TrkA

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neurotrophic tyrosine kinase, receptor, type 1
Identifiers
SymbolNTRK1
Entrez4914
HUGO8031
OMIM191315
RefSeqNM_002529
UniProtP04629
Other data
EC number2.7.1.112
LocusChr. 1 q23-q31

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 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.

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.[1]

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.

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.

Regulation of TrkA

The levels of distinct proteins can be regulated by the "ubiquitin/proteasome" system. In this system, a small peptide 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.

References

[2] The trk proto-oncogene product: a signal transducing receptor for nerve growth factor

[3] Origin and evolution of the Trk family of neurotrophic receptors

[4] Cell Survival through Trk Neurotrophin Receptors Is Differentially Regulated by Ubiquitination


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