ID NTRK1_HUMAN Reviewed; 796 AA. AC P04629; B2R6T5; B7ZM34; P08119; Q15655; Q15656; Q5D056; Q5VZS2; AC Q7Z5C3; Q9UIU7; DT 13-AUG-1987, integrated into UniProtKB/Swiss-Prot. DT 02-MAY-2006, sequence version 4. DT 07-SEP-2016, entry version 217. DE RecName: Full=High affinity nerve growth factor receptor; DE EC=2.7.10.1; DE AltName: Full=Neurotrophic tyrosine kinase receptor type 1; DE AltName: Full=TRK1-transforming tyrosine kinase protein; DE AltName: Full=Tropomyosin-related kinase A; DE AltName: Full=Tyrosine kinase receptor; DE AltName: Full=Tyrosine kinase receptor A; DE Short=Trk-A; DE AltName: Full=gp140trk; DE AltName: Full=p140-TrkA; DE Flags: Precursor; GN Name=NTRK1; Synonyms=MTC, TRK, TRKA; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; OC Catarrhini; Hominidae; Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM TRKA-I). RC TISSUE=Colon; RX PubMed=2927393; RA Martin-Zanca D., Oskam R., Mitra G., Copeland T.D., Barbacid M.; RT "Molecular and biochemical characterization of the human trk proto- RT oncogene."; RL Mol. Cell. Biol. 9:24-33(1989). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA]. RC TISSUE=Brain; RX PubMed=7823156; RA Shelton D.L., Sutherland J., Gripp J., Camerato T., Armanini M.P., RA Phillips H.S., Carroll K., Spencer S.D., Levinson A.D.; RT "Human trks: molecular cloning, tissue distribution, and expression of RT extracellular domain immunoadhesins."; RL J. Neurosci. 15:477-491(1995). RN [3] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RX PubMed=9290260; DOI=10.1007/BF02766957; RA Indo Y., Mardy S., Tsuruta M., Karim M.A., Matsuda I.; RT "Structure and organization of the human TRKA gene encoding a high RT affinity receptor for nerve growth factor."; RL Jpn. J. Hum. Genet. 42:343-351(1997). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM TRKA-II), AND RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 1-175 (ISOFORM 3). RC TISSUE=Uterus; RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=16710414; DOI=10.1038/nature04727; RA Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D., RA Dunham A., Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A., RA Jones M.C., Gillson C., Searle S., Zhou Y., Kokocinski F., RA McDonald L., Evans R., Phillips K., Atkinson A., Cooper R., Jones C., RA Hall R.E., Andrews T.D., Lloyd C., Ainscough R., Almeida J.P., RA Ambrose K.D., Anderson F., Andrew R.W., Ashwell R.I.S., Aubin K., RA Babbage A.K., Bagguley C.L., Bailey J., Beasley H., Bethel G., RA Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J., Buckley D., RA Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y., Clarke G., RA Clee C., Cobley V., Collier R.E., Corby N., Coville G.J., Davies J., RA Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H., RA Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L., RA Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J., RA Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R., RA Hammond S., Harrison E.S.I., Hart E., Haugen E., Heath P.D., RA Holmes S., Holt K., Howden P.J., Hunt A.R., Hunt S.E., Hunter G., RA Isherwood J., James R., Johnson C., Johnson D., Joy A., Kay M., RA Kershaw J.K., Kibukawa M., Kimberley A.M., King A., Knights A.J., RA Lad H., Laird G., Lawlor S., Leongamornlert D.A., Lloyd D.M., RA Loveland J., Lovell J., Lush M.J., Lyne R., Martin S., RA Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W., McLaren S., RA Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N., RA Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V., RA Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J., RA Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E., RA Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C., RA Subramanian S., Sycamore N., Tracey A., Tromans A., Van Helmond Z., RA Wall M., Wallis J.M., White S., Whitehead S.L., Wilkinson J.E., RA Willey D.L., Williams H., Wilming L., Wray P.W., Wu Z., Coulson A., RA Vaudin M., Sulston J.E., Durbin R.M., Hubbard T., Wooster R., RA Dunham I., Carter N.P., McVean G., Ross M.T., Harrow J., Olson M.V., RA Beck S., Rogers J., Bentley D.R.; RT "The DNA sequence and biological annotation of human chromosome 1."; RL Nature 441:315-321(2006). RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS TRKA-I AND TRKA-II). RC TISSUE=Brain; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA RT project: the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [7] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-71. RX PubMed=15870692; DOI=10.1038/sj.onc.1208697; RA Fujimoto M., Kitazawa R., Maeda S., Kitazawa S.; RT "Methylation adjacent to negatively regulating AP-1 site reactivates RT TrkA gene expression during cancer progression."; RL Oncogene 24:5108-5118(2005). RN [8] RP NUCLEOTIDE SEQUENCE [MRNA] OF 399-796, AND CHROMOSOMAL TRANSLOCATION RP WITH TPM3. RX PubMed=2869410; DOI=10.1038/319743a0; RA Martin-Zanca D., Hughes S.H., Barbacid M.; RT "A human oncogene formed by the fusion of truncated tropomyosin and RT protein tyrosine kinase sequences."; RL Nature 319:743-748(1986). RN [9] RP NUCLEOTIDE SEQUENCE [MRNA] OF 399-796. RX PubMed=2966065; RA Kozma S.C., Redmond S.M.S., Saurer S.M., Groner B., Hynes N.E.; RT "Activation of the receptor kinase domain of the trk oncogene by RT recombination with two different cellular sequences."; RL EMBO J. 7:147-154(1988). RN [10] RP NUCLEOTIDE SEQUENCE [MRNA] OF 399-796, AND CHROMOSOMAL TRANSLOCATION RP WITH TFG. RX PubMed=7565764; RA Greco A., Mariani C., Miranda C., Lupas A., Pagliardini S., Pomati M., RA Pierotti M.A.; RT "The DNA rearrangement that generates the TRK-T3 oncogene involves a RT novel gene on chromosome 3 whose product has a potential coiled-coil RT domain."; RL Mol. Cell. Biol. 15:6118-6127(1995). RN [11] RP NUCLEOTIDE SEQUENCE [MRNA] OF 486-796, AND CHROMOSOMAL REARRANGEMENT RP WITH TPR. RX PubMed=1532241; RA Greco A., Pierotti M.A., Bongarzone I., Pagliardini S., Lanzi C., RA Della Porta G.; RT "TRK-T1 is a novel oncogene formed by the fusion of TPR and TRK genes RT in human papillary thyroid carcinomas."; RL Oncogene 7:237-242(1992). RN [12] RP FUNCTION AS RECEPTOR FOR NGF. RX PubMed=1850821; DOI=10.1038/350678a0; RA Hempstead B.L., Martin-Zanca D., Kaplan D.R., Parada L.F., Chao M.V.; RT "High-affinity NGF binding requires coexpression of the trk proto- RT oncogene and the low-affinity NGF receptor."; RL Nature 350:678-683(1991). RN [13] RP FUNCTION IN NGF SIGNALING, AND IDENTIFICATION AS THE HIGH AFFINITY NGF RP RECEPTOR. RX PubMed=1849459; DOI=10.1016/0092-8674(91)90419-Y; RA Klein R., Jing S., Nanduri V., O'Rourke E., Barbacid M.; RT "The trk proto-oncogene encodes a receptor for nerve growth factor."; RL Cell 65:189-197(1991). RN [14] RP ALTERNATIVE SPLICING (ISOFORMS TRKA-I AND TRKA-II), FUNCTION IN CELL RP SURVIVAL, NGF-BINDING, PHOSPHORYLATION, AND TISSUE SPECIFICITY. RX PubMed=8325889; RA Barker P.A., Lomen-Hoerth C., Gensch E.M., Meakin S.O., Glass D.J., RA Shooter E.M.; RT "Tissue-specific alternative splicing generates two isoforms of the RT trkA receptor."; RL J. Biol. Chem. 268:15150-15157(1993). RN [15] RP PHOSPHORYLATION AT TYR-791, INTERACTION WITH PLCG1, AND MUTAGENESIS OF RP TYR-791. RX PubMed=7510697; RA Loeb D.M., Stephens R.M., Copeland T.D., Kaplan D.R., Greene L.A.; RT "A Trk nerve growth factor (NGF) receptor point mutation affecting RT interaction with phospholipase C-gamma 1 abolishes NGF-promoted RT peripherin induction but not neurite outgrowth."; RL J. Biol. Chem. 269:8901-8910(1994). RN [16] RP FUNCTION IN NEURONAL DIFFERENTIATION, FUNCTION IN PHOSPHORYLATION OF RP SHC1 AND PLCG1, INTERACTION WITH SHC1, MUTAGENESIS OF TYR-496; LYS-544 RP AND TYR-791, AND PHOSPHORYLATION AT TYR-496 AND TYR-791. RX PubMed=8155326; DOI=10.1016/0896-6273(94)90223-2; RA Stephens R.M., Loeb D.M., Copeland T.D., Pawson T., Greene L.A., RA Kaplan D.R.; RT "Trk receptors use redundant signal transduction pathways involving RT SHC and PLC-gamma 1 to mediate NGF responses."; RL Neuron 12:691-705(1994). RN [17] RP FUNCTION IN NF-KAPPA-B ACTIVATION, AND INTERACTION WITH SQSTM1. RX PubMed=11244088; DOI=10.1074/jbc.C000869200; RA Wooten M.W., Seibenhener M.L., Mamidipudi V., Diaz-Meco M.T., RA Barker P.A., Moscat J.; RT "The atypical protein kinase C-interacting protein p62 is a scaffold RT for NF-kappaB activation by nerve growth factor."; RL J. Biol. Chem. 276:7709-7712(2001). RN [18] RP FUNCTION IN NEURONAL CELL PROLIFERATION AND DIFFERENTIATION, FUNCTION RP IN SIGNALING CASCADE ACTIVATION, NGF-BINDING, SUBCELLULAR LOCATION, RP ALTERNATIVE SPLICING (ISOFORM TRKA-III), CHARACTERIZATION OF ISOFORM RP TRKA-III, PHOSPHORYLATION AT TYR-496; TYR-680; TYR-681 AND TYR-791, RP INTERACTION WITH FRS2; GRB2; PIK3R1; PLCG1; SHC1, GLYCOSYLATION, RP TISSUE SPECIFICITY, AND INDUCTION BY HYPOXIA. RX PubMed=15488758; DOI=10.1016/j.ccr.2004.09.011; RA Tacconelli A., Farina A.R., Cappabianca L., Desantis G., Tessitore A., RA Vetuschi A., Sferra R., Rucci N., Argenti B., Screpanti I., Gulino A., RA Mackay A.R.; RT "TrkA alternative splicing: a regulated tumor-promoting switch in RT human neuroblastoma."; RL Cancer Cell 6:347-360(2004). RN [19] RP INTERACTION WITH SORT1, AND ENZYME REGULATION. RX PubMed=21102451; DOI=10.1038/nn.2689; RA Vaegter C.B., Jansen P., Fjorback A.W., Glerup S., Skeldal S., RA Kjolby M., Richner M., Erdmann B., Nyengaard J.R., Tessarollo L., RA Lewin G.R., Willnow T.E., Chao M.V., Nykjaer A.; RT "Sortilin associates with Trk receptors to enhance anterograde RT transport and neurotrophin signaling."; RL Nat. Neurosci. 14:54-61(2011). RN [20] RP STRUCTURE BY NMR OF 489-500. RX PubMed=8524391; DOI=10.1038/378584a0; RA Zhou M.-M., Ravichandran K.S., Olejniczak E.F., Petros A.M., RA Meadows R.P., Sattler M., Harlan J.E., Wade W.S., Burakoff S.J., RA Fesik S.W.; RT "Structure and ligand recognition of the phosphotyrosine binding RT domain of Shc."; RL Nature 378:584-592(1995). RN [21] RP X-RAY CRYSTALLOGRAPHY (2.5 ANGSTROMS) OF 278-386. RX PubMed=10388563; DOI=10.1006/jmbi.1999.2816; RA Ultsch M.H., Wiesmann C., Simmons L.C., Henrich J., Yang M., RA Reilly D., Bass S.H., de Vos A.M.; RT "Crystal structures of the neurotrophin-binding domain of TrkA, TrkB RT and TrkC."; RL J. Mol. Biol. 290:149-159(1999). RN [22] RP X-RAY CRYSTALLOGRAPHY (2.2 ANGSTROMS) OF 282-382. RX PubMed=10490030; DOI=10.1038/43705; RA Wiesmann C., Ultsch M.H., Bass S.H., de Vos A.M.; RT "Crystal structure of nerve growth factor in complex with the ligand- RT binding domain of the TrkA receptor."; RL Nature 401:184-188(1999). RN [23] RP X-RAY CRYSTALLOGRAPHY (3.4 ANGSTROMS) OF 36-382 IN COMPLEX WITH NGF, RP HOMODIMERIZATION, DISULFIDE BONDS, AND GLYCOSYLATION AT ASN-95; RP ASN-121; ASN-188; ASN-262; ASN-281 AND ASN-358. RX PubMed=17196528; DOI=10.1016/j.neuron.2006.09.034; RA Wehrman T., He X., Raab B., Dukipatti A., Blau H., Garcia K.C.; RT "Structural and mechanistic insights into nerve growth factor RT interactions with the TrkA and p75 receptors."; RL Neuron 53:25-38(2007). RN [24] RP VARIANT CIPA ARG-577. RX PubMed=8696348; DOI=10.1038/ng0896-485; RA Indo Y., Tsuruta M., Hayashida Y., Karim M.A., Ohta K., Kawano T., RA Mitsubuchi H., Tonoki H., Awaya Y., Matsuda I.; RT "Mutations in the TRKA/NGF receptor gene in patients with congenital RT insensitivity to pain with anhidrosis."; RL Nat. Genet. 13:485-488(1996). RN [25] RP VARIANT CIPA PRO-780. RX PubMed=10090906; DOI=10.1086/302319; RA Greco A., Villa R., Tubino B., Romano L., Penso D., Pierotti M.A.; RT "A novel NTRK1 mutation associated with congenital insensitivity to RT pain with anhidrosis."; RL Am. J. Hum. Genet. 64:1207-1210(1999). RN [26] RP VARIANTS CIPA PRO-213; TRP-649 AND SER-714, AND VARIANTS SER-85; RP TYR-604 AND VAL-613. RX PubMed=10330344; DOI=10.1086/302422; RA Mardy S., Miura Y., Endo F., Matsuda I., Sztriha L., Frossard P., RA Moosa A., Ismail E.A.R., Macaya A., Andria G., Toscano E., Gibson W., RA Graham G.E., Indo Y.; RT "Congenital insensitivity to pain with anhidrosis: novel mutations in RT the TRKA (NTRK1) gene encoding a high-affinity receptor for nerve RT growth factor."; RL Am. J. Hum. Genet. 64:1570-1579(1999). RN [27] RP VARIANTS TYR-604; VAL-613 AND GLN-780. RX PubMed=10443680; DOI=10.1210/jc.84.8.2784; RA Gimm O., Greco A., Hoang-Vu C., Dralle H., Pierotti M.A., Eng C.; RT "Mutation analysis reveals novel sequence variants in NTRK1 in RT sporadic human medullary thyroid carcinoma."; RL J. Clin. Endocrinol. Metab. 