RET_HUMAN
ID RET_HUMAN Reviewed; 1114 AA.
AC P07949; A8K6Z2; Q15250; Q9BTB0; Q9H4A2;
DT 01-AUG-1988, integrated into UniProtKB/Swiss-Prot.
DT 01-JUN-1994, sequence version 3.
DT 03-AUG-2022, entry version 267.
DE RecName: Full=Proto-oncogene tyrosine-protein kinase receptor Ret {ECO:0000305};
DE EC=2.7.10.1;
DE AltName: Full=Cadherin family member 12;
DE AltName: Full=Proto-oncogene c-Ret;
DE Contains:
DE RecName: Full=Soluble RET kinase fragment;
DE Contains:
DE RecName: Full=Extracellular cell-membrane anchored RET cadherin 120 kDa fragment;
DE Flags: Precursor;
GN Name=RET {ECO:0000312|HGNC:HGNC:9967}; Synonyms=CDHF12, CDHR16, PTC, RET51;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC TISSUE=Prostate;
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., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., 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., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA 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 [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15164054; DOI=10.1038/nature02462;
RA Deloukas P., Earthrowl M.E., Grafham D.V., Rubenfield M., French L.,
RA Steward C.A., Sims S.K., Jones M.C., Searle S., Scott C., Howe K.,
RA Hunt S.E., Andrews T.D., Gilbert J.G.R., Swarbreck D., Ashurst J.L.,
RA Taylor A., Battles J., Bird C.P., Ainscough R., Almeida J.P.,
RA Ashwell R.I.S., Ambrose K.D., Babbage A.K., Bagguley C.L., Bailey J.,
RA Banerjee R., Bates K., Beasley H., Bray-Allen S., Brown A.J., Brown J.Y.,
RA Burford D.C., Burrill W., Burton J., Cahill P., Camire D., Carter N.P.,
RA Chapman J.C., Clark S.Y., Clarke G., Clee C.M., Clegg S., Corby N.,
RA Coulson A., Dhami P., Dutta I., Dunn M., Faulkner L., Frankish A.,
RA Frankland J.A., Garner P., Garnett J., Gribble S., Griffiths C.,
RA Grocock R., Gustafson E., Hammond S., Harley J.L., Hart E., Heath P.D.,
RA Ho T.P., Hopkins B., Horne J., Howden P.J., Huckle E., Hynds C.,
RA Johnson C., Johnson D., Kana A., Kay M., Kimberley A.M., Kershaw J.K.,
RA Kokkinaki M., Laird G.K., Lawlor S., Lee H.M., Leongamornlert D.A.,
RA Laird G., Lloyd C., Lloyd D.M., Loveland J., Lovell J., McLaren S.,
RA McLay K.E., McMurray A., Mashreghi-Mohammadi M., Matthews L., Milne S.,
RA Nickerson T., Nguyen M., Overton-Larty E., Palmer S.A., Pearce A.V.,
RA Peck A.I., Pelan S., Phillimore B., Porter K., Rice C.M., Rogosin A.,
RA Ross M.T., Sarafidou T., Sehra H.K., Shownkeen R., Skuce C.D., Smith M.,
RA Standring L., Sycamore N., Tester J., Thorpe A., Torcasso W., Tracey A.,
RA Tromans A., Tsolas J., Wall M., Walsh J., Wang H., Weinstock K., West A.P.,
RA Willey D.L., Whitehead S.L., Wilming L., Wray P.W., Young L., Chen Y.,
RA Lovering R.C., Moschonas N.K., Siebert R., Fechtel K., Bentley D.,
RA Durbin R.M., Hubbard T., Doucette-Stamm L., Beck S., Smith D.R., Rogers J.;
RT "The DNA sequence and comparative analysis of human chromosome 10.";
RL Nature 429:375-381(2004).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2), AND VARIANT CYS-982.
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 project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 1-280 (ISOFORMS 1/2).
RX PubMed=2660074;
RA Takahashi M.;
RT "Isolation of ret proto-oncogene cDNA with an amino-terminal signal
RT sequence.";
RL Oncogene 4:805-806(1989).
RN [5]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 255-1114 (ISOFORM 1).
RX PubMed=3078962;
RA Takahashi M., Buma Y., Iwamoto T., Inaguma Y., Ikeda H., Hiai H.;
RT "Cloning and expression of the ret proto-oncogene encoding a tyrosine
RT kinase with two potential transmembrane domains.";
RL Oncogene 3:571-578(1988).
RN [6]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 588-1063 (ISOFORM 2), AND CHROMOSOMAL
RP TRANSLOCATION WITH TRIM27.
RX PubMed=3037315; DOI=10.1128/mcb.7.4.1378-1385.1987;
RA Takahashi M., Cooper G.M.;
RT "ret transforming gene encodes a fusion protein homologous to tyrosine
RT kinases.";
RL Mol. Cell. Biol. 7:1378-1385(1987).
RN [7]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 713-1114 (ISOFORM 1), AND CHROMOSOMAL
RP TRANSLOCATION WITH GOLGA5.
RC TISSUE=Fibroblast;
RX PubMed=2734021;
RA Ishizaka Y., Ochiai M., Tahira T., Suhimura T., Nahao M.;
RT "Activation of the ret-II oncogene without a sequence encoding a
RT transmembrane domain and transforming activity of two ret-II oncogene
RT products differing in carboxy-termini due to alternative splicing.";
RL Oncogene 4:789-794(1989).
RN [8]
RP ERRATUM OF PUBMED:2734021.
RA Ishizaka Y., Ochiai M., Tahira T., Suhimura T., Nahao M.;
RL Oncogene 4:1415-1415(1989).
RN [9]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 713-1114 (ISOFORM 1), AND CHROMOSOMAL
RP TRANSLOCATION WITH CCDC6.
RC TISSUE=Thyroid papillary carcinoma;
RX PubMed=2406025; DOI=10.1016/0092-8674(90)90659-3;
RA Grieco M., Santoro M., Berlingieri M.T., Melillo R.M., Donghi R.,
RA Bongarzone I., Pierotti M.A., Della Porta G., Fusco A., Vecchio G.;
RT "PTC is a novel rearranged form of the ret proto-oncogene and is frequently
RT detected in vivo in human thyroid papillary carcinomas.";
RL Cell 60:557-563(1990).
RN [10]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 713-770 (ISOFORMS 1/2), AND CHROMOSOMAL
RP TRANSLOCATION WITH PCM1.
RX PubMed=10980597; DOI=10.1038/sj.onc.1203772;
RA Corvi R., Berger N., Balczon R., Romeo G.;
RT "RET/PCM-1: a novel fusion gene in papillary thyroid carcinoma.";
RL Oncogene 19:4236-4242(2000).
RN [11]
RP CHROMOSOMAL TRANSLOCATION WITH TRIM33 AND TRIM24.
RX PubMed=10439047; DOI=10.1038/sj.onc.1202824;
RA Klugbauer S., Rabes H.M.;
RT "The transcription coactivator HTIF1 and a related protein are fused to the
RT RET receptor tyrosine kinase in childhood papillary thyroid carcinomas.";
RL Oncogene 18:4388-4393(1999).
RN [12]
RP PHOSPHORYLATION AT TYR-1015 AND TYR-1062.
RX PubMed=11061555; DOI=10.1210/jcem.85.10.6882;
RA Salvatore D., Barone M.V., Salvatore G., Melillo R.M., Chiappetta G.,
RA Mineo A., Fenzi G., Vecchio G., Fusco A., Santoro M.;
RT "Tyrosines 1015 and 1062 are in vivo autophosphorylation sites in ret and
RT ret-derived oncoproteins.";
RL J. Clin. Endocrinol. Metab. 85:3898-3907(2000).
RN [13]
RP PHOSPHORYLATION AT TYR-806; TYR-809; TYR-900; TYR-905; TYR-981; TYR-1015;
RP TYR-1062; TYR-1090 AND TYR-1096.
RX PubMed=14711813; DOI=10.1074/jbc.m312600200;
RA Kawamoto Y., Takeda K., Okuno Y., Yamakawa Y., Ito Y., Taguchi R., Kato M.,
RA Suzuki H., Takahashi M., Nakashima I.;
RT "Identification of RET autophosphorylation sites by mass spectrometry.";
RL J. Biol. Chem. 279:14213-14224(2004).
RN [14]
RP CHROMOSOMAL TRANSLOCATION WITH TRIM27.
RX PubMed=12787916; DOI=10.1016/s0027-5107(03)00056-3;
RA Saenko V., Rogounovitch T., Shimizu-Yoshida Y., Abrosimov A., Lushnikov E.,
RA Roumiantsev P., Matsumoto N., Nakashima M., Meirmanov S., Ohtsuru A.,
RA Namba H., Tsyb A., Yamashita S.;
RT "Novel tumorigenic rearrangement, Delta rfp/ret, in a papillary thyroid
RT carcinoma from externally irradiated patient.";
RL Mutat. Res. 527:81-90(2003).
RN [15]
RP PHOSPHORYLATION AT TYR-905; TYR-1015 AND TYR-1062, AND DEPHOSPHORYLATION AT
RP TYR-905; TYR-1015 AND TYR-1062 BY PTPRJ.
RX PubMed=16778204; DOI=10.1158/0008-5472.can-06-0228;
RA Iervolino A., Iuliano R., Trapasso F., Viglietto G., Melillo R.M.,
RA Carlomagno F., Santoro M., Fusco A.;
RT "The receptor-type protein tyrosine phosphatase J antagonizes the
RT biochemical and biological effects of RET-derived oncoproteins.";
RL Cancer Res. 66:6280-6287(2006).
RN [16]
RP ACTIVITY REGULATION.
RX PubMed=17884497; DOI=10.1016/j.bmcl.2007.07.104;
RA Graham Robinett R., Freemerman A.J., Skinner M.A., Shewchuk L., Lackey K.;
RT "The discovery of substituted 4-(3-hydroxyanilino)-quinolines as potent RET
RT kinase inhibitors.";
RL Bioorg. Med. Chem. Lett. 17:5886-5893(2007).
RN [17]
RP ACTIVITY REGULATION BY SORAFENIB.
RX PubMed=17664273; DOI=10.1074/jbc.m703461200;
RA Plaza-Menacho I., Mologni L., Sala E., Gambacorti-Passerini C., Magee A.I.,
RA Links T.P., Hofstra R.M.W., Barford D., Isacke C.M.;
RT "Sorafenib functions to potently suppress RET tyrosine kinase activity by
RT direct enzymatic inhibition and promoting RET lysosomal degradation
RT independent of proteasomal targeting.";
RL J. Biol. Chem. 282:29230-29240(2007).
RN [18]
RP ACTIVITY REGULATION BY 3- AND 4-SUBSTITUTED BETA-CARBOLIN-1-ONES.
RX PubMed=19053769; DOI=10.1021/jm8007823;
RA Cincinelli R., Cassinelli G., Dallavalle S., Lanzi C., Merlini L.,
RA Botta M., Tuccinardi T., Martinelli A., Penco S., Zunino F.;
RT "Synthesis, modeling, and RET protein kinase inhibitory activity of 3- and
RT 4-substituted beta-carbolin-1-ones.";
RL J. Med. Chem. 51:7777-7787(2008).
RN [19]
RP INTERACTION WITH CD2AP, AND MUTAGENESIS OF LYS-758.
RX PubMed=18753381; DOI=10.1523/jneurosci.2738-08.2008;
RA Tsui C.C., Pierchala B.A.;
RT "CD2AP and Cbl-3/Cbl-c constitute a critical checkpoint in the regulation
RT of ret signal transduction.";
RL J. Neurosci. 28:8789-8800(2008).
RN [20]
RP INTERACTION WITH AIP.
RX PubMed=19366855; DOI=10.1210/jc.2008-1980;
RA Vargiolu M., Fusco D., Kurelac I., Dirnberger D., Baumeister R., Morra I.,
RA Melcarne A., Rimondini R., Romeo G., Bonora E.;
RT "The tyrosine kinase receptor RET interacts in vivo with aryl hydrocarbon
RT receptor-interacting protein to alter survivin availability.";
RL J. Clin. Endocrinol. Metab. 94:2571-2578(2009).
RN [21]
RP INDUCTION BY NKX2-1; PHOX2B; SOX10 AND PAX3.
