High affinity nerve growth factor receptor also known as neurotrophic tyrosine kinase receptor type 1 or TRK1-transforming tyrosine kinase protein or Trk-A 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.
^Martin-Zanca D, Hughes SH, Barbacid M (April 1986). "A human oncogene formed by the fusion of truncated tropomyosin and protein tyrosine kinase sequences". Nature319 (6056): 743–8. doi:10.1038/319743a0. PMID2869410.
^ abcMeakin, S O; MacDonald J I; Gryz E A; Kubu C J; Verdi J M (April 1999). "The signaling adapter FRS-2 competes with Shc for binding to the nerve growth factor receptor TrkA. A model for discriminating proliferation and differentiation". J. Biol. Chem.274 (14): 9861–70. doi:10.1074/jbc.274.14.9861. PMID10092678.
^Song, Cheng; Perides George; Liu Ya Fang (February 2002). "Expression of full-length polyglutamine-expanded Huntingtin disrupts growth factor receptor signaling in rat pheochromocytoma (PC12) cells". J. Biol. Chem.277 (8): 6703–7. doi:10.1074/jbc.M110338200. PMID11733534.
^MacDonald, J I; Gryz E A; Kubu C J; Verdi J M; Meakin S O (June 2000). "Direct binding of the signaling adapter protein Grb2 to the activation loop tyrosines on the nerve growth factor receptor tyrosine kinase, TrkA". J. Biol. Chem.275 (24): 18225–33. doi:10.1074/jbc.M001862200. PMID10748052.
^Yamashita, H; Avraham S; Jiang S; Dikic I; Avraham H (May 1999). "The Csk homologous kinase associates with TrkA receptors and is involved in neurite outgrowth of PC12 cells". J. Biol. Chem.274 (21): 15059–65. doi:10.1074/jbc.274.21.15059. PMID10329710.
^Nykjaer, Anders; Lee Ramee, Teng Kenneth K, Jansen Pernille, Madsen Peder, Nielsen Morten S, Jacobsen Christian, Kliemannel Marco, Schwarz Elisabeth, Willnow Thomas E, Hempstead Barbara L, Petersen Claus M (February 2004). "Sortilin is essential for proNGF-induced neuronal cell death". Nature427 (6977): 843–8. doi:10.1038/nature02319. PMID14985763.Cite uses deprecated parameters (help)
^Wiesmann, C; Ultsch M H; Bass S H; de Vos A M (September 1999). "Crystal structure of nerve growth factor in complex with the ligand-binding domain of the TrkA receptor". Nature401 (6749): 184–8. doi:10.1038/43705. PMID10490030.
^Ohmichi, M; Decker S J; Pang L; Saltiel A R (August 1991). "Nerve growth factor binds to the 140 kd trk proto-oncogene product and stimulates its association with the src homology domain of phospholipase C gamma 1". Biochem. Biophys. Res. Commun.179 (1): 217–23. doi:10.1016/0006-291X(91)91357-I. PMID1715690.
^Wooten, M W; Seibenhener M L; Mamidipudi V; Diaz-Meco M T; Barker P A; Moscat J (March 2001). "The atypical protein kinase C-interacting protein p62 is a scaffold for NF-kappaB activation by nerve growth factor". J. Biol. Chem.276 (11): 7709–12. doi:10.1074/jbc.C000869200. PMID11244088.
^Geetha T, Wooten MW (February 2003). "Association of the atypical protein kinase C-interacting protein p62/ZIP with nerve growth factor receptor TrkA regulates receptor trafficking and Erk5 signaling". J. Biol. Chem.278 (7): 4730–9. doi:10.1074/jbc.M208468200. PMID12471037.
^Wooten MW, Geetha T, Babu JR, Seibenhener ML, Peng J, Cox N, Diaz-Meco MT, Moscat J (March 2008). "Essential role of sequestosome 1/p62 in regulating accumulation of Lys63-ubiquitinated proteins". J. Biol. Chem.283 (11): 6783–9. doi:10.1074/jbc.M709496200. PMID18174161.
^Borrello, M G; Pelicci G; Arighi E; De Filippis L; Greco A; Bongarzone I; Rizzetti M; Pelicci P G; Pierotti M A (June 1994). "The oncogenic versions of the Ret and Trk tyrosine kinases bind Shc and Grb2 adaptor proteins". Oncogene9 (6): 1661–8. PMID8183561.
Indo Y (2002). "Genetics of congenital insensitivity to pain with anhidrosis (CIPA) or hereditary sensory and autonomic neuropathy type IV. Clinical, biological and molecular aspects of mutations in TRKA(NTRK1) gene encoding the receptor tyrosine kinase for nerve growth factor.". Clin. Auton. Res.12 (Suppl 1): I20–32. doi:10.1007/s102860200016. PMID12102460.
Micera A, Lambiase A, Stampachiacchiere B, et al. (2007). "Nerve growth factor and tissue repair remodeling: trkA(NGFR) and p75(NTR), two receptors one fate.". Cytokine Growth Factor Rev.18 (3–4): 245–56. doi:10.1016/j.cytogfr.2007.04.004. PMID17531524.