84:2784-2787(1999). RN [28] RP VARIANT CIPA VAL-587. RX PubMed=10233776; DOI=10.1046/j.1523-1747.1999.00569.x; RA Yotsumoto S., Setoyama M., Hozumi H., Mizoguchi S., Fukumaru S., RA Kobayashi K., Saheki T., Kanzaki T.; RT "A novel point mutation affecting the tyrosine kinase domain of the RT TRKA gene in a family with congenital insensitivity to pain with RT anhidrosis."; RL J. Invest. Dermatol. 112:810-814(1999). RN [29] RP VARIANTS TYR-604 AND VAL-613. RX PubMed=10391209; DOI=10.1038/10290; RA Cargill M., Altshuler D., Ireland J., Sklar P., Ardlie K., Patil N., RA Shaw N., Lane C.R., Lim E.P., Kalyanaraman N., Nemesh J., Ziaugra L., RA Friedland L., Rolfe A., Warrington J., Lipshutz R., Daley G.Q., RA Lander E.S.; RT "Characterization of single-nucleotide polymorphisms in coding regions RT of human genes."; RL Nat. Genet. 22:231-238(1999). RN [30] RP ERRATUM. RA Cargill M., Altshuler D., Ireland J., Sklar P., Ardlie K., Patil N., RA Shaw N., Lane C.R., Lim E.P., Kalyanaraman N., Nemesh J., Ziaugra L., RA Friedland L., Rolfe A., Warrington J., Lipshutz R., Daley G.Q., RA Lander E.S.; RL Nat. Genet. 23:373-373(1999). RN [31] RP VARIANT CIPA LEU-695, AND VARIANT VAL-613. RC TISSUE=Peripheral blood; RX PubMed=10861667; RX DOI=10.1002/1096-8628(20000619)92:5<353::AID-AJMG12>3.0.CO;2-C; RA Shatzky S., Moses S., Levy J., Pinsk V., Hershkovitz E., Herzog L., RA Shorer Z., Luder A., Parvari R.; RT "Congenital insensitivity to pain with anhidrosis (CIPA) in Israeli- RT Bedouins: genetic heterogeneity, novel mutations in the TRKA/NGF RT receptor gene, clinical findings, and results of nerve conduction RT studies."; RL Am. J. Med. Genet. 92:353-360(2000). RN [32] RP VARIANTS CIPA PRO-93; ARG-522; ARG-577; CYS-654 AND TYR-674. RX PubMed=10982191; DOI=10.1007/s004390051018; RA Miura Y., Mardy S., Awaya Y., Nihei K., Endo F., Matsuda I., Indo Y.; RT "Mutation and polymorphism analysis of the TRKA (NTRK1) gene encoding RT a high-affinity receptor for nerve growth factor in congenital RT insensitivity to pain with anhidrosis (CIPA) families."; RL Hum. Genet. 106:116-124(2000). RN [33] RP VARIANT CIPA ARG-577. RX PubMed=10567924; RX DOI=10.1002/(SICI)1097-4652(200001)182:1<127::AID-JCP14>3.0.CO;2-0; RA Greco A., Villa R., Fusetti L., Orlandi R., Pierotti M.A.; RT "The Gly571Arg mutation, associated with the autonomic and sensory RT disorder congenital insensitivity to pain with anhidrosis, causes the RT inactivation of the NTRK1/nerve growth factor receptor."; RL J. Cell. Physiol. 182:127-133(2000). RN [34] RP VARIANT CIPA CYS-359, AND VARIANTS TYR-604 AND VAL-613. RX PubMed=11310631; DOI=10.1002/ana.103; RA Houlden H., King R.H., Hashemi-Nejad A., Wood N.W., Mathias C.J., RA Reilly M., Thomas P.K.; RT "A novel TRK A (NTRK1) mutation associated with hereditary sensory and RT autonomic neuropathy type V."; RL Ann. Neurol. 49:521-525(2001). RN [35] RP CHARACTERIZATION OF VARIANTS CIPA PRO-93; PRO-213; ARG-522; ARG-577; RP TRP-649; CYS-654 AND SER-714, AND CHARACTERIZATION OF VARIANTS SER-85; RP TYR-604; VAL-613 AND TYR-674. RX PubMed=11159935; DOI=10.1093/hmg/10.3.179; RA Mardy S., Miura Y., Endo F., Matsuda I., Indo Y.; RT "Congenital insensitivity to pain with anhidrosis (CIPA): effect of RT TRKA (NTRK1) missense mutations on autophosphorylation of the receptor RT tyrosine kinase for nerve growth factor."; RL Hum. Mol. Genet. 10:179-188(2001). RN [36] RP VARIANTS [LARGE SCALE ANALYSIS] ARG-80; VAL-107; MET-237; GLY-238; RP GLY-260; GLN-444; CYS-452; THR-566; TYR-604; VAL-613; GLN-780 AND RP ILE-790. RX PubMed=17344846; DOI=10.1038/nature05610; RA Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C., RA Bignell G., Davies H., Teague J., Butler A., Stevens C., Edkins S., RA O'Meara S., Vastrik I., Schmidt E.E., Avis T., Barthorpe S., RA Bhamra G., Buck G., Choudhury B., Clements J., Cole J., Dicks E., RA Forbes S., Gray K., Halliday K., Harrison R., Hills K., Hinton J., RA Jenkinson A., Jones D., Menzies A., Mironenko T., Perry J., Raine K., RA Richardson D., Shepherd R., Small A., Tofts C., Varian J., Webb T., RA West S., Widaa S., Yates A., Cahill D.P., Louis D.N., Goldstraw P., RA Nicholson A.G., Brasseur F., Looijenga L., Weber B.L., Chiew Y.-E., RA DeFazio A., Greaves M.F., Green A.R., Campbell P., Birney E., RA Easton D.F., Chenevix-Trench G., Tan M.-H., Khoo S.K., Teh B.T., RA Yuen S.T., Leung S.Y., Wooster R., Futreal P.A., Stratton M.R.; RT "Patterns of somatic mutation in human cancer genomes."; RL Nature 446:153-158(2007). RN [37] RP VARIANTS CIPA LYS-492 AND CYS-654, AND VARIANT TRP-6. RX PubMed=22302274; DOI=10.1007/s00415-011-6397-y; RA Davidson G.L., Murphy S.M., Polke J.M., Laura M., Salih M.A., RA Muntoni F., Blake J., Brandner S., Davies N., Horvath R., Price S., RA Donaghy M., Roberts M., Foulds N., Ramdharry G., Soler D., Lunn M.P., RA Manji H., Davis M.B., Houlden H., Reilly M.M.; RT "Frequency of mutations in the genes associated with hereditary RT sensory and autonomic neuropathy in a UK cohort."; RL J. Neurol. 259:1673-1685(2012). CC -!- FUNCTION: Receptor tyrosine kinase involved in the development and CC the maturation of the central and peripheral nervous systems CC through regulation of proliferation, differentiation and survival CC of sympathetic and nervous neurons. High affinity receptor for NGF CC which is its primary ligand, it can also bind and be activated by CC NTF3/neurotrophin-3. However, NTF3 only supports axonal extension CC through NTRK1 but has no effect on neuron survival. Upon dimeric CC NGF ligand-binding, undergoes homodimerization, CC autophosphorylation and activation. Recruits, phosphorylates CC and/or activates several downstream effectors including SHC1, CC FRS2, SH2B1, SH2B2 and PLCG1 that regulate distinct overlapping CC signaling cascades driving cell survival and differentiation. CC Through SHC1 and FRS2 activates a GRB2-Ras-MAPK cascade that CC regulates cell differentiation and survival. Through PLCG1 CC controls NF-Kappa-B activation and the transcription of genes CC involved in cell survival. Through SHC1 and SH2B1 controls a Ras- CC PI3 kinase-AKT1 signaling cascade that is also regulating CC survival. In absence of ligand and activation, may promote cell CC death, making the survival of neurons dependent on trophic CC factors. CC -!