RX PubMed=19853745; DOI=10.1016/j.jpedsurg.2008.11.055;
RA Leon T.Y.Y., Ngan E.S.W., Poon H.-C., So M.-T., Lui V.C.H., Tam P.K.H.,
RA Garcia-Barcelo M.M.;
RT "Transcriptional regulation of RET by Nkx2-1, Phox2b, Sox10, and Pax3.";
RL J. Pediatr. Surg. 44:1904-1912(2009).
RN [22]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-696, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19369195; DOI=10.1074/mcp.m800588-mcp200;
RA Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G.,
RA Mann M., Daub H.;
RT "Large-scale proteomics analysis of the human kinome.";
RL Mol. Cell. Proteomics 8:1751-1764(2009).
RN [23]
RP FUNCTION IN DEVELOPMENT OF MECHANORECEPTORS.
RX PubMed=20064382; DOI=10.1016/j.neuron.2009.12.014;
RA Ma Q.;
RT "RETouching upon mechanoreceptors.";
RL Neuron 64:773-776(2009).
RN [24]
RP ACTIVITY REGULATION, AND REVIEW ON KINASE INHIBITORS.
RX PubMed=20605972; DOI=10.1210/er.2009-0031;
RA Ye L., Santarpia L., Gagel R.F.;
RT "The evolving field of tyrosine kinase inhibitors in the treatment of
RT endocrine tumors.";
RL Endocr. Rev. 31:578-599(2010).
RN [25]
RP ACTIVITY REGULATION.
RX PubMed=20409618; DOI=10.1016/j.ejmech.2010.03.017;
RA Brandt W., Mologni L., Preu L., Lemcke T., Gambacorti-Passerini C.,
RA Kunick C.;
RT "Inhibitors of the RET tyrosine kinase based on a 2-(alkylsulfanyl)-4-(3-
RT thienyl)nicotinonitrile scaffold.";
RL Eur. J. Med. Chem. 45:2919-2927(2010).
RN [26]
RP FUNCTION IN PITUITARY.
RX PubMed=20616503; DOI=10.1159/000318502;
RA Garcia-Lavandeira M., Diaz-Rodriguez E., Garcia-Rendueles M.E.,
RA Rodrigues J.S., Perez-Romero S., Bravo S.B., Alvarez C.V.;
RT "Functional role of the RET dependence receptor, GFRa co-receptors and
RT ligands in the pituitary.";
RL Front. Horm. Res. 38:127-138(2010).
RN [27]
RP FUNCTION IN CELL ADHESION/MIGRATION.
RX PubMed=20702524; DOI=10.1210/jc.2010-0771;
RA Cockburn J.G., Richardson D.S., Gujral T.S., Mulligan L.M.;
RT "RET-mediated cell adhesion and migration require multiple integrin
RT subunits.";
RL J. Clin. Endocrinol. Metab. 95:E342-E346(2010).
RN [28]
RP SUBCELLULAR LOCATION.
RX PubMed=19823924; DOI=10.1007/s10895-009-0548-x;
RA Richardson D.S., Mulligan L.M.;
RT "Direct visualization of vesicle maturation and plasma membrane protein
RT trafficking.";
RL J. Fluoresc. 20:401-405(2010).
RN [29]
RP ACTIVITY REGULATION.
RX PubMed=21134556; DOI=10.1016/j.surg.2010.09.026;
RA Samadi A.K., Mukerji R., Shah A., Timmermann B.N., Cohen M.S.;
RT "A novel RET inhibitor with potent efficacy against medullary thyroid
RT cancer in vivo.";
RL Surgery 148:1228-1236(2010).
RN [30]
RP FUNCTION IN CELL ADHESION, FUNCTION IN APOPTOSIS, PROTEOLYTIC PROCESSING BY
RP CASPASE-3 AT ASP-707 AND ASP-1017, MUTAGENESIS OF ASP-707; LYS-758 AND
RP 708-ALA--SER-1114, AND SUBUNIT.
RX PubMed=21357690; DOI=10.1074/jbc.m110.195461;
RA Cabrera J.R., Bouzas-Rodriguez J., Tauszig-Delamasure S., Mehlen P.;
RT "RET modulates cell adhesion via its cleavage by caspase in sympathetic
RT neurons.";
RL J. Biol. Chem. 286:14628-14638(2011).
RN [31]
RP INTERACTION WITH PTK2/FAK1, AND FUNCTION IN PTK2/FAK1 PHOSPHORYLATION.
RX PubMed=21454698; DOI=10.1074/jbc.m110.168500;
RA Plaza-Menacho I., Morandi A., Mologni L., Boender P.,
RA Gambacorti-Passerini C., Magee A.I., Hofstra R.M.W., Knowles P.,
RA McDonald N.Q., Isacke C.M.;
RT "Focal adhesion kinase (FAK) binds RET kinase via its FERM domain, priming
RT a direct and reciprocal RET-FAK transactivation mechanism.";
RL J. Biol. Chem. 286:17292-17302(2011).
RN [32]
RP INTERACTION WITH GDNF, AND SUBCELLULAR LOCATION.
RX PubMed=21994944; DOI=10.1074/jbc.m111.246413;
RA Geng Z., Xu F.Y., Huang S.H., Chen Z.Y.;
RT "Sorting protein-related receptor SorLA controls regulated secretion of
RT glial cell line-derived neurotrophic factor.";
RL J. Biol. Chem. 286:41871-41882(2011).
RN [33]
RP INTERACTION WITH GFRA1, AND SUBCELLULAR LOCATION.
RX PubMed=23333276; DOI=10.1016/j.celrep.2012.12.011;
RA Glerup S., Lume M., Olsen D., Nyengaard J.R., Vaegter C.B., Gustafsen C.,
RA Christensen E.I., Kjolby M., Hay-Schmidt A., Bender D., Madsen P.,
RA Saarma M., Nykjaer A., Petersen C.M.;
RT "SorLA controls neurotrophic activity by sorting of GDNF and its receptors
RT GFRalpha1 and RET.";
RL Cell Rep. 3:186-199(2013).
RN [34]
RP INTERACTION WITH GFRAL, SUBCELLULAR LOCATION, FUNCTION, AND MUTAGENESIS OF
RP TYR-1062.
RX PubMed=28953886; DOI=10.1038/nature24042;
RA Hsu J.Y., Crawley S., Chen M., Ayupova D.A., Lindhout D.A., Higbee J.,
RA Kutach A., Joo W., Gao Z., Fu D., To C., Mondal K., Li B., Kekatpure A.,
RA Wang M., Laird T., Horner G., Chan J., McEntee M., Lopez M.,
RA Lakshminarasimhan D., White A., Wang S.P., Yao J., Yie J., Matern H.,
RA Solloway M., Haldankar R., Parsons T., Tang J., Shen W.D., Alice Chen Y.,
RA Tian H., Allan B.B.;
RT "Non-homeostatic body weight regulation through a brainstem-restricted
RT receptor for GDF15.";
RL Nature 550:255-259(2017).
RN [35]
RP ERRATUM OF PUBMED:28953886.
RX PubMed=29144449; DOI=10.1038/nature24481;
RA Hsu J.Y., Crawley S., Chen M., Ayupova D.A., Lindhout D.A., Higbee J.,
RA Kutach A., Joo W., Gao Z., Fu D., To C., Mondal K., Li B., Kekatpure A.,
RA Wang M., Laird T., Horner G., Chan J., McEntee M., Lopez M.,
RA Lakshminarasimhan D., White A., Wang S.P., Yao J., Yie J., Matern H.,
RA Solloway M., Haldankar R., Parsons T., Tang J., Shen W.D., Alice Chen Y.,
RA Tian H., Allan B.B.;
RT "Non-homeostatic body weight regulation through a brainstem-restricted
RT receptor for GDF15.";
RL Nature 551:398-398(2017).
RN [36]
RP FUNCTION, AND INTERACTION WITH GFRAL.
RX PubMed=28846097; DOI=10.1038/nm.4392;
RA Mullican S.E., Lin-Schmidt X., Chin C.N., Chavez J.A., Furman J.L.,
RA Armstrong A.A., Beck S.C., South V.J., Dinh T.Q., Cash-Mason T.D.,
RA Cavanaugh C.R., Nelson S., Huang C., Hunter M.J., Rangwala S.M.;
RT "GFRAL is the receptor for GDF15 and the ligand promotes weight loss in
RT mice and nonhuman primates.";
RL Nat. Med. 23:1150-1157(2017).
RN [37]
RP FUNCTION, INTERACTION WITH GFRAL, AND PHOSPHORYLATION AT TYR-905 AND
RP TYR-1062.
RX PubMed=28846099; DOI=10.1038/nm.4394;
RA Yang L., Chang C.C., Sun Z., Madsen D., Zhu H., Padkjaer S.B., Wu X.,
RA Huang T., Hultman K., Paulsen S.J., Wang J., Bugge A., Frantzen J.B.,
RA Noergaard P., Jeppesen J.F., Yang Z., Secher A., Chen H., Li X., John L.M.,
RA Shan B., He Z., Gao X., Su J., Hansen K.T., Yang W., Joergensen S.B.;
RT "GFRAL is the receptor for GDF15 and is required for the anti-obesity
RT effects of the ligand.";
RL Nat. Med. 23:1158-1166(2017).
RN [38] {ECO:0007744|PDB:2IVS, ECO:0007744|PDB:2IVT, ECO:0007744|PDB:2IVU, ECO:0007744|PDB:2IVV}
RP X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 705-1013 ALONE AND IN COMPLEX WITH
RP INHIBITORS, IDENTIFICATION BY MASS SPECTROMETRY, AND PHOSPHORYLATION AT
RP TYR-900 AND TYR-905.
RX PubMed=16928683; DOI=10.1074/jbc.m605604200;
RA Knowles P.P., Murray-Rust J., Kjaer S., Scott R.P., Hanrahan S.,
RA Santoro M., Ibanez C.F., McDonald N.Q.;
RT "Structure and chemical inhibition of the RET tyrosine kinase domain.";
RL J. Biol. Chem. 281:33577-33587(2006).
RN [39] {ECO:0007744|PDB:2X2K, ECO:0007744|PDB:2X2L, ECO:0007744|PDB:2X2M}
RP X-RAY CRYSTALLOGRAPHY (2.00 ANGSTROMS) OF 705-1013 IN COMPLEX WITH
RP INHIBITORS, ACTIVITY REGULATION, AND PHOSPHORYLATION AT TYR-905.
RX PubMed=20117004; DOI=10.1016/j.bmc.2010.01.011;
RA Mologni L., Rostagno R., Brussolo S., Knowles P.P., Kjaer S.,
RA Murray-Rust J., Rosso E., Zambon A., Scapozza L., McDonald N.Q.,
RA Lucchini V., Gambacorti-Passerini C.;
RT "Synthesis, structure-activity relationship and crystallographic studies of
RT 3-substituted indolin-2-one RET inhibitors.";
RL Bioorg. Med. Chem. 18:1482-1496(2010).
RN [40] {ECO:0007744|PDB:2X2U}
RP X-RAY CRYSTALLOGRAPHY (2.00 ANGSTROMS) OF 29-270, GLYCOSYLATION AT ASN-151,
RP AND DISULFIDE BOND.
RX PubMed=20473317; DOI=10.1038/nsmb.1808;
RA Kjaer S., Hanrahan S., Totty N., McDonald N.Q.;
RT "Mammal-restricted elements predispose human RET to folding impairment by
RT HSCR mutations.";
RL Nat. Struct. Mol. Biol. 17:726-731(2010).
RN [41]
RP REVIEW ON HSCR VARIANTS.
RX PubMed=9359036;
RA Hofstra R.M.W., Osinga J., Buys C.H.C.M.;
RT "Mutations in Hirschsprung disease: when does a mutation contribute to the
RT phenotype.";
RL Eur. J. Hum. Genet. 5:180-185(1997).
RN [42]
RP REVIEW ON VARIANTS.
RX PubMed=9067749;
RX DOI=10.1002/(sici)1098-1004(1997)9:2<97::aid-humu1>3.0.co;2-m;
RA Eng C., Mulligan L.M.;
RT "Mutations of the RET proto-oncogene in the multiple endocrine neoplasia
RT type 2 syndromes, related sporadic tumours, and Hirschsprung disease.";
RL Hum. Mutat. 9:97-109(1997).
