Tropomyosin receptor kinase A (TrkA), also known as high affinity nerve growth factor receptor, neurotrophic tyrosine kinase receptor type 1, or TRK1-transforming tyrosine kinase protein is a protein that in humans is encoded by the NTRK1gene.
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.
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.
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.
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.
Small molecules such as amitriptyline and gambogic acid derivatives have been claimed to activate TrkA. Amitriptyline activates TrkA and facilitate the heterodimerisation of TrkA and TrkB in the absence of NGF. Binding of Amitriptyline to TrkA occurs to the Leucine Rich Region (LRR) of the extracellular domain of the receptor, which is distinct from the NGF binding site. Amitryptiline possess neurotrophic activity both in-vitro and in-vivo (mouse model). Gambogic Amide, a derivative of Gambogic acid, selectively activates TrkA (but not TrkB and TrkC) both in-vitro and in-vivo by interacting with the cytoplasmic juxtamembrane domain of TrkA.
^Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 8: Atypical neurotransmitters". In Sydor A, Brown RY. Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. pp. –. ISBN9780071481274. 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 tryosine receptor kinase family). ...
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.
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