- FUNCTION: Isoform TrkA-III is resistant to NGF, constitutively CC activates AKT1 and NF-kappa-B and is unable to activate the Ras- CC MAPK signaling cascade. Antagonizes the anti-proliferative NGF- CC NTRK1 signaling that promotes neuronal precursors differentiation. CC Isoform TrkA-III promotes angiogenesis and has oncogenic activity CC when overexpressed. CC -!- CATALYTIC ACTIVITY: ATP + a [protein]-L-tyrosine = ADP + a CC [protein]-L-tyrosine phosphate. {ECO:0000255|PROSITE- CC ProRule:PRU10028}. CC -!- ENZYME REGULATION: The pro-survival signaling effect of NTRK1 in CC neurons requires its endocytosis into signaling early endosomes CC and its retrograde axonal transport. This is regulated by CC different proteins including CFL1, RAC1 and SORT1. NTF3 is unable CC to induce this signaling probably due to the lability of the NTF3- CC NTRK1 complex in endosomes. SH2D1A inhibits the CC autophosphorylation of the receptor, and alters the recruitment CC and activation of downstream effectors and signaling cascades (By CC similarity). Regulated by NGFR (By similarity). {ECO:0000250}. CC -!- SUBUNIT: Exists in a dynamic equilibrium between monomeric (low CC affinity) and dimeric (high affinity) structures. Homodimerization CC is induced by binding of a NGF dimer. Interacts with SQSTM1; CC bridges NTRK1 to NGFR. Forms a ternary complex with NGFR and CC KIDINS220; this complex is affected by the expression levels of CC KIDINS220 and an increase in KIDINS220 expression leads to a CC decreased association of NGFR and NTRK1 (By similarity). Interacts CC with SH2D1A; regulates NTRK1 (By similarity). Interacts CC (phosphorylated upon activation by NGF) with SHC1; mediates SHC1 CC phosphorylation and activation. Interacts (phosphorylated upon CC activation by NGF) with PLCG1; mediates PLCG1 phosphorylation and CC activation. Interacts (phosphorylated) with SH2B1 and SH2B2. CC Interacts with GRB2. Interacts with PIK3R1. Interacts with FRS2. CC Interacts with SORT1; may regulate NTRK1 anterograde axonal CC transport. Interacts with RAB7A (By similarity). Found in a CC complex, at least composed of KIDINS220, MAGI2, NTRK1 and RAPGEF2; CC the complex is mainly formed at late endosomes in a nerve growth CC factor (NGF)-dependent manner (By similarity). Interacts with CC RAPGEF2; the interaction is strengthened after NGF stimulation (By CC similarity). {ECO:0000250}. CC -!- INTERACTION: CC P22681:CBL; NbExp=2; IntAct=EBI-1028226, EBI-518228; CC P01138:NGF; NbExp=2; IntAct=EBI-1028226, EBI-1028250; CC Q8K4V6:Pirb (xeno); NbExp=2; IntAct=EBI-1028226, EBI-8602514; CC P18031:PTPN1; NbExp=2; IntAct=EBI-1028226, EBI-968788; CC Q99523:SORT1; NbExp=3; IntAct=EBI-1028226, EBI-1057058; CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:15488758}; CC Single-pass type I membrane protein {ECO:0000269|PubMed:15488758}. CC Early endosome membrane {ECO:0000250}; Single-pass type I membrane CC protein {ECO:0000250}. Late endosome membrane {ECO:0000250}; CC Single-pass type I membrane protein {ECO:0000250}. CC Note=Internalized to endosomes upon binding of NGF or NTF3 and CC further transported to the cell body via a retrograde axonal CC transport. Localized at cell membrane and early endosomes before CC nerve growth factor (NGF) stimulation. Recruited to late endosomes CC after NGF stimulation. Colocalized with RAPGEF2 at late endosomes CC (By similarity). {ECO:0000250}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=4; CC Comment=TrkA-I and TrkA-II isoforms have similar biological CC properties but are differentially expressed.; CC Name=TrkA-II; Synonyms=TrkAII; CC IsoId=P04629-1; Sequence=Displayed; CC Note=Major isoform.; CC Name=TrkA-I; Synonyms=TrkAI; CC IsoId=P04629-2; Sequence=VSP_002899; CC Note=Has enhanced responsiveness to NTF3 neurotrophin.; CC Name=3; CC IsoId=P04629-3; Sequence=VSP_041905, VSP_002899; CC Name=TrkA-III; Synonyms=TrkAIII; CC IsoId=P04629-4; Sequence=VSP_042152, VSP_002899; CC Note=Constitutively active. Does not bind NGF and does not CC interact with GRB2 and FRS2.; CC -!- TISSUE SPECIFICITY: Isoform TrkA-I is found in most non-neuronal CC tissues. Isoform TrkA-II is primarily expressed in neuronal cells. CC TrkA-III is specifically expressed by pluripotent neural stem and CC neural crest progenitors. {ECO:0000269|PubMed:15488758, CC ECO:0000269|PubMed:8325889}. CC -!- INDUCTION: Isoform TrkA-III is up-regulated upon hypoxia in cells CC normally expressing it. {ECO:0000269|PubMed:15488758}. CC -!- DOMAIN: The transmembrane domain mediates interaction with CC KIDINS220. {ECO:0000250}. CC -!- DOMAIN: The extracellular domain mediates interaction with NGFR. CC {ECO:0000250}. CC -!- PTM: Ligand-mediated autophosphorylation. Interaction with SQSTM1 CC is phosphotyrosine-dependent. Autophosphorylation at Tyr-496 CC mediates interaction and phosphorylation of SHC1. CC {ECO:0000269|PubMed:15488758, ECO:0000269|PubMed:7510697, CC ECO:0000269|PubMed:8155326, ECO:0000269|PubMed:8325889}. CC -!- PTM: N-glycosylated (Probable). Isoform TrkA-I is N-glycosylated. CC {ECO:0000269|PubMed:15488758, ECO:0000269|PubMed:17196528, CC ECO:0000305}. CC -!- PTM: Ubiquitinated. Undergoes polyubiquitination upon activation; CC regulated by NGFR. Ubiquitination regulates the internalization of CC the receptor (By similarity). {ECO:0000250}. CC -!- DISEASE: Congenital insensitivity to pain with anhidrosis (CIPA) CC [MIM:256800]: Characterized by a congenital insensitivity to pain, CC anhidrosis (absence of sweating), absence of reaction to noxious CC stimuli, self-mutilating behavior, and mental retardation. This CC rare autosomal recessive disorder is also known as congenital CC sensory neuropathy with anhidrosis or hereditary sensory and CC autonomic neuropathy type IV or familial dysautonomia type II. CC {ECO:0000269|PubMed:10090906, ECO:0000269|PubMed:10233776, CC ECO:0000269|PubMed:10330344, ECO:0000269|PubMed:10567924, CC ECO:0000269|PubMed:10861667, ECO:0000269|PubMed:10982191, CC ECO:0000269|PubMed:11310631, ECO:0000269|PubMed:22302274, CC ECO:0000269|PubMed:8696348}. Note=The disease is caused by CC mutations affecting the gene represented in this entry. CC -!