RN [43]
RP VARIANTS MEN2A/MTC TRP-611; SER-618; ARG-620; TYR-620 AND ARG-634.
RX PubMed=8103403; DOI=10.1093/hmg/2.7.851;
RA Donis-Keller H., Dou S., Chi D., Carlson K.M., Toshima K., Lairmore T.C.,
RA Howe J.R., Moley J.F., Goodfellow P., Wells S.A. Jr.;
RT "Mutations in the RET proto-oncogene are associated with MEN 2A and FMTC.";
RL Hum. Mol. Genet. 2:851-856(1993).
RN [44]
RP VARIANTS MEN2A GLY-618; 632-ASP--ARG-634; GLY-634; PHE-634; TYR-634 AND
RP SER-634.
RX PubMed=8099202; DOI=10.1038/363458a0;
RA Mulligan L.M., Kwok J.B.J., Healey C.S., Elsdon M.J., Eng C., Gardner E.,
RA Love D.R., Mole S.E., Moore J.K., Papi L., Ponder M.A., Telenius H.,
RA Tunnacliffe A., Ponder B.A.J.;
RT "Germ-line mutations of the RET proto-oncogene in multiple endocrine
RT neoplasia type 2A.";
RL Nature 363:458-460(1993).
RN [45]
RP VARIANTS HSCR1 PRO-40; LEU-399; GLN-762; PRO-765; GLN-897; GLY-972 AND
RP LEU-973.
RX PubMed=7704557; DOI=10.1159/000472371;
RA Yin L., Barone V., Seri M., Bolino A., Bocciardi R., Ceccherini I.,
RA Pasini B., Tocco T., Lerone M., Cywes S., Moore S., Vanderwinden J.-M.,
RA Abramowicz M.J., Kristoffersson U., Larsson L.T., Hamel B.C.J., Silengo M.,
RA Martucciello G., Romeo G.;
RT "Heterogeneity and low detection rate of RET mutations in Hirschsprung
RT disease.";
RL Eur. J. Hum. Genet. 2:272-280(1994).
RN [46]
RP VARIANT MEN2B THR-918.
RX PubMed=7911697; DOI=10.1093/hmg/3.2.237;
RA Eng C., Smith D.P., Mulligan L.M., Nagai M.A., Healey C.S., Ponder M.A.,
RA Gardner E., Scheumann G.F., Jackson C.E., Tunnacliffe A., Ponder B.A.J.;
RT "Point mutation within the tyrosine kinase domain of the RET proto-oncogene
RT in multiple endocrine neoplasia type 2B and related sporadic tumours.";
RL Hum. Mol. Genet. 3:237-241(1994).
RN [47]
RP VARIANTS MEN2A/MTC ARG-618; SER-618; PHE-620; ARG-620; PHE-634; GLY-634 AND
RP TYR-634.
RX PubMed=7915165; DOI=10.1093/hmg/3.4.635;
RA Xue F., Yu H., Maurer L.H., Memoli V.A., Nutile-Mcmenemy N., Schuster M.K.,
RA Browden D.W., Mao J.-I., Noll W.W.;
RT "Germline RET mutations in MEN 2A and FMTC and their detection by simple
RT DNA diagnostic tests.";
RL Hum. Mol. Genet. 3:635-638(1994).
RN [48]
RP VARIANTS MTC/MEN2A TYR-609; ARG-618; SER-618 AND SER-620.
RX PubMed=7849720; DOI=10.1093/hmg/3.10.1895;
RA Blaugrund J.E., Johns M.M. Jr., Eby Y.J., Ball D.W., Baylin S.B.,
RA Hruban R.H., Sidransky D.;
RT "RET proto-oncogene mutations in inherited and sporadic medullary thyroid
RT cancer.";
RL Hum. Mol. Genet. 3:1895-1897(1994).
RN [49]
RP VARIANTS MTC, AND VARIANTS MEN2A.
RX PubMed=7874109; DOI=10.1093/hmg/3.11.1939;
RA Schuffenecker I., Billaud M., Calender A., Chambe B., Ginet N.,
RA Calmettes C., Modigliani E., Lenoir G.M.;
RT "RET proto-oncogene mutations in French MEN 2A and FMTC families.";
RL Hum. Mol. Genet. 3:1939-1943(1994).
RN [50]
RP VARIANTS HSCR1 TRP-609; ARG-618 AND ARG-620, VARIANT MEN2A ARG-618, AND
RP VARIANT MTC ARG-620.
RX PubMed=7881414; DOI=10.1093/hmg/3.12.2163;
RA Mulligan L.M., Eng C., Attie T., Lyonnet S., Marsh D.J., Hyland V.J.,
RA Robinson B.G., Frilling A., Verellen-Dumoulin C., Safar A., Venter D.J.,
RA Munnich A., Ponder B.A.J.;
RT "Diverse phenotypes associated with exon 10 mutations of the RET proto-
RT oncogene.";
RL Hum. Mol. Genet. 3:2163-2167(1994).
RN [51]
RP VARIANT MEN2B THR-918.
RX PubMed=7906866; DOI=10.1038/367375a0;
RA Hofstra R.M.W., Landsvater R.M., Ceccherini I., Stulp R.P., Stelwagen T.,
RA Luo Y., Pasini B., Hoeppener J.W.M., Ploos van Amstel H.K., Romeo G.,
RA Lips C.J.M., Buys C.H.C.M.;
RT "A mutation in the RET proto-oncogene associated with multiple endocrine
RT neoplasia type 2B and sporadic medullary thyroid carcinoma.";
RL Nature 367:375-376(1994).
RN [52]
RP VARIANTS HSCR1 PRO-765; GLN-897 AND GLY-972.
RX PubMed=8114938; DOI=10.1038/367377a0;
RA Romeo G., Ronchetto P., Luo Y., Barone V., Seri M., Ceccherini I.,
RA Pasini B., Bocciardi R., Lerone M., Kaarlainen H., Martucciello G.;
RT "Point mutations affecting the tyrosine kinase domain of the RET proto-
RT oncogene in Hirschsprung's disease.";
RL Nature 367:377-378(1994).
RN [53]
RP VARIANTS HSCR1 LEU-32; LEU-64; GLN-330 AND LEU-393.
RX PubMed=8114939; DOI=10.1038/367378a0;
RA Edery P., Lyonnet S., Mulligan L.M., Pelet A., Dow E., Abel L., Holder S.,
RA Nihoul-Fkete C., Ponder B.A.J., Munnich A.;
RT "Mutations of the RET proto-oncogene in Hirschsprung's disease.";
RL Nature 367:378-380(1994).
RN [54]
RP VARIANT MEN2B THR-918.
RX PubMed=7906417; DOI=10.1073/pnas.91.4.1579;
RA Carlson K.M., Dou S., Chi D., Scavarda N., Toshima K., Jackson C.E.,
RA Wells S.A. Jr., Goodfellow P.J., Donis-Keller H.;
RT "Single missense mutation in the tyrosine kinase catalytic domain of the
RT RET protooncogene is associated with multiple endocrine neoplasia type
RT 2B.";
RL Proc. Natl. Acad. Sci. U.S.A. 91:1579-1583(1994).
RN [55]
RP VARIANTS MTC; MEN2A AND MEN2B.
RX PubMed=8625130;
RX DOI=10.1002/1097-0142(19950801)76:3<479::aid-cncr2820760319>3.0.co;2-m;
RA Komminoth P., Kunz E.K., Matias-Guiu X., Hiort O., Christiansen G.,
RA Colomer A., Roth J., Heitz P.U.;
RT "Analysis of RET protooncogene point mutations distinguishes heritable from
RT nonheritable medullary thyroid carcinomas.";
RL Cancer 76:479-489(1995).
RN [56]
RP VARIANTS MEN2A SER-618; SER-620; ARG-634 AND TYR-634.
RX PubMed=7860065; DOI=10.1007/bf00209399;
RA Takiguchi-Shirahama S., Koyama K., Miyauchi A., Wakasugi T., Oishi S.,
RA Takami H., Hikiji K., Nakamura Y.;
RT "Germline mutations of the RET proto-oncogene in eight Japanese patients
RT with multiple endocrine neoplasia type 2A (MEN2A).";
RL Hum. Genet. 95:187-190(1995).
RN [57]
RP VARIANTS HSCR1 LEU-20; SER-93; GLN-330; TYR-609 AND ARG-620, AND VARIANT
RP CYS-982.
RC TISSUE=Blood;
RX PubMed=7633441; DOI=10.1093/hmg/4.5.821;
RA Angrist M., Bolk S., Thiel B., Puffenberger E.G., Hofstra R.M.W.,
RA Buys C.H.C.M., Cass D.T., Chakravarti A.;
RT "Mutation analysis of the RET receptor tyrosine kinase in Hirschsprung
RT disease.";
RL Hum. Mol. Genet. 4:821-830(1995).
RN [58]
RP VARIANTS HSCR1.
RC TISSUE=Leukocyte;
RX PubMed=7581377; DOI=10.1093/hmg/4.8.1381;
RA Attie T., Pelet A., Edery P., Eng C., Mulligan L.M., Amiel J., Boutrand L.,
RA Beldjord C., Nihoul-Fekete C., Munnich A., Ponder B.A.J., Lyonnet S.;
RT "Diversity of RET proto-oncogene mutations in familial and sporadic
RT Hirschsprung disease.";
RL Hum. Mol. Genet. 4:1381-1386(1995).
RN [59]
RP VARIANT MEN2B THR-918, AND VARIANT TYR-922.
RX PubMed=8595427; DOI=10.1093/hmg/4.10.1987;
RA Kitamura Y., Scavarda N., Wells S.A. Jr., Jackson C.E., Goodfellow P.J.;
RT "Two maternally derived missense mutations in the tyrosine kinase domain of
RT the RET protooncogene in a patient with de novo MEN 2B.";
RL Hum. Mol. Genet. 4:1987-1988(1995).
RN [60]
RP VARIANT MTC ASP-768.
RX PubMed=7845675;
RA Eng C., Smith D.P., Mulligan L.M., Healey C.S., Zvelebil M.J.,
RA Stonehouse T.J., Ponder M.A., Jackson C.E., Waterfield M.D., Ponder B.A.J.;
RT "A novel point mutation in the tyrosine kinase domain of the RET proto-
RT oncogene in sporadic medullary thyroid carcinoma and in a family with
RT FMTC.";
RL Oncogene 10:509-513(1995).
RN [61]
RP VARIANTS MTC ASP-768 AND LEU-804.
RX PubMed=7784092;
RA Bolino A., Schuffenecker I., Luo Y., Seri M., Silengo M., Tocco T.,
RA Chabrier G., Houdent C., Murat A., Schlumberger M., Tournaire J.,
RA Lenoir G.M., Romeo G.;
RT "RET mutations in exons 13 and 14 of FMTC patients.";
RL Oncogene 10:2415-2419(1995).
RN [62]
RP VARIANTS HSCR1 TYR-157; LYS-359; TYR-609; ARG-620; ASN-1059 DEL AND
RP PRO-1061.
RA Hofstra R.M.W., Osinga J., Stulp R.P., Scheffer H., Meijers C.,
RA Buys C.H.C.M.;
RT "Mutations in three genes are found associated with the development of
RT Hirschsprung disease: RET, EDNRB and EDN3.";
RL Am. J. Hum. Genet. 59:A263-A263(1996).
RN [63]
RP VARIANTS HSCR1 PRO-40 AND PRO-765.
RX PubMed=9043870; DOI=10.1159/000472232;
RA Yin L., Seri M., Barone V., Tocco T., Scaranari M., Romeo G.;
RT "Prevalence and parental origin of de novo RET mutations in Hirschsprung's
RT disease.";
RL Eur. J. Hum. Genet. 4:356-358(1996).
RN [64]
RP VARIANTS MTC/MEN2A.
RX PubMed=8557249; DOI=10.1007/bf00218825;
RA Landsvater R.M., Jansen R.P.M., Hofstra R.M.W., Buys C.H.C.M., Lips C.J.M.,
RA van Amstel H.K.P.;
RT "Mutation analysis of the RET proto-oncogene in Dutch families with MEN 2A,
RT MEN 2B and FMTC: two novel mutations and one de novo mutation for MEN 2A.";
RL Hum. Genet. 97:11-14(1996).
