Tropomyosin receptor kinase A

1HE7, 1SHC, 1WWA, 1WWW, 2IFG, 4AOJ, 4F0I, 4GT5, 4CRP, 4PMM, 4PMP, 4PMS, 4PMT, 4YNE, 4YPS491418211ENSG00000198400ENSMUSG00000028072P04629Q3UFB7NM_002529NM_001007792NM_001012331NM_001033124NP_001007793NP_001012331NP_002520NP_001028296Tropomyosin 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 NTRK1 gene.1he7: HUMAN NERVE GROWTH FACTOR RECEPTOR TRKA1wwa: NGF BINDING DOMAIN OF HUMAN TRKA RECEPTOR1www: NGF IN COMPLEX WITH DOMAIN 5 OF THE TRKA RECEPTOR2ifg: Structure of the extracellular segment of human TRKA in complex with nerve growth factor 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 NTRK1 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 (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 congenital insensitivity to pain with anhidrosis, self-mutilating behaviors, intellectual disability and/or cognitive impairment and certain cancers. Alternate transcriptional splice variants of this gene have been found, but only three have been characterized to date. 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 include neuronal differentiation and avoidance of programmed cell death. 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. 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. 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. 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.