- DISEASE: Note=Chromosomal aberrations involving NTRK1 are found in CC papillary thyroid carcinomas (PTCs) (PubMed:2869410, CC PubMed:7565764, PubMed:1532241). Translocation t(1;3)(q21;q11) CC with TFG generates the TRKT3 (TRK-T3) transcript by fusing TFG to CC the 3'-end of NTRK1 (PubMed:7565764). A rearrangement with TPM3 CC generates the TRK transcript by fusing TPM3 to the 3'-end of NTRK1 CC (PubMed:2869410). An intrachromosomal rearrangement that links the CC protein kinase domain of NTRK1 to the 5'-end of the TPR gene forms CC the fusion protein TRK-T1. TRK-T1 is a 55 kDa protein reacting CC with antibodies against the C-terminus of the NTRK1 protein CC (PubMed:1532241). {ECO:0000269|PubMed:1532241, CC ECO:0000269|PubMed:2869410, ECO:0000269|PubMed:7565764}. CC -!- MISCELLANEOUS: Trk also stands for tropomyosin-related kinase CC since it was first isolated as an oncogenic protein which was the CC result of a fusion between the tropomyosin gene TPM3 and NTRK1. CC -!- SIMILARITY: Belongs to the protein kinase superfamily. Tyr protein CC kinase family. Insulin receptor subfamily. {ECO:0000255|PROSITE- CC ProRule:PRU00159}. CC -!- SIMILARITY: Contains 2 Ig-like C2-type (immunoglobulin-like) CC domains. {ECO:0000305}. CC -!- SIMILARITY: Contains 2 LRR (leucine-rich) repeats. {ECO:0000305}. CC -!- SIMILARITY: Contains 1 LRRCT domain. {ECO:0000305}. CC -!- SIMILARITY: Contains 1 protein kinase domain. CC {ECO:0000255|PROSITE-ProRule:PRU00159}. CC -!- SEQUENCE CAUTION: CC Sequence=CAA27243.1; Type=Erroneous termination; Positions=786; Note=Translated as Gln.; Evidence={ECO:0000305}; CC Sequence=CAA27243.1; Type=Frameshift; Positions=769; Evidence={ECO:0000305}; CC Sequence=CAA27243.1; Type=Miscellaneous discrepancy; Note=Contaminating sequence. Sequence of unknown origin in the N-terminal part.; Evidence={ECO:0000305}; CC Sequence=CAA29888.1; Type=Miscellaneous discrepancy; Note=Contaminating sequence. Sequence of unknown origin in the N-terminal part.; Evidence={ECO:0000305}; CC Sequence=CAA44719.1; Type=Miscellaneous discrepancy; Note=Contaminating sequence. Sequence of unknown origin in the N-terminal part.; Evidence={ECO:0000305}; CC Sequence=CAA59936.1; Type=Miscellaneous discrepancy; Note=Contaminating sequence. Sequence of unknown origin in the N-terminal part.; Evidence={ECO:0000305}; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; M23102; AAA36770.1; -; mRNA. DR EMBL; AB019488; BAA34355.1; -; Genomic_DNA. DR EMBL; AK312704; BAG35582.1; -; mRNA. DR EMBL; DB265639; -; NOT_ANNOTATED_CDS; mRNA. DR EMBL; AL158169; CAH70010.1; -; Genomic_DNA. DR EMBL; BC062580; AAH62580.1; -; mRNA. DR EMBL; BC136554; AAI36555.1; -; mRNA. DR EMBL; BC144239; AAI44240.1; -; mRNA. DR EMBL; AY321513; AAP88292.1; -; Genomic_DNA. DR EMBL; X03541; CAA27243.1; ALT_SEQ; mRNA. DR EMBL; X06704; CAA29888.1; ALT_SEQ; mRNA. DR EMBL; X85960; CAA59936.1; ALT_SEQ; mRNA. DR EMBL; X62947; CAA44719.1; ALT_SEQ; mRNA. DR CCDS; CCDS1161.1; -. [P04629-1] DR CCDS; CCDS30890.1; -. [P04629-3] DR CCDS; CCDS30891.1; -. [P04629-2] DR PIR; A30124; TVHUTT. DR PIR; S23741; S23741. DR RefSeq; NP_001007793.1; NM_001007792.1. [P04629-3] DR RefSeq; NP_001012331.1; NM_001012331.1. [P04629-2] DR RefSeq; NP_002520.2; NM_002529.3. [P04629-1] DR UniGene; Hs.406293; -. DR PDB; 1HE7; X-ray; 2.00 A; A=285-413. DR PDB; 1SHC; NMR; -; B=489-500. DR PDB; 1WWA; X-ray; 2.50 A; X/Y=278-386. DR PDB; 1WWW; X-ray; 2.20 A; X/Y=282-382. DR PDB; 2IFG; X-ray; 3.40 A; A/B=36-382. DR PDB; 4AOJ; X-ray; 2.75 A; A/B/C=473-796. DR PDB; 4CRP; NMR; -; A=282-383. DR PDB; 4F0I; X-ray; 2.30 A; A/B=498-796. DR PDB; 4GT5; X-ray; 2.40 A; A=498-796. DR PDB; 4PMM; X-ray; 2.00 A; A=501-787. DR PDB; 4PMP; X-ray; 1.80 A; A=501-787. DR PDB; 4PMS; X-ray; 2.80 A; A=501-787. DR PDB; 4PMT; X-ray; 2.10 A; A=501-787. DR PDB; 4YNE; X-ray; 2.02 A; A=502-796. DR PDB; 4YPS; X-ray; 2.10 A; A=502-796. DR PDBsum; 1HE7; -. DR PDBsum; 1SHC; -. DR PDBsum; 1WWA; -. DR PDBsum; 1WWW; -. DR PDBsum; 2IFG; -. DR PDBsum; 4AOJ; -. DR PDBsum; 4CRP; -. DR PDBsum; 4F0I; -. DR PDBsum; 4GT5; -. DR PDBsum; 4PMM; -. DR PDBsum; 4PMP; -. DR PDBsum; 4PMS; -. DR PDBsum; 4PMT; -. DR PDBsum; 4YNE; -. DR PDBsum; 4YPS; -. DR ProteinModelPortal; P04629; -. DR SMR; P04629; 36-382, 459-794. DR BioGrid; 110969; 1942. DR DIP; DIP-5714N; -. DR IntAct; P04629; 17. DR MINT; MINT-124106; -. DR STRING; 9606.ENSP00000431418; -. DR BindingDB; P04629; -. DR ChEMBL; CHEMBL3559684; -. DR DrugBank; DB00321; Amitriptyline. DR DrugBank; DB00619; Imatinib. DR DrugBank; DB08896; Regorafenib. DR GuidetoPHARMACOLOGY; 1817; -. DR iPTMnet; P04629; -. DR PhosphoSite; P04629; -. DR BioMuta; NTRK1; -. DR DMDM; 94730402; -. DR PaxDb; P04629; -. DR PeptideAtlas; P04629; -. DR PRIDE; P04629; -. DR Ensembl; ENST00000368196; ENSP00000357179; ENSG00000198400. [P04629-2] DR Ensembl; ENST00000392302; ENSP00000376120; ENSG00000198400. [P04629-3] DR Ensembl; ENST00000524377; ENSP00000431418; ENSG00000198400. [P04629-1] DR GeneID; 4914; -. DR KEGG; hsa:4914; -. DR UCSC; uc001fqf.2; human. [P04629-1] DR CTD; 4914; -. DR GeneCards; NTRK1; -. DR GeneReviews; NTRK1; -. DR HGNC; HGNC:8031; NTRK1. DR HPA; CAB004606; -. DR HPA; HPA035799; -. DR MalaCards; NTRK1; -. DR MIM; 164970; gene. DR MIM; 191315; gene. DR MIM; 256800; phenotype. DR neXtProt; NX_P04629; -. DR Orphanet; 99361; Familial medullary thyroid carcinoma. DR Orphanet; 642; Hereditary sensory and autonomic neuropathy type 4. DR Orphanet; 64752; Hereditary sensory and autonomic neuropathy type 5. DR Orphanet; 146; Papillary or follicular thyroid carcinoma. DR PharmGKB; PA31817; -. DR eggNOG; ENOG410IMMI; Eukaryota. DR eggNOG; ENOG410XTGG; LUCA. DR GeneTree; ENSGT00760000118818; -. DR HOVERGEN; HBG056735; -. DR InParanoid; P04629; -. DR KO; K03176; -. DR OMA; KNVTCWA; -. DR OrthoDB; EOG091G01JY; -. DR PhylomeDB; P04629; -. DR TreeFam; TF106465; -. DR BRENDA; 2.7.10.1; 2681. DR Reactome; R-HSA-167021; PLC-gamma1 signalling. DR Reactome; R-HSA-167044; Signalling to RAS. DR Reactome; R-HSA-170968; Frs2-mediated activation. DR Reactome; R-HSA-170984; ARMS-mediated activation. DR Reactome; R-HSA-177504; Retrograde neurotrophin signalling. DR Reactome; R-HSA-187024; NGF-independant TRKA activation. DR Reactome; R-HSA-187042; TRKA activation by NGF. DR