RN [65]
RP VARIANTS MEN2A, VARIANT MTC ASP-768, AND VARIANT MEN2B THR-918.
RX PubMed=8807338;
RX DOI=10.1002/(sici)1098-1004(1996)8:1<64::aid-humu9>3.0.co;2-p;
RA Kambouris M., Jackson C.E., Feldman G.L.;
RT "Diagnosis of multiple endocrine neoplasia [MEN] 2A, 2B and familial
RT medullary thyroid cancer [FMTC] by multiplex PCR and heteroduplex analyses
RT of RET proto-oncogene mutations.";
RL Hum. Mutat. 8:64-70(1996).
RN [66]
RP VARIANTS MEN2A.
RX PubMed=8626834; DOI=10.1210/jcem.81.5.8626834;
RA Frank-Raue K., Hoeppner W., Frilling A., Kotzerke J., Dralle H., Haase R.,
RA Mann K., Seif F., Kirchner R., Rendl J., Deckart H.F., Ritter M.M.,
RA Hampel R., Klempa J., Scholz G.H., Raue F., Bogner U., Brabant G.,
RA Grussendorf M., Hartenstein C.H., Heidemann P., Hensen J., Doerr A.G.,
RA Hoehne T., Hoernig-Franz I., Huefner M., Kress J., Langer H.J.,
RA Lottermoser K., Schweikert H.U., Kusterer K., Menken U., Mercier J.,
RA Oelkers W., Sauer J., Simon D., Starrach G., Ziegler R.;
RT "Mutations of the ret protooncogene in German multiple endocrine neoplasia
RT families: relation between genotype and phenotype.";
RL J. Clin. Endocrinol. Metab. 81:1780-1783(1996).
RN [67]
RP VARIANT MEN2A HIS-GLU-LEU-CYS-634 INS.
RX PubMed=9097963; DOI=10.1093/hmg/6.4.587;
RA Hoeppner W., Ritter M.M.;
RT "A duplication of 12 bp in the critical cysteine rich domain of the RET
RT proto-oncogene results in a distinct phenotype of multiple endocrine
RT neoplasia type 2A.";
RL Hum. Mol. Genet. 6:587-590(1997).
RN [68]
RP VARIANTS HSCR1 PRO-180; GLN-313; ARG-620 AND PHE-791.
RX PubMed=9090527;
RX DOI=10.1002/(sici)1098-1004(1997)9:3<243::aid-humu5>3.0.co;2-8;
RA Seri M., Yin L., Barone V., Bolino A., Celli I., Bocciardi R., Pasini B.,
RA Ceccherini I., Lerone M., Kristoffersson U., Larsson L.T., Casasa J.M.,
RA Cass D.T., Abramowicz M.J., Vanderwinden J.-M., Kravcenkiene I., Baric I.,
RA Silengo M., Martucciello G., Romeo G.;
RT "Frequency of RET mutations in long- and short-segment Hirschsprung
RT disease.";
RL Hum. Mutat. 9:243-249(1997).
RN [69]
RP VARIANT MTC ARG-618, AND VARIANT HSCR1 ARG-618.
RX PubMed=9259198;
RX DOI=10.1002/(sici)1098-1004(1997)10:2<155::aid-humu7>3.0.co;2-j;
RA Peretz H., Luboshitsky R., Baron E., Biton A., Gershoni R., Usher S.,
RA Grynberg E., Yakobson E., Graff E., Lapidot M.;
RT "Cys 618 Arg mutation in the RET proto-oncogene associated with familial
RT medullary thyroid carcinoma and maternally transmitted Hirschsprung's
RT disease suggesting a role for imprinting.";
RL Hum. Mutat. 10:155-159(1997).
RN [70]
RP VARIANT MEN2B PHE-883.
RC TISSUE=Peripheral blood leukocyte;
RX PubMed=9360560; DOI=10.1210/jcem.82.11.4508;
RA Gimm O., Marsh D.J., Andrew S.D., Frilling A., Dahia P.L.M., Mulligan L.M.,
RA Zajac J.D., Robinson B.G., Eng C.;
RT "Germline dinucleotide mutation in codon 883 of the RET proto-oncogene in
RT multiple endocrine neoplasia type 2B without codon 918 mutation.";
RL J. Clin. Endocrinol. Metab. 82:3902-3904(1997).
RN [71]
RP VARIANT MTC ALA-891.
RX PubMed=9398735; DOI=10.1210/jcem.82.12.4439;
RA Hofstra R.M.W., Fattoruso O., Quadro L., Wu Y., Libroia A., Verga U.,
RA Colantuoni V., Buys C.H.C.M.;
RT "A novel point mutation in the intracellular domain of the ret
RT protooncogene in a family with medullary thyroid carcinoma.";
RL J. Clin. Endocrinol. Metab. 82:4176-4178(1997).
RN [72]
RP VARIANTS HSCR1 SER-174 AND TYR-197.
RX PubMed=9094028; DOI=10.1016/s0022-3468(97)90616-3;
RA Kusafuka T., Wang Y., Puri P.;
RT "Mutation analysis of the RET, the endothelin-B receptor, and the
RT endothelin-3 genes in sporadic cases of Hirschsprung's disease.";
RL J. Pediatr. Surg. 32:501-504(1997).
RN [73]
RP VARIANTS MTC; MEN2A AND MEN2B, AND VARIANT SER-691.
RX PubMed=9223675; DOI=10.1038/sj.onc.1201102;
RA Kitamura Y., Goodfellow P.J., Shimizu K., Nagahama M., Ito K., Kitagawa W.,
RA Akasu H., Takami H., Tanaka S., Wells S.A. Jr.;
RT "Novel germline RET proto-oncogene mutations associated with medullary
RT thyroid carcinoma (MTC): mutation analysis in Japanese patients with MTC.";
RL Oncogene 14:3103-3106(1997).
RN [74]
RP VARIANT MEN2B PHE-883.
RX PubMed=9294615; DOI=10.1038/sj.onc.1201481;
RA Smith D.P., Houghton C., Ponder B.A.J.;
RT "Germline mutation of RET codon 883 in two cases of de novo MEN 2B.";
RL Oncogene 15:1213-1217(1997).
RN [75]
RP VARIANT HSCR1 LEU-1039, AND VARIANT SER-691.
RX PubMed=9497256; DOI=10.1086/301759;
RA Amiel J., Salomon R., Attie T., Pelet A., Trang H., Mokhtari M.,
RA Gaultier C., Munnich A., Lyonnet S.;
RT "Mutations of the RET-GDNF signaling pathway in Ondine's curse.";
RL Am. J. Hum. Genet. 62:715-717(1998).
RN [76]
RP VARIANT MTC GLY-611.
RX PubMed=9677065;
RX DOI=10.1002/(sici)1096-8628(19980707)78:3<271::aid-ajmg13>3.0.co;2-c;
RA Oriola J., Paramo C., Halperin I., Garcia-Mayor R.V., Rivera-Fillat F.;
RT "Novel point mutation in exon 10 of the RET proto-oncogene in a family with
RT medullary thyroid carcinoma.";
RL Am. J. Med. Genet. 78:271-273(1998).
RN [77]
RP VARIANT CYS-982.
RX PubMed=9760196; DOI=10.1007/s004390050797;
RA Svensson P.J., Anvret M., Molander M.L., Nordenskjold A.;
RT "Phenotypic variation in a family with mutations in two Hirschsprung-
RT related genes (RET and endothelin receptor B).";
RL Hum. Genet. 103:145-148(1998).
RN [78]
RP VARIANTS MEN2A TYR-609; SER-618; ARG-620 AND TRP-620, AND VARIANTS HSCR1
RP TYR-609; SER-618; ARG-620 AND TRP-620.
RX PubMed=9384613; DOI=10.1093/hmg/7.1.129;
RA Decker R.A., Peacock M.L., Watson P.;
RT "Hirschsprung disease in MEN 2A: increased spectrum of RET exon 10
RT genotypes and strong genotype-phenotype correlation.";
RL Hum. Mol. Genet. 7:129-134(1998).
RN [79]
RP VARIANT MEN2A CYS-ARG-THR-636 INS.
RX PubMed=9452064; DOI=10.1002/humu.1380110143;
RA Hoeppner W., Dralle H., Brabant G.;
RT "Duplication of 9 base pairs in the critical cysteine-rich domain of the
RT RET proto-oncogene causes multiple endocrine neoplasia type 2A.";
RL Hum. Mutat. Suppl. 1:S128-S130(1998).
RN [80]
RP VARIANT MTC MET-804.
RX PubMed=9452077; DOI=10.1002/humu.1380110156;
RA Fattoruso O., Quadro L., Libroia A., Verga U., Lupoli G., Cascone E.,
RA Colantuoni V.;
RT "A GTG to ATG novel point mutation at codon 804 in exon 14 of the RET
RT proto-oncogene in two families affected by familial medullary thyroid
RT carcinoma.";
RL Hum. Mutat. Suppl. 1:S167-S171(1998).
RN [81]
RP VARIANTS MTC/MEN2A PHE-790 AND PHE-791.
RX PubMed=9506724; DOI=10.1210/jcem.83.3.4619;
RA Berndt I., Reuter M., Saller B., Frank-Raue K., Groth P., Grussendorf M.,
RA Raue F., Ritter M.M., Hoeppner W.;
RT "A new hot spot for mutations in the ret protooncogene causing familial
RT medullary thyroid carcinoma and multiple endocrine neoplasia type 2A.";
RL J. Clin. Endocrinol. Metab. 83:770-774(1998).
RN [82]
RP VARIANTS MTC AND MEN2A.
RX PubMed=9621513; DOI=10.1007/s100380050048;
RA Shirahama S., Ogura K., Takami H., Ito K., Tohsen T., Miyauchi A.,
RA Nakamura Y.;
RT "Mutational analysis of the RET proto-oncogene in 71 Japanese patients with
RT medullary thyroid carcinoma.";
RL J. Hum. Genet. 43:101-106(1998).
RN [83]
RP VARIANTS HSCR1 LYS-626 AND GLN-813.
RX PubMed=10090908; DOI=10.1086/302329;
RA Auricchio A., Griseri P., Carpentieri M.L., Betsos N., Staiano A.,
RA Tozzi A., Priolo M., Thompson H., Bocciardi R., Romeo G., Ballabio A.,
RA Ceccherini I.;
RT "Double heterozygosity for a RET substitution interfering with splicing and
RT an EDNRB missense mutation in Hirschsprung disease.";
RL Am. J. Hum. Genet. 64:1216-1221(1999).
RN [84]
RP VARIANTS HSCR1 ASN-1059 DEL AND PRO-1061.
RX PubMed=10484767; DOI=10.1093/hmg/8.11.1989;
RA Geneste O., Bidaud C., De Vita G., Hofstra R.M.W., Tartare-Deckert S.,
RA Buys C.H.C.M., Lenoir G.M., Santoro M., Billaud M.;
RT "Two distinct mutations of the RET receptor causing Hirschsprung's disease
RT impair the binding of signalling effectors to a multifunctional docking
RT site.";
RL Hum. Mol. Genet. 8:1989-1999(1999).
RN [85]
RP VARIANT MTC GLU-GLU-CYS-531 INS.
RX PubMed=10323403; DOI=10.1210/jcem.84.5.5665;
RA Pigny P., Bauters C., Wemeau J.-L., Houcke M.L., Crepin M., Caron P.,
RA Giraud S., Calender A., Buisine M.-P., Kerckaert J.-P., Porchet N.;
RT "A novel 9-base pair duplication in RET exon 8 in familial medullary
RT thyroid carcinoma.";
RL J. Clin. Endocrinol. Metab. 84:1700-1704(1999).
RN [86]
RP VARIANT MEN2A GLY-640.
RX PubMed=10522989; DOI=10.1210/jcem.84.10.6056;
RA Tessitore A., Sinisi A.A., Pasquali D., Cardone M., Vitale D.,
RA Bellastella A., Colantuoni V.;
RT "A novel case of multiple endocrine neoplasia type 2A associated with two
RT de novo mutations of the RET protooncogene.";
RL J. Clin. Endocrinol. Metab. 84:3522-3527(1999).
