:. PMID 17531524.