Reactome; R-HSA-187706; Signalling to p38 via RIT and RIN. DR Reactome; R-HSA-198203; PI3K/AKT activation. DR Reactome; R-HSA-198745; Signalling to STAT3. DR SignaLink; P04629; -. DR SIGNOR; P04629; -. DR ChiTaRS; NTRK1; human. DR EvolutionaryTrace; P04629; -. DR GenomeRNAi; 4914; -. DR PRO; PR:P04629; -. DR Proteomes; UP000005640; Chromosome 1. DR Bgee; ENSG00000198400; -. DR ExpressionAtlas; P04629; baseline and differential. DR Genevisible; P04629; HS. DR GO; GO:0030424; C:axon; IEA:Ensembl. DR GO; GO:0009986; C:cell surface; IEA:Ensembl. DR GO; GO:0031410; C:cytoplasmic vesicle; IEA:Ensembl. DR GO; GO:0030425; C:dendrite; IEA:Ensembl. DR GO; GO:0005769; C:early endosome; ISS:UniProtKB. DR GO; GO:0031901; C:early endosome membrane; IEA:UniProtKB-SubCell. DR GO; GO:0005768; C:endosome; TAS:Reactome. DR GO; GO:0005887; C:integral component of plasma membrane; IDA:UniProtKB. DR GO; GO:0005770; C:late endosome; ISS:UniProtKB. DR GO; GO:0031902; C:late endosome membrane; IEA:UniProtKB-SubCell. DR GO; GO:0043025; C:neuronal cell body; IEA:Ensembl. DR GO; GO:0005886; C:plasma membrane; ISS:UniProtKB. DR GO; GO:0043234; C:protein complex; ISS:UniProtKB. DR GO; GO:0043235; C:receptor complex; IDA:MGI. DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW. DR GO; GO:0005004; F:GPI-linked ephrin receptor activity; IEA:Ensembl. DR GO; GO:0048406; F:nerve growth factor binding; IDA:UniProtKB. DR GO; GO:0010465; F:nerve growth factor receptor activity; IDA:UniProtKB. DR GO; GO:0043121; F:neurotrophin binding; TAS:ProtInc. DR GO; GO:0042803; F:protein homodimerization activity; IDA:UniProtKB. DR GO; GO:0004714; F:transmembrane receptor protein tyrosine kinase activity; IDA:UniProtKB. DR GO; GO:0000186; P:activation of MAPKK activity; TAS:Reactome. DR GO; GO:0007568; P:aging; IEA:Ensembl. DR GO; GO:0007411; P:axon guidance; IEA:Ensembl. DR GO; GO:0060385; P:axonogenesis involved in innervation; ISS:UniProtKB. DR GO; GO:0030183; P:B cell differentiation; IEA:Ensembl. DR GO; GO:0061368; P:behavioral response to formalin induced pain; IEA:Ensembl. DR GO; GO:1990090; P:cellular response to nerve growth factor stimulus; ISS:UniProtKB. DR GO; GO:0071316; P:cellular response to nicotine; IEA:Ensembl. DR GO; GO:0007623; P:circadian rhythm; IEA:Ensembl. DR GO; GO:0050966; P:detection of mechanical stimulus involved in sensory perception of pain; IEA:Ensembl. DR GO; GO:0050965; P:detection of temperature stimulus involved in sensory perception of pain; IEA:Ensembl. DR GO; GO:0007611; P:learning or memory; IEA:Ensembl. DR GO; GO:0042490; P:mechanoreceptor differentiation; IEA:Ensembl. DR GO; GO:0007018; P:microtubule-based movement; TAS:Reactome. DR GO; GO:0008285; P:negative regulation of cell proliferation; IDA:UniProtKB. DR GO; GO:0043524; P:negative regulation of neuron apoptotic process; ISS:UniProtKB. DR GO; GO:0048011; P:neurotrophin TRK receptor signaling pathway; IDA:UniProtKB. DR GO; GO:0021553; P:olfactory nerve development; IEA:Ensembl. DR GO; GO:0048015; P:phosphatidylinositol-mediated signaling; TAS:Reactome. DR GO; GO:0045766; P:positive regulation of angiogenesis; IDA:UniProtKB. DR GO; GO:0070374; P:positive regulation of ERK1 and ERK2 cascade; IDA:UniProtKB. DR GO; GO:0043547; P:positive regulation of GTPase activity; IDA:UniProtKB. DR GO; GO:0010976; P:positive regulation of neuron projection development; IDA:UniProtKB. DR GO; GO:0051092; P:positive regulation of NF-kappaB transcription factor activity; IDA:UniProtKB. DR GO; GO:0043068; P:positive regulation of programmed cell death; ISS:UniProtKB. DR GO; GO:0001934; P:positive regulation of protein phosphorylation; TAS:BHF-UCL. DR GO; GO:0046579; P:positive regulation of Ras protein signal transduction; IDA:UniProtKB. DR GO; GO:0051965; P:positive regulation of synapse assembly; IEA:Ensembl. DR GO; GO:0051968; P:positive regulation of synaptic transmission, glutamatergic; IEA:Ensembl. DR GO; GO:0010623; P:programmed cell death involved in cell development; ISS:UniProtKB. DR GO; GO:0046777; P:protein autophosphorylation; IDA:UniProtKB. DR GO; GO:0006468; P:protein phosphorylation; IDA:UniProtKB. DR GO; GO:0014823; P:response to activity; IEA:Ensembl. DR GO; GO:0048678; P:response to axon injury; IEA:Ensembl. DR GO; GO:0042493; P:response to drug; IEA:Ensembl. DR GO; GO:0051602; P:response to electrical stimulus; IEA:Ensembl. DR GO; GO:0045471; P:response to ethanol; IEA:Ensembl. DR GO; GO:0051599; P:response to hydrostatic pressure; IEA:Ensembl. DR GO; GO:0031667; P:response to nutrient levels; IEA:Ensembl. DR GO; GO:0009314; P:response to radiation; IEA:Ensembl. DR GO; GO:0060009; P:Sertoli cell development; IEA:Ensembl. DR GO; GO:0048485; P:sympathetic nervous system development; ISS:UniProtKB. DR Gene3D; 2.60.40.10; -; 2. DR Gene3D; 3.80.10.10; -; 1. DR InterPro; IPR000483; Cys-rich_flank_reg_C. DR InterPro; IPR007110; Ig-like_dom. DR InterPro; IPR013783; Ig-like_fold. DR InterPro; IPR011009; Kinase-like_dom. DR InterPro; IPR032675; L_dom-like. DR InterPro; IPR001611; Leu-rich_rpt. DR InterPro; IPR031635; NTRK_C2. DR InterPro; IPR000719; Prot_kinase_dom. DR InterPro; IPR017441; Protein_kinase_ATP_BS. DR InterPro; IPR001245; Ser-Thr/Tyr_kinase_cat_dom. DR InterPro; IPR008266; Tyr_kinase_AS. DR InterPro; IPR020635; Tyr_kinase_cat_dom. DR InterPro; IPR020461; Tyr_kinase_neurotrophic_rcpt_1. DR InterPro; IPR020777; Tyr_kinase_NGF_rcpt. DR InterPro; IPR002011; Tyr_kinase_rcpt_2_CS. DR Pfam; PF13855; LRR_8; 1. DR Pfam; PF07714; Pkinase_Tyr; 1. DR Pfam; PF16920; TPKR_C2; 1. DR PRINTS; PR01939; NTKRECEPTOR. DR PRINTS; PR01940; NTKRECEPTOR1. DR PRINTS; PR00109; TYRKINASE. DR SMART; SM00082; LRRCT; 1. DR SMART; SM00219; TyrKc; 1. DR SUPFAM; SSF48726; SSF48726; 2. DR SUPFAM; SSF52058; SSF52058; 1. DR SUPFAM; SSF56112; SSF56112; 1. DR PROSITE; PS50835; IG_LIKE; 1. DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 1. DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1. DR PROSITE; PS00109; PROTEIN_KINASE_TYR; 1. DR PROSITE; PS00239; RECEPTOR_TYR_KIN_II; 1. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; ATP-binding; Cell membrane; KW Chromosomal rearrangement; Complete proteome; Developmental protein; KW Differentiation; Disease mutation; Disulfide bond; Endosome; KW Glycoprotein; Immunoglobulin domain; Kinase; Leucine-rich repeat; KW Membrane; Neurogenesis; Nucleotide-binding; Phosphoprotein; KW Polymorphism; Proto-oncogene; Receptor; Reference proteome; Repeat; KW Signal; Transferase; Transmembrane; Transmembrane helix; KW Tyrosine-protein kinase; Ubl conjugation. FT SIGNAL 1 32 {ECO:0000255}. FT CHAIN 33 796 High affinity nerve growth factor FT receptor. FT /FTId=PRO_0000016724. FT TOPO_DOM 33 423 Extracellular. {ECO:0000255}. FT TRANSMEM 424 439 Helical. {ECO:0000255}. FT TOPO_DOM 440 796 Cytoplasmic. {ECO:0000255}. FT REPEAT 90 113 LRR 1. FT REPEAT 116 137 LRR 2. FT DOMAIN 148 193 LRRCT. FT DOMAIN 194 283 Ig-like C2-type 1. FT DOMAIN 299 365 Ig-like C2-type 2. FT DOMAIN 510 781 Protein kinase. {ECO:0000255|PROSITE- FT ProRule:PRU00159}. FT NP_BIND 516 524 ATP. {ECO:0000255|PROSITE- FT ProRule:PRU00159}. FT REGION 469 490 Interaction with SQSTM1. {ECO:0000250}. FT ACT_SITE 650 650 Proton acceptor. {ECO:0000255|PROSITE- FT ProRule:PRU00159, ECO:0000255|PROSITE- FT ProRule:PRU10028}. FT BINDING 544 544 ATP. {ECO:0000255|PROSITE- FT ProRule:PRU00159}. FT SITE 398 399 Breakpoint for translocation to form TRK FT and TRK-T3. FT SITE 486 486 Breakpoint for translocation to form TRK- FT T1. FT SITE 496 496 Interaction with SHC1. FT SITE 791 791 Interaction with PLCG1. FT MOD_RES 496 496 Phosphotyrosine; by autocatalysis. FT {ECO:0000269|PubMed:15488758, FT ECO:0000269|PubMed:8155326}. FT MOD_RES 676 676 Phosphotyrosine; by autocatalysis. FT {ECO:0000305|PubMed:8325889}. FT MOD_RES 680 680 Phosphotyrosine; by autocatalysis. FT {ECO:0000269|PubMed:15488758}. FT MOD_RES 681 681 Phosphotyrosine; by autocatalysis. FT {ECO:0000269|PubMed:15488758}. FT MOD_RES 791 791 Phosphotyrosine; by autocatalysis. FT {ECO:0000269|PubMed:15488758, FT ECO:0000269|PubMed:7510697, FT ECO:0000269|PubMed:8155326}. FT CARBOHYD 67 67 N-linked (GlcNAc...). {ECO:0000255}. FT CARBOHYD 95 95 N-linked (GlcNAc...). FT {ECO:0000269|PubMed:17196528}. FT CARBOHYD 121 121 N-linked (GlcNAc...). FT {ECO:0000269|PubMed:17196528}. FT CARBOHYD 188 188 N-linked (GlcNAc...). FT {ECO:0000269|PubMed:17196528}. FT CARBOHYD 202 202 N-linked (GlcNAc...). {ECO:0000255}. FT CARBOHYD 253 253 N-linked (GlcNAc...). {ECO:0000255}. FT CARBOHYD 262 262 N-linked (GlcNAc...). FT {ECO:0000269|PubMed:17196528}. FT CARBOHYD 281 281 N-linked (GlcNAc...). FT {ECO:0000269|PubMed:17196528}. FT CARBOHYD 318 318 N-linked (GlcNAc...). {ECO:0000255}. FT CARBOHYD 323 323 N-linked (GlcNAc...). {ECO:0000255}. FT CARBOHYD 338 338 N-linked (GlcNAc...). {ECO:0000255}. FT CARBOHYD 358 358 N-linked (GlcNAc...). FT {ECO:0000269|PubMed:17196528}. FT CARBOHYD 401 401 N-linked (GlcNAc...). {ECO:0000255}. FT DISULFID 154 191 {ECO:0000255|PROSITE-ProRule:PRU00114, FT ECO:0000269|PubMed:17196528}. FT DISULFID 215 265 {ECO:0000255|PROSITE-ProRule:PRU00114, FT ECO:0000269|PubMed:17196528}. FT VAR_SEQ 1 71 MLRGGRRGQLGWHSWAAGPGSLLAWLILASAGAAPCPDACC FT PHGSSGLRCTRDGALDSLHHLPGAENLTEL -> MKEAALI FT CLAPSVPPILTVKSWDTMQLRAARSRCTNLLAAS (in FT isoform 3). FT {ECO:0000303|PubMed:14702039}. FT /FTId=VSP_041905. FT VAR_SEQ 192 284 GVPTLKVQVPNASVDVGDDVLLRCQVEGRGLEQAGWILTEL FT EQSATVMKSGGLPSLGLTLANVTSDLNRKNVTCWAENDVGR FT AEVSVQVNVSF -> V (in isoform TrkA-III). FT {ECO:0000305}. FT /FTId=VSP_042152. FT VAR_SEQ 393 398 Missing (in isoform TrkA-I, isoform 3 and FT isoform TrkA-III). FT {ECO:0000303|PubMed:14702039, FT ECO:0000303|PubMed:15489334, FT ECO:0000303|PubMed:2927393}. FT /FTId=VSP_002899. FT VARIANT 6 6 R -> W (in dbSNP:rs201472270). FT {ECO:0000269|PubMed:22302274}. FT /FTId=VAR_068480. FT VARIANT 18 18 G -> E (in dbSNP:rs1007211). FT /FTId=VAR_049714. FT VARIANT 80 80 Q -> R (in dbSNP:rs55891455). FT {ECO:0000269|PubMed:17344846}. FT /FTId=VAR_041461. FT VARIANT 85 85 R -> S (in dbSNP:rs543320028). FT {ECO:0000269|PubMed:10330344, FT ECO:0000269|PubMed:11159935}. FT /FTId=VAR_009623. FT VARIANT 93 93 L -> P (in CIPA; aberrantly processed; FT shows diminished autophosphorylation in FT neuronal cells). FT {ECO:0000269|PubMed:10982191, FT ECO:0000269|PubMed:11159935}. FT /FTId=VAR_009624. FT VARIANT 107 107 A -> V (in an ovarian serous carcinoma FT sample; somatic mutation; FT dbSNP:rs540521894). FT {ECO:0000269|PubMed:17344846}. FT /FTId=VAR_041462. FT VARIANT 213 213 L -> P (in CIPA; aberrantly processed; FT shows diminished autophosphorylation in FT neuronal cells; dbSNP:rs747711259). FT {ECO:0000269|PubMed:10330344, FT ECO:0000269|PubMed:11159935}. FT /FTId=VAR_009625. FT VARIANT 237 237 T -> M (in dbSNP:rs55909005). FT {ECO:0000269|PubMed:17344846}. FT /FTId=VAR_041463. FT VARIANT 238 238 V -> G (in dbSNP:rs56000394). FT {ECO:0000269|PubMed:17344846}. FT /FTId=VAR_041464. FT VARIANT 260 260 R -> G (in dbSNP:rs35116695). FT {ECO:0000269|PubMed:17344846}. FT /FTId=VAR_041465. FT VARIANT 359 359 Y -> C (in CIPA; dbSNP:rs121964869). FT {ECO:0000269|PubMed:11310631}. FT /FTId=VAR_068481. FT VARIANT 444 444 R -> Q (in dbSNP:rs56320207). FT {ECO:0000269|PubMed:17344846}. FT /FTId=VAR_041466. FT VARIANT 452 452 R -> C (in dbSNP:rs34900547). FT {ECO:0000269|PubMed:17344846}. FT /FTId=VAR_041467. FT VARIANT 492 492 E -> K (in CIPA; dbSNP:rs144901788). FT {ECO:0000269|PubMed:22302274}. FT /FTId=VAR_068482. FT VARIANT 522 522 G -> R (in CIPA; processed as wild-type FT but shows significantly diminished FT autophosphorylation in both neuronal and FT non-neuronal cells). FT {ECO:0000269|PubMed:10982191, FT ECO:0000269|PubMed:11159935}. FT /FTId=VAR_009626. FT VARIANT 566 566 M -> T (in dbSNP:rs55892037). FT {ECO:0000269|PubMed:17344846}. FT /FTId=VAR_041468. FT VARIANT 577 577 G -> R (in CIPA; loss of function; FT processed as wild-type but shows FT significantly diminished FT autophosphorylation in both neuronal and FT non-neuronal cells; dbSNP:rs121964866). FT {ECO:0000269|PubMed:10567924, FT ECO:0000269|PubMed:10982191, FT ECO:0000269|PubMed:11159935, FT ECO:0000269|PubMed:8696348}. FT /FTId=VAR_004103. FT VARIANT 587 587 M -> V (in CIPA; dbSNP:rs121964870). FT {ECO:0000269|PubMed:10233776}. FT /FTId=VAR_009627. FT VARIANT 604 604 H -> Y (in dbSNP:rs6336). FT {ECO:0000269|PubMed:10330344, FT ECO:0000269|PubMed:10391209, FT ECO:0000269|PubMed:10443680, FT