RN [87]
RP VARIANTS MTC MET-804 AND LEU-844.
RX PubMed=10826520; DOI=10.1055/s-2000-5806;
RA Bartsch D.K., Hasse C., Schug C., Barth P., Rothmund M., Hoeppner W.;
RT "A RET double mutation in the germline of a kindred with FMTC.";
RL Exp. Clin. Endocrinol. Diabetes 108:128-132(2000).
RN [88]
RP VARIANT GLN-600.
RX PubMed=10612852;
RX DOI=10.1002/(sici)1098-1004(200001)15:1<122::aid-humu41>3.0.co;2-7;
RA Saez M.E., Ruiz A., Cebrian A., Morales F., Robledo M., Antinolo G.,
RA Borrego S.;
RT "A new germline mutation, R600Q, within the coding region of RET proto-
RT oncogene: a rare polymorphism or a MEN 2 causing mutation?";
RL Hum. Mutat. 15:122-122(2000).
RN [89]
RP VARIANTS HSCR1 LEU-32; CYS-77; TRP-360 AND LYS-394.
RX PubMed=10618407; DOI=10.1073/pnas.97.1.268;
RA Bolk S., Pelet A., Hofstra R.M.W., Angrist M., Salomon R., Croaker D.,
RA Buys C.H.C.M., Lyonnet S., Chakravarti A.;
RT "A human model for multigenic inheritance: phenotypic expression in
RT Hirschsprung disease requires both the RET gene and a new 9q31 locus.";
RL Proc. Natl. Acad. Sci. U.S.A. 97:268-273(2000).
RN [90]
RP VARIANTS MTC GLY-639; GLY-641 AND PHE-922.
RX PubMed=11692159; DOI=10.1007/s001090100250;
RA Kalinin V.N., Amosenko F.A., Shabanov M.A., Lubchenko L.N., Hosch S.B.,
RA Garkavtseva R.F., Izbicki J.R.;
RT "Three novel mutations in the RET proto-oncogene.";
RL J. Mol. Med. 79:609-612(2001).
RN [91]
RP VARIANTS PHEOCHROMOCYTOMA ARG-634; GLY-634; TYR-634; SER-634; PHE-634;
RP TRP-634 AND PHE-791.
RX PubMed=12000816; DOI=10.1056/nejmoa020152;
RG The Freiburg-Warsaw-Columbus pheochromocytoma study group;
RA Neumann H.P.H., Bausch B., McWhinney S.R., Bender B.U., Gimm O., Franke G.,
RA Schipper J., Klisch J., Altehoefer C., Zerres K., Januszewicz A.,
RA Smith W.M., Munk R., Manz T., Glaesker S., Apel T.W., Treier M.,
RA Reineke M., Walz M.K., Hoang-Vu C., Brauckhoff M., Klein-Franke A.,
RA Klose P., Schmidt H., Maier-Woelfle M., Peczkowska M., Szmigielski C.,
RA Eng C.;
RT "Germ-line mutations in nonsyndromic pheochromocytoma.";
RL N. Engl. J. Med. 346:1459-1466(2002).
RN [92]
RP VARIANT HIS-114.
RX PubMed=12086152; DOI=10.1620/tjem.196.241;
RA Kanai M., Numakura C., Sasaki A., Shirahata E., Akaba K., Hashimoto M.,
RA Hasegawa H., Shirasawa S., Hayasaka K.;
RT "Congenital central hypoventilation syndrome: a novel mutation of the RET
RT gene in an isolated case.";
RL Tohoku J. Exp. Med. 196:241-246(2002).
RN [93]
RP VARIANTS HIS-67; HIS-114; GLU-432; ASN-489; SER-691 AND CYS-982.
RX PubMed=14566559; DOI=10.1007/s00439-003-1036-z;
RA Sasaki A., Kanai M., Kijima K., Akaba K., Hashimoto M., Hasegawa H.,
RA Otaki S., Koizumi T., Kusuda S., Ogawa Y., Tuchiya K., Yamamoto W.,
RA Nakamura T., Hayasaka K.;
RT "Molecular analysis of congenital central hypoventilation syndrome.";
RL Hum. Genet. 114:22-26(2003).
RN [94]
RP VARIANTS [LARGE SCALE ANALYSIS] GLY-145; TRP-360 AND GLU-593.
RX PubMed=16959974; DOI=10.1126/science.1133427;
RA Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D.,
RA Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S., Buckhaults P.,
RA Farrell C., Meeh P., Markowitz S.D., Willis J., Dawson D., Willson J.K.V.,
RA Gazdar A.F., Hartigan J., Wu L., Liu C., Parmigiani G., Park B.H.,
RA Bachman K.E., Papadopoulos N., Vogelstein B., Kinzler K.W.,
RA Velculescu V.E.;
RT "The consensus coding sequences of human breast and colorectal cancers.";
RL Science 314:268-274(2006).
RN [95]
RP VARIANTS [LARGE SCALE ANALYSIS] GLN-163; ASN-278; MET-292; ASN-489;
RP SER-691; THR-749; SER-826; LEU-844; CYS-982 AND TYR-1112.
RX PubMed=17344846; DOI=10.1038/nature05610;
RA Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C., Bignell G.,
RA Davies H., Teague J., Butler A., Stevens C., Edkins S., O'Meara S.,
RA Vastrik I., Schmidt E.E., Avis T., Barthorpe S., Bhamra G., Buck G.,
RA Choudhury B., Clements J., Cole J., Dicks E., Forbes S., Gray K.,
RA Halliday K., Harrison R., Hills K., Hinton J., Jenkinson A., Jones D.,
RA Menzies A., Mironenko T., Perry J., Raine K., Richardson D., Shepherd R.,
RA Small A., Tofts C., Varian J., Webb T., West S., Widaa S., Yates A.,
RA Cahill D.P., Louis D.N., Goldstraw P., Nicholson A.G., Brasseur F.,
RA Looijenga L., Weber B.L., Chiew Y.-E., DeFazio A., Greaves M.F.,
RA Green A.R., Campbell P., Birney E., Easton D.F., Chenevix-Trench G.,
RA Tan M.-H., Khoo S.K., Teh B.T., Yuen S.T., Leung S.Y., Wooster R.,
RA Futreal P.A., Stratton M.R.;
RT "Patterns of somatic mutation in human cancer genomes.";
RL Nature 446:153-158(2007).
RN [96]
RP VARIANTS THR-198; ALA-376; HIS-394; ILE-778; SER-894; THR-918; LEU-1049 AND
RP SER-1067, POSSIBLE INVOLVEMENT IN RENAL AGENESIS, AND CHARACTERIZATION OF
RP VARIANTS THR-198; ALA-376; HIS-394; ILE-778; SER-894; LEU-1049 AND
RP SER-1067.
RX PubMed=18252215; DOI=10.1016/j.ajhg.2007.10.008;
RA Skinner M.A., Safford S.D., Reeves J.G., Jackson M.E., Freemerman A.J.;
RT "Renal aplasia in humans is associated with RET mutations.";
RL Am. J. Hum. Genet. 82:344-351(2008).
RN [97]
RP VARIANTS HSCR1 549-LYS-GLY-550 DEL; CYS-114; GLY-145; LEU-155; PRO-175;
RP ALA-278; PRO-278; ASN-300; GLN-313; ILE-316; LEU-339; TYR-353; GLN-360;
RP MET-397; MET-412; ARG-423; LYS-480; GLN-595; LEU-679; GLN-694; SER-783;
RP ARG-830; THR-907; LEU-961; VAL-1052; CYS-1062 AND THR-1064, AND VARIANTS
RP HIS-114; ASN-278 AND MET-292.
RX PubMed=22174939; DOI=10.1371/journal.pone.0028986;
RA So M.T., Leon T.Y., Cheng G., Tang C.S., Miao X.P., Cornes B.K., Diem N.N.,
RA Cui L., Ngan E.S., Lui V.C., Wu X.Z., Wang B., Wang H., Yuan Z.W.,
RA Huang L.M., Li L., Xia H., Zhu D., Liu J., Nguyen T.L., Chan I.H.,
RA Chung P.H., Liu X.L., Zhang R., Wong K.K., Sham P.C., Cherny S.S.,
RA Tam P.K., Garcia-Barcelo M.M.;
RT "RET mutational spectrum in Hirschsprung disease: evaluation of 601 Chinese
RT patients.";
RL PLoS ONE 6:E28986-E28986(2011).
CC -!- FUNCTION: Receptor tyrosine-protein kinase involved in numerous
CC cellular mechanisms including cell proliferation, neuronal navigation,
CC cell migration, and cell differentiation upon binding with glial cell
CC derived neurotrophic factor family ligands. Phosphorylates PTK2/FAK1.
CC Regulates both cell death/survival balance and positional information.
CC Required for the molecular mechanisms orchestration during intestine
CC organogenesis; involved in the development of enteric nervous system
CC and renal organogenesis during embryonic life, and promotes the
CC formation of Peyer's patch-like structures, a major component of the
CC gut-associated lymphoid tissue. Modulates cell adhesion via its
CC cleavage by caspase in sympathetic neurons and mediates cell migration
CC in an integrin (e.g. ITGB1 and ITGB3)-dependent manner. Involved in the
CC development of the neural crest. Active in the absence of ligand,
CC triggering apoptosis through a mechanism that requires receptor
CC intracellular caspase cleavage. Acts as a dependence receptor; in the
CC presence of the ligand GDNF in somatotrophs (within pituitary),
CC promotes survival and down regulates growth hormone (GH) production,
CC but triggers apoptosis in absence of GDNF. Regulates nociceptor
CC survival and size. Triggers the differentiation of rapidly adapting
CC (RA) mechanoreceptors. Mediator of several diseases such as
CC neuroendocrine cancers; these diseases are characterized by aberrant
CC integrins-regulated cell migration. Mediates, through interaction with
CC GDF15-receptor GFRAL, GDF15-induced cell-signaling in the brainstem
CC which induces inhibition of food-intake. Activates MAPK- and AKT-
CC signaling pathways (PubMed:28846097, PubMed:28953886, PubMed:28846099).
CC Isoform 1 in complex with GFRAL induces higher activation of MAPK-
CC signaling pathway than isoform 2 in complex with GFRAL
CC (PubMed:28846099). {ECO:0000269|PubMed:20064382,
CC ECO:0000269|PubMed:20616503, ECO:0000269|PubMed:20702524,
CC ECO:0000269|PubMed:21357690, ECO:0000269|PubMed:21454698,
CC ECO:0000269|PubMed:28846097, ECO:0000269|PubMed:28846099,
CC ECO:0000269|PubMed:28953886}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-tyrosyl-[protein] = ADP + H(+) + O-phospho-L-tyrosyl-
CC [protein]; Xref=Rhea:RHEA:10596, Rhea:RHEA-COMP:10136, Rhea:RHEA-
CC COMP:10137, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, ChEBI:CHEBI:46858,
CC ChEBI:CHEBI:82620, ChEBI:CHEBI:456216; EC=2.7.10.1;
CC Evidence={ECO:0000255|PROSITE-ProRule:PRU10028};
CC -!- ACTIVITY REGULATION: Repressed by 4-(3-hydroxyanilino)-quinolines
CC derivatives, indolin-2-one-derivatives, 2-(alkylsulfanyl)-4-(3-thienyl)
CC nicotinonitrile analogs, 3- and 4-substituted beta-carbolin-1-ones,
CC vandetanib, motesanib, sorafenib (BAY 43-9006), cabozantinib (XL184),
CC sunitinib, and withaferin A (WA). Inactivation by sorafenib both
CC reduces kinase activity and promotes lysosomal degradation.
CC {ECO:0000269|PubMed:17664273, ECO:0000269|PubMed:17884497,
CC ECO:0000269|PubMed:19053769, ECO:0000269|PubMed:20117004,
CC ECO:0000269|PubMed:20409618, ECO:0000269|PubMed:20605972,
CC ECO:0000269|PubMed:21134556}.
