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, NT-3 and NT-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. There is one other NGF receptor besides TrkA, called the "LNGFR". 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. In one study, a total absence of TrkA receptor was found in keratoconus-affected corneas, along with an increased level of repressor isoform of Sp3 transcription factor. Gene fusions involving NTRK1 have been shown to be oncogenic, leading to the constitutive TrkA activation. In a research study by Vaishnavi A. et al., NTRK1 fusions are estimated to occur in 3.3% of lung cancer as assessed through next generation sequencing or fluoresence in situ hybridization.
Regulation
The levels of distinct proteins can be regulated by the "ubiquitin/proteasome" system. In this system, a small 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 of the extracellular domain of the receptor, which is distinct from the NGF binding site. Amitryptiline possesses neurotrophic activity both in-vitro and in-vivo. Gambogic amide, a derivative of gambogic acid, selectively activates TrkA both in-vitro and in-vivo by interacting with the cytoplasmic juxtamembrane domain of TrkA.
Role in cancer
Although originally identified as an oncogenic fusion in 1982, 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, NTRK2 and NTRK3 gene fusions and other oncogenic alterations in a number of tumor types. A number of Trk inhibitors are in clinical trials and have shown early promise in shrinking human tumors.
Inhibitors in development
Entrectinib is an investigational drug developed by Ignyta, Inc., which has potential antitumor activity. It is a selective pan-trk receptor tyrosine kinase inhibitor targeting gene fusions in trkA, trkB, and trkC that is currently in phase 2 clinical testing.