ECO:0000269|PubMed:11159935, FT ECO:0000269|PubMed:11310631, FT ECO:0000269|PubMed:17344846}. FT /FTId=VAR_009628. FT VARIANT 613 613 G -> V (in dbSNP:rs6339). FT {ECO:0000269|PubMed:10330344, FT ECO:0000269|PubMed:10391209, FT ECO:0000269|PubMed:10443680, FT ECO:0000269|PubMed:10861667, FT ECO:0000269|PubMed:11159935, FT ECO:0000269|PubMed:11310631, FT ECO:0000269|PubMed:17344846}. FT /FTId=VAR_009629. FT VARIANT 649 649 R -> W (in CIPA; processed as wild-type FT but shows significantly diminished FT autophosphorylation in both neuronal and FT non-neuronal cells; dbSNP:rs369353892). FT {ECO:0000269|PubMed:10330344, FT ECO:0000269|PubMed:11159935}. FT /FTId=VAR_009630. FT VARIANT 654 654 R -> C (in CIPA; processed as wild-type FT but shows significantly diminished FT autophosphorylation in both neuronal and FT non-neuronal cells; dbSNP:rs764992664). FT {ECO:0000269|PubMed:10982191, FT ECO:0000269|PubMed:11159935, FT ECO:0000269|PubMed:22302274}. FT /FTId=VAR_009631. FT VARIANT 674 674 D -> Y (in CIPA; unknown pathological FT significance; might impair the function FT of the enzyme without compromising FT autophosphorylation; dbSNP:rs80356677). FT {ECO:0000269|PubMed:10982191, FT ECO:0000269|PubMed:11159935}. FT /FTId=VAR_009632. FT VARIANT 695 695 P -> L (in CIPA; dbSNP:rs121964868). FT {ECO:0000269|PubMed:10861667}. FT /FTId=VAR_009633. FT VARIANT 714 714 G -> S (in CIPA; processed as wild-type FT but shows significantly diminished FT autophosphorylation in both neuronal and FT non-neuronal cells; dbSNP:rs770727871). FT {ECO:0000269|PubMed:10330344, FT ECO:0000269|PubMed:11159935}. FT /FTId=VAR_009634. FT VARIANT 780 780 R -> P (in CIPA; loss of function; FT dbSNP:rs35669708). FT {ECO:0000269|PubMed:10090906}. FT /FTId=VAR_009635. FT VARIANT 780 780 R -> Q (in dbSNP:rs35669708). FT {ECO:0000269|PubMed:10443680, FT ECO:0000269|PubMed:17344846}. FT /FTId=VAR_009636. FT VARIANT 790 790 V -> I (in dbSNP:rs55948542). FT {ECO:0000269|PubMed:17344846}. FT /FTId=VAR_041469. FT MUTAGEN 496 496 Y->F: Loss of interaction with SHC1 and FT altered phosphorylation of SHC1. Altered FT neurite outgrowth and altered activation FT of the MAPK pathway; when associated with FT F-791. {ECO:0000269|PubMed:8155326}. FT MUTAGEN 544 544 K->N: Loss of kinase activity. FT {ECO:0000269|PubMed:8155326}. FT MUTAGEN 791 791 Y->F: Loss of interaction with PLCG1 and FT altered phosphorylation of PLCG1. Altered FT neurite outgrowth and altered activation FT of the MAPK pathway; when associated with FT F-496. {ECO:0000269|PubMed:7510697, FT ECO:0000269|PubMed:8155326}. FT CONFLICT 263 263 V -> L (in Ref. 1; AAA36770). FT {ECO:0000305}. FT CONFLICT 300 300 C -> S (in Ref. 1; AAA36770). FT {ECO:0000305}. FT CONFLICT 529 529 C -> S (in Ref. 10; CAA59936). FT {ECO:0000305}. FT STRAND 38 40 {ECO:0000244|PDB:2IFG}. FT STRAND 43 46 {ECO:0000244|PDB:2IFG}. FT TURN 57 61 {ECO:0000244|PDB:2IFG}. FT STRAND 69 72 {ECO:0000244|PDB:2IFG}. FT HELIX 84 86 {ECO:0000244|PDB:2IFG}. FT STRAND 94 97 {ECO:0000244|PDB:2IFG}. FT HELIX 110 112 {ECO:0000244|PDB:2IFG}. FT STRAND 119 121 {ECO:0000244|PDB:2IFG}. FT TURN 133 135 {ECO:0000244|PDB:2IFG}. FT STRAND 142 144 {ECO:0000244|PDB:2IFG}. FT HELIX 154 156 {ECO:0000244|PDB:2IFG}. FT HELIX 157 164 {ECO:0000244|PDB:2IFG}. FT HELIX 171 173 {ECO:0000244|PDB:2IFG}. FT STRAND 178 181 {ECO:0000244|PDB:2IFG}. FT STRAND 195 199 {ECO:0000244|PDB:2IFG}. FT STRAND 211 218 {ECO:0000244|PDB:2IFG}. FT STRAND 227 230 {ECO:0000244|PDB:2IFG}. FT STRAND 234 238 {ECO:0000244|PDB:2IFG}. FT STRAND 244 253 {ECO:0000244|PDB:2IFG}. FT TURN 257 260 {ECO:0000244|PDB:2IFG}. FT STRAND 263 265 {ECO:0000244|PDB:2IFG}. FT STRAND 276 278 {ECO:0000244|PDB:2IFG}. FT STRAND 284 290 {ECO:0000244|PDB:1WWW}. FT STRAND 298 305 {ECO:0000244|PDB:1HE7}. FT STRAND 312 317 {ECO:0000244|PDB:1HE7}. FT STRAND 326 333 {ECO:0000244|PDB:1HE7}. FT STRAND 342 350 {ECO:0000244|PDB:1HE7}. FT HELIX 353 355 {ECO:0000244|PDB:1HE7}. FT STRAND 357 365 {ECO:0000244|PDB:1HE7}. FT STRAND 368 376 {ECO:0000244|PDB:1HE7}. FT TURN 494 496 {ECO:0000244|PDB:1SHC}. FT HELIX 507 509 {ECO:0000244|PDB:4PMP}. FT STRAND 510 518 {ECO:0000244|PDB:4PMP}. FT STRAND 520 531 {ECO:0000244|PDB:4PMP}. FT STRAND 540 546 {ECO:0000244|PDB:4PMP}. FT HELIX 553 566 {ECO:0000244|PDB:4PMP}. FT STRAND 575 579 {ECO:0000244|PDB:4PMP}. FT STRAND 581 584 {ECO:0000244|PDB:4PMP}. FT STRAND 586 590 {ECO:0000244|PDB:4PMP}. FT HELIX 597 603 {ECO:0000244|PDB:4PMP}. FT STRAND 605 607 {ECO:0000244|PDB:4F0I}. FT HELIX 608 611 {ECO:0000244|PDB:4PMP}. FT STRAND 615 617 {ECO:0000244|PDB:4YNE}. FT STRAND 619 621 {ECO:0000244|PDB:4YNE}. FT HELIX 624 643 {ECO:0000244|PDB:4PMP}. FT HELIX 653 655 {ECO:0000244|PDB:4PMP}. FT STRAND 656 659 {ECO:0000244|PDB:4PMP}. FT TURN 660 662 {ECO:0000244|PDB:4PMP}. FT STRAND 663 666 {ECO:0000244|PDB:4PMP}. FT HELIX 672 675 {ECO:0000244|PDB:4PMM}. FT HELIX 677 679 {ECO:0000244|PDB:4PMP}. FT STRAND 681 684 {ECO:0000244|PDB:4PMM}. FT STRAND 687 689 {ECO:0000244|PDB:4PMM}. FT HELIX 691 693 {ECO:0000244|PDB:4PMP}. FT HELIX 696 701 {ECO:0000244|PDB:4PMP}. FT HELIX 706 721 {ECO:0000244|PDB:4PMP}. FT TURN 727 730 {ECO:0000244|PDB:4PMP}. FT HELIX 733 742 {ECO:0000244|PDB:4PMP}. FT HELIX 754 763 {ECO:0000244|PDB:4PMP}. FT HELIX 768 770 {ECO:0000244|PDB:4PMP}. FT HELIX 774 787 {ECO:0000244|PDB:4PMP}. SQ SEQUENCE 796 AA; 87497 MW; 6C15C721E336B601 CRC64; MLRGGRRGQL GWHSWAAGPG SLLAWLILAS AGAAPCPDAC CPHGSSGLRC TRDGALDSLH HLPGAENLTE LYIENQQHLQ HLELRDLRGL GELRNLTIVK SGLRFVAPDA FHFTPRLSRL NLSFNALESL SWKTVQGLSL QELVLSGNPL HCSCALRWLQ RWEEEGLGGV PEQKLQCHGQ GPLAHMPNAS CGVPTLKVQV PNASVDVGDD VLLRCQVEGR GLEQAGWILT ELEQSATVMK SGGLPSLGLT LANVTSDLNR KNVTCWAEND VGRAEVSVQV NVSFPASVQL HTAVEMHHWC IPFSVDGQPA PSLRWLFNGS VLNETSFIFT EFLEPAANET VRHGCLRLNQ PTHVNNGNYT LLAANPFGQA SASIMAAFMD NPFEFNPEDP IPVSFSPVDT NSTSGDPVEK KDETPFGVSV AVGLAVFACL FLSTLLLVLN KCGRRNKFGI NRPAVLAPED GLAMSLHFMT LGGSSLSPTE GKGSGLQGHI IENPQYFSDA CVHHIKRRDI VLKWELGEGA FGKVFLAECH NLLPEQDKML VAVKALKEAS ESARQDFQRE AELLTMLQHQ HIVRFFGVCT EGRPLLMVFE YMRHGDLNRF LRSHGPDAKL LAGGEDVAPG PLGLGQLLAV ASQVAAGMVY LAGLHFVHRD LATRNCLVGQ GLVVKIGDFG MSRDIYSTDY YRVGGRTMLP IRWMPPESIL YRKFTTESDV WSFGVVLWEI FTYGKQPWYQ LSNTEAIDCI TQGRELERPR ACPPEVYAIM RGCWQREPQQ RHSIKDVHAR LQALAQAPPV YLDVLG //