CC -!- SUBUNIT: Phosphorylated form interacts with the PBT domain of DOK2,
CC DOK4 and DOK5 (By similarity). The phosphorylated form interacts with
CC PLCG1 and GRB7 (By similarity). Interacts (not phosphorylated) with
CC PTK2/FAK1 (via FERM domain) (PubMed:21454698). Extracellular cell-
CC membrane anchored RET cadherin fragments form complex in neurons with
CC reduced trophic status, preferentially at the contact sites between
CC somas (PubMed:21357690). Interacts with AIP in the pituitary gland;
CC this interaction prevents the formation of the AIP-survivin complex
CC (PubMed:19366855). Binds to ARTN (By similarity). Interacts (inactive)
CC with CBLC and CD2AP; dissociates upon activation by GDNF which
CC increases CBLC:CD2AP interaction (PubMed:18753381). Interacts (via the
CC extracellular domain) with GFRAL (via the extracellular domain); the
CC interaction mediates cellular signaling upon interaction of GFRAL with
CC its ligand GDF15 (PubMed:28953886, PubMed:28846097, PubMed:28846099).
CC Interaction with GFRAL requires previous GDF15-binding to GFRAL
CC (PubMed:28846097, PubMed:28846099). Interacts with GFRA1; in the
CC presence of SORL1, the GFRA1/RET complex is targeted to endosomes
CC (PubMed:23333276). Interacts with GDNF (PubMed:21994944).
CC {ECO:0000250|UniProtKB:P35546, ECO:0000269|PubMed:18753381,
CC ECO:0000269|PubMed:19366855, ECO:0000269|PubMed:21357690,
CC ECO:0000269|PubMed:21454698, ECO:0000269|PubMed:21994944,
CC ECO:0000269|PubMed:23333276, ECO:0000269|PubMed:28846097,
CC ECO:0000269|PubMed:28846099, ECO:0000269|PubMed:28953886}.
CC -!- INTERACTION:
CC P07949; Q7Z3S9: NOTCH2NLA; NbExp=3; IntAct=EBI-2480756, EBI-945833;
CC P07949; P40763: STAT3; NbExp=3; IntAct=EBI-2480756, EBI-518675;
CC P07949; Q62985: Sh2b1; Xeno; NbExp=3; IntAct=EBI-2480756, EBI-7395583;
CC P07949-2; Q7Z3S9: NOTCH2NLA; NbExp=3; IntAct=EBI-4423689, EBI-945833;
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:19823924,
CC ECO:0000269|PubMed:21994944, ECO:0000269|PubMed:23333276,
CC ECO:0000269|PubMed:28953886}; Single-pass type I membrane protein
CC {ECO:0000269|PubMed:19823924}. Endosome membrane
CC {ECO:0000269|PubMed:19823924, ECO:0000269|PubMed:23333276}; Single-pass
CC type I membrane protein {ECO:0000269|PubMed:19823924}.
CC Note=Predominantly located on the plasma membrane. In the presence of
CC SORL1 and GFRA1, directed to endosomes. {ECO:0000269|PubMed:23333276}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1; Synonyms=RET51;
CC IsoId=P07949-1; Sequence=Displayed;
CC Name=2; Synonyms=RET9;
CC IsoId=P07949-2; Sequence=VSP_040735;
CC -!- INDUCTION: Positively regulated by NKX2-1, PHOX2B, SOX10 and PAX3.
CC {ECO:0000269|PubMed:19853745}.
CC -!- PTM: Autophosphorylated on C-terminal tyrosine residues upon ligand
CC stimulation. Dephosphorylated by PTPRJ on Tyr-905, Tyr-1015 and Tyr-
CC 1062. {ECO:0000269|PubMed:11061555, ECO:0000269|PubMed:14711813,
CC ECO:0000269|PubMed:16778204, ECO:0000269|PubMed:16928683,
CC ECO:0000269|PubMed:20117004, ECO:0000269|PubMed:28846099}.
CC -!- PTM: Proteolytically cleaved by caspase-3. The soluble RET kinase
CC fragment is able to induce cell death. The extracellular cell-membrane
CC anchored RET cadherin fragment accelerates cell adhesion in sympathetic
CC neurons. {ECO:0000269|PubMed:21357690}.
CC -!- POLYMORPHISM: The Cys-982 polymorphism may be associated with an
CC increased risk for developing Hirschsprung disease.
CC -!- DISEASE: Colorectal cancer (CRC) [MIM:114500]: A complex disease
CC characterized by malignant lesions arising from the inner wall of the
CC large intestine (the colon) and the rectum. Genetic alterations are
CC often associated with progression from premalignant lesion (adenoma) to
CC invasive adenocarcinoma. Risk factors for cancer of the colon and
CC rectum include colon polyps, long-standing ulcerative colitis, and
CC genetic family history. Note=The disease may be caused by variants
CC affecting the gene represented in this entry.
CC -!- DISEASE: Hirschsprung disease 1 (HSCR1) [MIM:142623]: A disorder of
CC neural crest development characterized by absence of enteric ganglia
CC along a variable length of the intestine. It is the most common cause
CC of congenital intestinal obstruction. Early symptoms range from
CC complete acute neonatal obstruction, characterized by vomiting,
CC abdominal distention and failure to pass stool, to chronic constipation
CC in the older child. {ECO:0000269|PubMed:10090908,
CC ECO:0000269|PubMed:10484767, ECO:0000269|PubMed:10618407,
CC ECO:0000269|PubMed:22174939, ECO:0000269|PubMed:7581377,
CC ECO:0000269|PubMed:7633441, ECO:0000269|PubMed:7704557,
CC ECO:0000269|PubMed:7881414, ECO:0000269|PubMed:8114938,
CC ECO:0000269|PubMed:8114939, ECO:0000269|PubMed:9043870,
CC ECO:0000269|PubMed:9090527, ECO:0000269|PubMed:9094028,
CC ECO:0000269|PubMed:9259198, ECO:0000269|PubMed:9384613,
CC ECO:0000269|PubMed:9497256, ECO:0000269|Ref.62}. Note=The disease is
CC caused by variants affecting the gene represented in this entry.
CC -!- DISEASE: Medullary thyroid carcinoma (MTC) [MIM:155240]: Rare tumor
CC derived from the C cells of the thyroid. Three hereditary forms are
CC known, that are transmitted in an autosomal dominant fashion: (a)
CC multiple neoplasia type 2A (MEN2A), (b) multiple neoplasia type IIB
CC (MEN2B) and (c) familial MTC (FMTC), which occurs in 25-30% of MTC
CC cases and where MTC is the only clinical manifestation.
CC {ECO:0000269|PubMed:10323403, ECO:0000269|PubMed:10826520,
CC ECO:0000269|PubMed:11692159, ECO:0000269|PubMed:7784092,
CC ECO:0000269|PubMed:7845675, ECO:0000269|PubMed:7849720,
CC ECO:0000269|PubMed:7874109, ECO:0000269|PubMed:7881414,
CC ECO:0000269|PubMed:7915165, ECO:0000269|PubMed:8103403,
CC ECO:0000269|PubMed:8557249, ECO:0000269|PubMed:8625130,
CC ECO:0000269|PubMed:8807338, ECO:0000269|PubMed:9223675,
CC ECO:0000269|PubMed:9259198, ECO:0000269|PubMed:9398735,
CC ECO:0000269|PubMed:9452077, ECO:0000269|PubMed:9506724,
CC ECO:0000269|PubMed:9621513, ECO:0000269|PubMed:9677065}. Note=The
CC disease is caused by variants affecting the gene represented in this
CC entry.
CC -!- DISEASE: Multiple neoplasia 2B (MEN2B) [MIM:162300]: Uncommon inherited
CC cancer syndrome characterized by predisposition to MTC and
CC phaeochromocytoma which is associated with marfanoid habitus, mucosal
CC neuromas, skeletal and ophthalmic abnormalities, and ganglioneuromas of
CC the intestine tract. Then the disease progresses rapidly with the
CC development of metastatic MTC and a pheochromocytome in 50% of cases.
CC {ECO:0000269|PubMed:7906417, ECO:0000269|PubMed:7906866,
CC ECO:0000269|PubMed:7911697, ECO:0000269|PubMed:8595427,
CC ECO:0000269|PubMed:8807338, ECO:0000269|PubMed:9294615,
CC ECO:0000269|PubMed:9360560}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- DISEASE: Pheochromocytoma (PCC) [MIM:171300]: A catecholamine-producing
CC tumor of chromaffin tissue of the adrenal medulla or sympathetic
CC paraganglia. The cardinal symptom, reflecting the increased secretion
CC of epinephrine and norepinephrine, is hypertension, which may be
CC persistent or intermittent. {ECO:0000269|PubMed:12000816}. Note=Disease
CC susceptibility is associated with variants affecting the gene
CC represented in this entry.
CC -!- DISEASE: Multiple neoplasia 2A (MEN2A) [MIM:171400]: The most frequent
CC form of medullary thyroid cancer (MTC). It is an inherited cancer
CC syndrome characterized by MTC, phaeochromocytoma and/or
CC hyperparathyroidism. {ECO:0000269|PubMed:10522989,
CC ECO:0000269|PubMed:7860065, ECO:0000269|PubMed:7874109,
CC ECO:0000269|PubMed:7881414, ECO:0000269|PubMed:7915165,
CC ECO:0000269|PubMed:8099202, ECO:0000269|PubMed:8103403,
CC ECO:0000269|PubMed:8626834, ECO:0000269|PubMed:8807338,
CC ECO:0000269|PubMed:9097963, ECO:0000269|PubMed:9384613,
CC ECO:0000269|PubMed:9452064}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- DISEASE: Note=Various chromosomal aberrations involving RET are known.
CC Some of them have been found in papillary thyroid carcinomas (PTCs)
CC (PubMed:12787916, PubMed:2406025, PubMed:10980597, PubMed:10439047).
CC Inversion inv(10)(q11.2;q21) generates the RET/CCDC6 (PTC1) oncogene
CC (PubMed:2406025). Inversion inv(10)(q11.2;q11.2) generates the
CC RET/NCOA4 (PTC3) oncogene. Translocation t(10;14)(q11;q32) with GOLGA5
CC generates the RET/GOLGA5 (PTC5) oncogene (PubMed:2734021).
CC Translocation t(8;10)(p21.3;q11.2) with PCM1 generates the PCM1/RET
CC fusion (PubMed:10980597). Translocation t(6;10)(p21.3;q11.2) with
CC TRIM27/RFP generates the Delta RFP/RET oncogene (PubMed:12787916).
CC Translocation t(1;10)(p13;q11) with TRIM33 generates the TRIM33/RET
CC (PTC7) oncogene (PubMed:10439047). Translocation t(7;10)(q32;q11) with
CC TRIM24/TIF1 generates the TRIM24/RET (PTC6) oncogene (PubMed:10439047).
CC Translocation t(6;10)(p21.3;q11.2) with TRIM27/RFP generates the
CC TRIM27/RET oncogene (PubMed:3037315). {ECO:0000269|PubMed:10439047,
CC ECO:0000269|PubMed:10980597, ECO:0000269|PubMed:12787916,
CC ECO:0000269|PubMed:2406025, ECO:0000269|PubMed:2734021,
CC ECO:0000269|PubMed:3037315}.
CC -!- DISEASE: Note=Mutations in RET have been detected in patients with
CC renal agenesis suggesting a possible involvement of this gene in
CC disease pathogenesis.
CC -!- MISCELLANEOUS: Treatment with withaferin A (WA) leads tumor regression
CC in medullary thyroid carcinomas (MTC).
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. Tyr protein
CC kinase family. {ECO:0000255|PROSITE-ProRule:PRU00159}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAA36524.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};
CC Sequence=AAA36786.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};
CC Sequence=CAA33787.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};
CC Sequence=CAC14882.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and
CC Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/RETID76.html";
CC -!- WEB RESOURCE: Name=MEN2 RET database;
CC URL="http://www.arup.utah.edu/database/MEN2/MEN2_welcome.php";
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DR EMBL; AK291807; BAF84496.1; -; mRNA.
DR EMBL; AC010864; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC004257; AAH04257.1; -; mRNA.
DR EMBL; X15262; CAA33333.1; -; mRNA.
DR EMBL; X12949; CAA31408.1; -; mRNA.
DR EMBL; M16029; AAA36786.1; ALT_INIT; mRNA.
DR EMBL; X15786; CAA33787.1; ALT_INIT; mRNA.
DR EMBL; M31213; AAA36524.1; ALT_INIT; mRNA.
