Tropomyosin receptor kinase A

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 is_associated_with::protein that in humans is encoded by the NTRK1 is_associated_with::gene.

This gene encodes a member of the neurotrophic tyrosine kinase receptor (NTKR) family. This kinase is a membrane-bound receptor that, upon is_associated_with::neurotrophin binding, phosphorylates itself (is_associated_with::autophosphorylation) 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 is_associated_with::congenital insensitivity to pain with anhidrosis, self-mutilating behavior, is_associated_with::mental retardation and is_associated_with::cancer. Alternate transcriptional splice variants of this gene have been found, but only three have been characterized to date.

Function
TrkA is the high affinity is_associated_with::catalytic receptor for the is_associated_with::neurotrophin, is_associated_with::Nerve Growth Factor, or "NGF". As such, it mediates the multiple effects of NGF, which include is_associated_with::neuronal differentiation and avoidance of programmed cell death.

Family members
TrkA is part of a sub-family of protein kinases which includes is_associated_with::TrkB and is_associated_with::TrkC. Also, there are other neurotrophic factors structurally related to NGF: is_associated_with::BDNF (for Brain-Derived Neurotrophic Factor), NT-3 (for Neurotrophin-3) and NT-4 (for Neurotrophin-4). While TrkA mediates the effects of NGF, is_associated_with::TrkB is bound and activated by is_associated_with::BDNF, NT-4, and NT-3. Further, is_associated_with::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 "is_associated_with::LNGFR" (for "is_associated_with::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 is_associated_with::oncogene.

In one study, a total absence of TrkA receptor was found in is_associated_with::keratoconus-affected corneas, along with an increased level of repressor isoform of is_associated_with::Sp3 transcription factor.

Regulation of TrkA
The levels of distinct proteins can be regulated by the "is_associated_with::ubiquitin/is_associated_with::proteasome" system. In this system, a small (7–8 kd)protein called "is_associated_with::ubiquitin" is affixed to a target protein, and is thereby targeted for destruction by a structure called the "is_associated_with::proteasome". TrkA is targeted for proteasome-mediated destruction by an "E3 is_associated_with::ubiquitin ligase" called is_associated_with::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.

Interactions
TrkA has been shown to interact with:


 * is_associated_with::Abl gene,
 * is_associated_with::FRS2,
 * is_associated_with::Grb2,
 * MATK,
 * NGFB,
 * is_associated_with::PLCG1,
 * RICS,
 * SQSTM1,
 * is_associated_with::SH2B1,
 * is_associated_with::SH2B2, and
 * is_associated_with::SHC1.

Ligands
Small molecules such as is_associated_with::amitriptyline and is_associated_with::gambogic acid derivatives have been claimed to activate TrkA. Amitriptyline activates TrkA and facilitate the heterodimerisation of TrkA and is_associated_with::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 is_associated_with::TrkB and is_associated_with::TrkC) both in-vitro and in-vivo by interacting with the cytoplasmic juxtamembrane domain of TrkA.