Receptor nervnog faktora rasta visokog afiniteta (engl.High affinity nerve growth factor receptor; neurotrofni tirozinski kinazni receptor tipa 1, TRK1-transformišući tirozinski kinazni protein, Trk-A) protein je koji je kod ljudi kodiran NTRK1genom.[1]
Ovaj gen kodira člana familije neurotrofnih tirozinskih kinaznih receptora (NTKR). Ova kinaza je za membranu vezani receptor koji, nakon neurotrofinskog vezivanje, fosforiliše sebe (autofosforilacija) i članove MAPK puta. Prisustvo ove kinaze dovodi do ćelijske diferencijacije i može da ima ulogu u specificiranju senzornih neuronskih podtipova. Mutacije ovog gena su vezane za kongenitalnu insenzitivnost na bol sa anhidrozom, samo povređivanje, mentalnu retardaciju i kancer. Alternativne transkriptne splajsne varijante ovog gena su poznate, ali su samo tri do sada okarakterisane.[2]
Mali molekuli kao što su amitriptilin i derivat gamboginske kiseline aktiviraju TrkA. Amitriptilin aktivira TrkA i omogućava heterodimerizaciju TrkA i TrkB u odsustvu NGF. Do vezivanja amitriptilina za TrkA dolazi u leucinom bogatom regionu (LRR) ekstracelularnog domena receptora, koji je udaljen od NGF mesta vezivanje. Amitriptilin poseduje neurotrono dejstvo in-vitro i in-vivo (mišji model).[20] Gamboginski amid, derivat gamboginske kiseline, selektivno aktivira TrkA (a ne aktivira TrkB i TrkC) in-vitro i in-vivo putem interakcije sa citoplazmatičnim domenom u blizini membrane.[21]
↑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.
↑ 5,05,15,2Meakin, 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.
↑Lee, R; Kermani P; Teng K K; Hempstead B L (November 2001). „Regulation of cell survival by secreted proneurotrophins”. Science294 (5548): 1945–8. DOI:10.1126/science.1065057. PMID11729324.
↑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.
↑ 13,013,113,213,3Qian, X; Riccio A; Zhang Y; Ginty D D (November 1998). „Identification and characterization of novel substrates of Trk receptors in developing neurons”. Neuron21 (5): 1017–29. DOI:10.1016/S0896-6273(00)80620-0. PMID9856458.
↑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.
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.