DR EMBL; AJ297349; CAC14882.1; ALT_INIT; mRNA.
DR CCDS; CCDS53525.1; -. [P07949-2]
DR CCDS; CCDS7200.1; -. [P07949-1]
DR PIR; A27203; TVHURE.
DR PIR; A34630; A34630.
DR PIR; B34735; B34735.
DR PIR; S05582; S05582.
DR RefSeq; NP_065681.1; NM_020630.4. [P07949-2]
DR RefSeq; NP_066124.1; NM_020975.4. [P07949-1]
DR PDB; 2IVS; X-ray; 2.00 A; A/B=705-1013.
DR PDB; 2IVT; X-ray; 2.60 A; A=705-1013.
DR PDB; 2IVU; X-ray; 2.50 A; A=705-1013.
DR PDB; 2IVV; X-ray; 2.25 A; A=705-1013.
DR PDB; 2X2K; X-ray; 2.60 A; A=705-1013.
DR PDB; 2X2L; X-ray; 2.00 A; A=705-1013.
DR PDB; 2X2M; X-ray; 2.50 A; A/B=705-1013.
DR PDB; 2X2U; X-ray; 2.00 A; A=29-270.
DR PDB; 4CKI; X-ray; 2.12 A; A=705-1013.
DR PDB; 4CKJ; X-ray; 1.65 A; A=705-1013.
DR PDB; 4UX8; EM; 24.00 A; A/B=29-635.
DR PDB; 5AMN; X-ray; 2.57 A; A=705-1012.
DR PDB; 5FM2; X-ray; 3.30 A; A=659-1013.
DR PDB; 5FM3; X-ray; 2.95 A; A=659-1013.
DR PDB; 6FEK; X-ray; 2.30 A; A=705-1013.
DR PDB; 6GL7; EM; 6.30 A; E/F=29-635.
DR PDB; 6I82; X-ray; 2.05 A; A/B=705-1013.
DR PDB; 6I83; X-ray; 1.88 A; A=705-1013.
DR PDB; 6NE7; X-ray; 1.99 A; A=705-1013.
DR PDB; 6NEC; X-ray; 1.87 A; A/C=705-1013.
DR PDB; 6NJA; X-ray; 1.92 A; A=705-1013.
DR PDB; 6Q2J; EM; 4.10 A; E/F=29-635.
DR PDB; 6Q2N; EM; 4.40 A; E/F=29-635.
DR PDB; 6Q2O; EM; 3.65 A; E/F=29-635.
DR PDB; 6Q2R; EM; 4.30 A; E/F/Y/Z=29-635.
DR PDB; 6Q2S; EM; 3.80 A; E/F=29-635.
DR PDB; 6VHG; X-ray; 2.30 A; A=705-1013.
DR PDB; 7DU8; X-ray; 2.75 A; A/B=705-1013.
DR PDB; 7DU9; X-ray; 2.31 A; A/B=705-1013.
DR PDB; 7DUA; X-ray; 1.64 A; A/B=705-1013.
DR PDB; 7JU5; X-ray; 1.90 A; A/B=705-1013.
DR PDB; 7JU6; X-ray; 2.06 A; A/B=705-1013.
DR PDB; 7NZN; X-ray; 2.39 A; A=705-1013.
DR PDB; 7RUN; X-ray; 3.51 A; A/B=705-1013.
DR PDBsum; 2IVS; -.
DR PDBsum; 2IVT; -.
DR PDBsum; 2IVU; -.
DR PDBsum; 2IVV; -.
DR PDBsum; 2X2K; -.
DR PDBsum; 2X2L; -.
DR PDBsum; 2X2M; -.
DR PDBsum; 2X2U; -.
DR PDBsum; 4CKI; -.
DR PDBsum; 4CKJ; -.
DR PDBsum; 4UX8; -.
DR PDBsum; 5AMN; -.
DR PDBsum; 5FM2; -.
DR PDBsum; 5FM3; -.
DR PDBsum; 6FEK; -.
DR PDBsum; 6GL7; -.
DR PDBsum; 6I82; -.
DR PDBsum; 6I83; -.
DR PDBsum; 6NE7; -.
DR PDBsum; 6NEC; -.
DR PDBsum; 6NJA; -.
DR PDBsum; 6Q2J; -.
DR PDBsum; 6Q2N; -.
DR PDBsum; 6Q2O; -.
DR PDBsum; 6Q2R; -.
DR PDBsum; 6Q2S; -.
DR PDBsum; 6VHG; -.
DR PDBsum; 7DU8; -.
DR PDBsum; 7DU9; -.
DR PDBsum; 7DUA; -.
DR PDBsum; 7JU5; -.
DR PDBsum; 7JU6; -.
DR PDBsum; 7NZN; -.
DR PDBsum; 7RUN; -.
DR AlphaFoldDB; P07949; -.
DR SMR; P07949; -.
DR BioGRID; 111911; 141.
DR CORUM; P07949; -.
DR DIP; DIP-41449N; -.
DR IntAct; P07949; 80.
DR MINT; P07949; -.
DR STRING; 9606.ENSP00000347942; -.
DR BindingDB; P07949; -.
DR ChEMBL; CHEMBL2041; -.
DR DrugBank; DB01809; 1-Ter-Butyl-3-P-Tolyl-1h-Pyrazolo[3,4-D]Pyrimidin-4-Ylamine.
DR DrugBank; DB12742; Amuvatinib.
DR DrugBank; DB08875; Cabozantinib.
DR DrugBank; DB12010; Fostamatinib.
DR DrugBank; DB09078; Lenvatinib.
DR DrugBank; DB08901; Ponatinib.
DR DrugBank; DB15822; Pralsetinib.
DR DrugBank; DB08896; Regorafenib.
DR DrugBank; DB15685; Selpercatinib.
DR DrugBank; DB00398; Sorafenib.
DR DrugBank; DB05294; Vandetanib.
DR DrugCentral; P07949; -.
DR GuidetoPHARMACOLOGY; 2185; -.
DR GlyGen; P07949; 13 sites.
DR iPTMnet; P07949; -.
DR PhosphoSitePlus; P07949; -.
DR BioMuta; RET; -.
DR DMDM; 547807; -.
DR EPD; P07949; -.
DR jPOST; P07949; -.
DR MassIVE; P07949; -.
DR MaxQB; P07949; -.
DR PaxDb; P07949; -.
DR PeptideAtlas; P07949; -.
DR PRIDE; P07949; -.
DR ProteomicsDB; 52047; -. [P07949-1]
DR ProteomicsDB; 52048; -. [P07949-2]
DR TopDownProteomics; P07949-2; -. [P07949-2]
DR Antibodypedia; 1904; 1246 antibodies from 41 providers.
DR DNASU; 5979; -.
DR Ensembl; ENST00000340058.6; ENSP00000344798.4; ENSG00000165731.21. [P07949-2]
DR Ensembl; ENST00000355710.8; ENSP00000347942.3; ENSG00000165731.21. [P07949-1]
DR GeneID; 5979; -.
DR KEGG; hsa:5979; -.
DR MANE-Select; ENST00000355710.8; ENSP00000347942.3; NM_020975.6; NP_066124.1.
DR UCSC; uc001jak.2; human. [P07949-1]
DR CTD; 5979; -.
DR DisGeNET; 5979; -.
DR GeneCards; RET; -.
DR GeneReviews; RET; -.
DR HGNC; HGNC:9967; RET.
DR HPA; ENSG00000165731; Group enriched (adrenal gland, brain, parathyroid gland).
DR MalaCards; RET; -.
DR MIM; 114500; phenotype.
DR MIM; 142623; phenotype.
DR MIM; 155240; phenotype.
DR MIM; 162300; phenotype.
DR MIM; 164761; gene.
DR MIM; 171300; phenotype.
DR MIM; 171400; phenotype.
DR neXtProt; NX_P07949; -.
DR OpenTargets; ENSG00000165731; -.
DR Orphanet; 146; Differentiated thyroid carcinoma.
DR Orphanet; 99361; Familial medullary thyroid carcinoma.
DR Orphanet; 99803; Haddad syndrome.
DR Orphanet; 29072; Hereditary pheochromocytoma-paraganglioma.
DR Orphanet; 388; Hirschsprung disease.
DR Orphanet; 247698; Multiple endocrine neoplasia type 2A.
DR Orphanet; 247709; Multiple endocrine neoplasia type 2B.
DR Orphanet; 1848; Renal agenesis, bilateral.
DR Orphanet; 93100; Renal agenesis, unilateral.
DR Orphanet; 357191; Selection of therapeutic option in non-small cell lung carcinoma.
DR Orphanet; 276621; Sporadic pheochromocytoma/secreting paraganglioma.
DR PharmGKB; PA34335; -.
DR VEuPathDB; HostDB:ENSG00000165731; -.
DR eggNOG; KOG0200; Eukaryota.
DR GeneTree; ENSGT00940000158499; -.
DR HOGENOM; CLU_009530_0_0_1; -.
DR InParanoid; P07949; -.
DR OMA; FHLGQHL; -.
DR OrthoDB; 507784at2759; -.
DR PhylomeDB; P07949; -.
DR TreeFam; TF317640; -.
DR BRENDA; 2.7.10.1; 2681.
DR PathwayCommons; P07949; -.
DR Reactome; R-HSA-5673001; RAF/MAP kinase cascade.
DR Reactome; R-HSA-8853659; RET signaling.
DR SignaLink; P07949; -.
DR SIGNOR; P07949; -.
DR BioGRID-ORCS; 5979; 17 hits in 1108 CRISPR screens.
DR ChiTaRS; RET; human.
DR EvolutionaryTrace; P07949; -.
DR GeneWiki; RET_proto-oncogene; -.
DR GenomeRNAi; 5979; -.
DR Pharos; P07949; Tclin.
DR PRO; PR:P07949; -.
DR Proteomes; UP000005640; Chromosome 10.
DR RNAct; P07949; protein.
DR Bgee; ENSG00000165731; Expressed in substantia nigra pars reticulata and 129 other tissues.
DR ExpressionAtlas; P07949; baseline and differential.
DR Genevisible; P07949; HS.
DR GO; GO:0030424; C:axon; IBA:GO_Central.
DR GO; GO:0030425; C:dendrite; IEA:Ensembl.
DR GO; GO:0005769; C:early endosome; IEA:Ensembl.
DR GO; GO:0010008; C:endosome membrane; IDA:UniProtKB.
DR GO; GO:0005887; C:integral component of plasma membrane; IDA:UniProtKB.
DR GO; GO:0045121; C:membrane raft; IEA:Ensembl.
DR GO; GO:0043025; C:neuronal cell body; IEA:Ensembl.
DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB.
DR GO; GO:0098797; C:plasma membrane protein complex; IDA:CAFA.
DR GO; GO:0043235; C:receptor complex; IDA:MGI.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0005509; F:calcium ion binding; IDA:FlyBase.
DR GO; GO:0004713; F:protein tyrosine kinase activity; TAS:ProtInc.
DR GO; GO:0038023; F:signaling receptor activity; TAS:ProtInc.
DR GO; GO:0004714; F:transmembrane receptor protein tyrosine kinase activity; IDA:UniProtKB.
DR GO; GO:0006919; P:activation of cysteine-type endopeptidase activity involved in apoptotic process; IMP:UniProtKB.
DR GO; GO:0007411; P:axon guidance; TAS:Reactome.
DR GO; GO:0071300; P:cellular response to retinoic acid; IMP:BHF-UCL.
DR GO; GO:0001838; P:embryonic epithelial tube formation; IEA:Ensembl.
DR GO; GO:0048484; P:enteric nervous system development; IEA:Ensembl.
DR GO; GO:0035860; P:glial cell-derived neurotrophic factor receptor signaling pathway; IDA:UniProtKB.
DR GO; GO:0007156; P:homophilic cell adhesion via plasma membrane adhesion molecules; IEA:InterPro.
DR GO; GO:0060384; P:innervation; IEA:Ensembl.
DR GO; GO:0097021; P:lymphocyte migration into lymphoid organs; ISS:UniProtKB.
DR GO; GO:0000165; P:MAPK cascade; IEA:Ensembl.
DR GO; GO:0033619; P:membrane protein proteolysis; IDA:UniProtKB.
DR GO; GO:0001755; P:neural crest cell migration; IEA:Ensembl.
DR GO; GO:0007158; P:neuron cell-cell adhesion; IMP:UniProtKB.
DR GO; GO:0042551; P:neuron maturation; IEA:Ensembl.
DR GO; GO:0061146; P:Peyer's patch morphogenesis; ISS:UniProtKB.
DR GO; GO:0033630; P:positive regulation of cell adhesion mediated by integrin; IDA:UniProtKB.
DR GO; GO:0030335; P:positive regulation of cell migration; IDA:UniProtKB.
DR GO; GO:0045793; P:positive regulation of cell size; IEA:Ensembl.
DR GO; GO:2001241; P:positive regulation of extrinsic apoptotic signaling pathway in absence of ligand; IMP:UniProtKB.
DR GO; GO:0010628; P:positive regulation of gene expression; IEA:Ensembl.
DR GO; GO:0033674; P:positive regulation of kinase activity; IBA:GO_Central.
DR GO; GO:0043410; P:positive regulation of MAPK cascade; IDA:UniProtKB.
DR GO; GO:0072300; P:positive regulation of metanephric glomerulus development; ISS:UniProtKB.
DR GO; GO:0014042; P:positive regulation of neuron maturation; IEA:Ensembl.
DR GO; GO:0010976; P:positive regulation of neuron projection development; IMP:BHF-UCL.
DR GO; GO:0033141; P:positive regulation of peptidyl-serine phosphorylation of STAT protein; IEA:Ensembl.
DR GO; GO:0051897; P:positive regulation of protein kinase B signaling; IMP:UniProtKB.
DR GO; GO:0045893; P:positive regulation of transcription, DNA-templated; ISS:UniProtKB.
DR GO; GO:0007497; P:posterior midgut development; TAS:ProtInc.
DR GO; GO:0006468; P:protein phosphorylation; TAS:ProtInc.
DR GO; GO:0050770; P:regulation of axonogenesis; IEA:Ensembl.
DR GO; GO:0030155; P:regulation of cell adhesion; IDA:UniProtKB.
DR GO; GO:0048265; P:response to pain; ISS:UniProtKB.
DR GO; GO:0009410; P:response to xenobiotic stimulus; IEA:Ensembl.
DR GO; GO:0060041; P:retina development in camera-type eye; IEA:Ensembl.
DR GO; GO:0007165; P:signal transduction; TAS:ProtInc.
DR GO; GO:0007169; P:transmembrane receptor protein tyrosine kinase signaling pathway; IBA:GO_Central.
DR GO; GO:0035799; P:ureter maturation; IEA:Ensembl.
DR GO; GO:0001657; P:ureteric bud development; IEA:Ensembl.
DR InterPro; IPR002126; Cadherin-like_dom.
DR InterPro; IPR015919; Cadherin-like_sf.
DR InterPro; IPR011009; Kinase-like_dom_sf.
DR InterPro; IPR000719; Prot_kinase_dom.
DR InterPro; IPR017441; Protein_kinase_ATP_BS.
DR InterPro; IPR041163; Ret_CLD1.
DR InterPro; IPR040667; Ret_CLD3.
DR InterPro; IPR041317; RET_CLD4.
DR InterPro; IPR001245; Ser-Thr/Tyr_kinase_cat_dom.
DR InterPro; IPR008266; Tyr_kinase_AS.
DR InterPro; IPR020635; Tyr_kinase_cat_dom.
DR InterPro; IPR016249; Tyr_kinase_Ret_rcpt.
DR Pfam; PF00028; Cadherin; 1.
DR Pfam; PF07714; PK_Tyr_Ser-Thr; 1.
DR Pfam; PF17756; RET_CLD1; 1.
DR Pfam; PF17812; RET_CLD3; 1.
DR Pfam; PF17813; RET_CLD4; 1.
DR PIRSF; PIRSF000631; TyrPK_receptor_Ret; 1.
DR PRINTS; PR00109; TYRKINASE.
DR SMART; SM00219; TyrKc; 1.
DR SUPFAM; SSF49313; SSF49313; 1.
DR SUPFAM; SSF56112; SSF56112; 1.
DR PROSITE; PS50268; CADHERIN_2; 1.
DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 1.
DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
DR PROSITE; PS00109; PROTEIN_KINASE_TYR; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; ATP-binding; Cell adhesion;
KW Cell membrane; Chromosomal rearrangement; Disease variant; Disulfide bond;
KW Endosome; Glycoprotein; Hirschsprung disease; Kinase; Membrane;
KW Nucleotide-binding; Phosphoprotein; Proto-oncogene; Reference proteome;
KW Signal; Transferase; Transmembrane; Transmembrane helix;
KW Tyrosine-protein kinase.
FT SIGNAL 1..28
FT /evidence="ECO:0000255"
FT CHAIN 29..1114
FT /note="Proto-oncogene tyrosine-protein kinase receptor Ret"
FT /id="PRO_0000024450"
FT CHAIN 29..707
FT /note="Extracellular cell-membrane anchored RET cadherin
FT 120 kDa fragment"
FT /id="PRO_0000415292"
FT CHAIN 708..1017
FT /note="Soluble RET kinase fragment"
FT /id="PRO_0000415293"
FT TOPO_DOM 29..635
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 636..657
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 658..1114
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT DOMAIN 168..272
FT /note="Cadherin"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00043"
FT DOMAIN 724..1016
FT /note="Protein kinase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT ACT_SITE 874
FT /note="Proton acceptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159,
FT ECO:0000255|PROSITE-ProRule:PRU10028"
FT BINDING 730..738
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 758
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 805..807
FT /ligand="semaxanib"
FT /ligand_id="ChEBI:CHEBI:91083"
FT /ligand_note="inhibitor"
FT /evidence="ECO:0000269|PubMed:20117004,
FT ECO:0007744|PDB:2X2M"
FT SITE 587..588
FT /note="Breakpoint for translocation to form the TRIM27/RET
FT oncogene"
FT SITE 707..708
FT /note="Cleavage; by caspase-3"
FT SITE 712..713
FT /note="Breakpoint for translocation to form PCM1-RET; RET-
FT CCDC6; RET-GOLGA5; RET-TRIM24 and RET-TRIM33 oncogenes"
FT SITE 1017..1018
FT /note="Cleavage; by caspase-3"
FT MOD_RES 696
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:19369195"
FT MOD_RES 806
FT /note="Phosphotyrosine; by autocatalysis"
FT /evidence="ECO:0000269|PubMed:14711813"
FT MOD_RES 809
FT /note="Phosphotyrosine; by autocatalysis"
FT /evidence="ECO:0000269|PubMed:14711813"
FT MOD_RES 900
FT /note="Phosphotyrosine; by autocatalysis"
FT /evidence="ECO:0000269|PubMed:14711813,
FT ECO:0000269|PubMed:16928683"
FT MOD_RES 905
FT /note="Phosphotyrosine; by autocatalysis"
FT /evidence="ECO:0000269|PubMed:14711813,
FT ECO:0000269|PubMed:16778204, ECO:0000269|PubMed:16928683,
FT ECO:0000269|PubMed:20117004, ECO:0000269|PubMed:28846099"
FT MOD_RES 981
FT /note="Phosphotyrosine; by autocatalysis"
FT /evidence="ECO:0000269|PubMed:14711813"
FT MOD_RES 1015
FT /note="Phosphotyrosine; by autocatalysis"
FT /evidence="ECO:0000269|PubMed:11061555,
FT ECO:0000269|PubMed:14711813, ECO:0000269|PubMed:16778204"
FT MOD_RES 1062
FT /note="Phosphotyrosine; by autocatalysis"
FT /evidence="ECO:0000269|PubMed:11061555,
FT ECO:0000269|PubMed:14711813, ECO:0000269|PubMed:16778204,
FT ECO:0000269|PubMed:28846099"
FT MOD_RES 1090
FT /note="Phosphotyrosine; by autocatalysis"
FT /evidence="ECO:0000269|PubMed:14711813"
FT MOD_RES 1096
FT /note="Phosphotyrosine; by autocatalysis"
FT /evidence="ECO:0000269|PubMed:14711813"
FT CARBOHYD 98
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 151
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:20473317"
FT CARBOHYD 199
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 336
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 343
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 361
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 367
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 377
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 394
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 448
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 468
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 554
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 137..142
FT /evidence="ECO:0000269|PubMed:20473317"
FT VAR_SEQ 1064..1114
FT /note="MSDPNWPGESPVPLTRADGTNTGFPRYPNDSVYANWMLSPSAAKLMDTFDS
FT -> RISHAFTRF (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:14702039,
FT ECO:0000303|PubMed:15489334, ECO:0000303|PubMed:3037315"
FT /id="VSP_040735"
FT VARIANT 20
FT /note="P -> L (in HSCR1; sporadic form)"
FT /evidence="ECO:0000269|PubMed:7633441"
FT /id="VAR_009459"
FT VARIANT 32
FT /note="S -> L (in HSCR1; familial form; dbSNP:rs76764689)"
FT /evidence="ECO:0000269|PubMed:10618407,
FT ECO:0000269|PubMed:8114939"
FT /id="VAR_006295"
FT VARIANT 40
FT /note="L -> P (in HSCR1)"
FT /evidence="ECO:0000269|PubMed:7704557,
FT ECO:0000269|PubMed:9043870"
FT /id="VAR_009492"
FT VARIANT 64
FT /note="P -> L (in HSCR1; familial form; dbSNP:rs77596424)"
FT /evidence="ECO:0000269|PubMed:8114939"
FT /id="VAR_006296"
FT VARIANT 67
FT /note="R -> H (in dbSNP:rs192489011)"
FT /evidence="ECO:0000269|PubMed:14566559"
FT /id="VAR_018153"
FT VARIANT 77
FT /note="R -> C (in HSCR1)"
FT /evidence="ECO:0000269|PubMed:10618407"
FT /id="VAR_009460"
FT VARIANT 93
FT /note="G -> S (in HSCR1; unknown pathological significance;
FT dbSNP:rs1477699803)"
FT /evidence="ECO:0000269|PubMed:7633441"
FT /id="VAR_006297"
FT VARIANT 114
FT /note="R -> C (in HSCR1; unknown pathological significance;
FT dbSNP:rs747483905)"
FT /evidence="ECO:0000269|PubMed:22174939"
FT /id="VAR_067101"
FT VARIANT 114
FT /note="R -> H (in dbSNP:rs76397662)"
FT /evidence="ECO:0000269|PubMed:12086152,
FT ECO:0000269|PubMed:14566559, ECO:0000269|PubMed:22174939"
FT /id="VAR_018154"
FT VARIANT 142
FT /note="C -> S (in HSCR1; sporadic form)"
FT /id="VAR_006298"
FT VARIANT 145
FT /note="V -> G (in HSCR1; also in a colorectal cancer
FT sample; somatic mutation; dbSNP:rs1588863999)"
FT /evidence="ECO:0000269|PubMed:16959974,
FT ECO:0000269|PubMed:22174939"
FT /id="VAR_035711"
FT VARIANT 155
FT /note="P -> L (in HSCR1)"
FT /evidence="ECO:0000269|PubMed:22174939"
FT /id="VAR_067102"
FT VARIANT 157
FT /note="C -> Y (in HSCR1; unknown pathological
FT significance)"
FT /evidence="ECO:0000269|Ref.62"
FT /id="VAR_009461"
FT VARIANT 163
FT /note="R -> Q (in a colorectal adenocarcinoma sample;
FT somatic mutation; dbSNP:rs149403911)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_041762"
FT VARIANT 174
FT /note="F -> S (in HSCR1; sporadic form)"
FT /evidence="ECO:0000269|PubMed:9094028"
FT /id="VAR_009462"
FT VARIANT 175
FT /note="R -> P (in HSCR1)"
FT /evidence="ECO:0000269|PubMed:22174939"
FT /id="VAR_067103"
FT VARIANT 180
FT /note="R -> P (in HSCR1; sporadic form)"
FT /evidence="ECO:0000269|PubMed:9090527"
FT /id="VAR_009463"
FT VARIANT 197
FT /note="C -> Y (in HSCR1; sporadic form)"
FT /evidence="ECO:0000269|PubMed:9094028"
FT /id="VAR_009464"
FT VARIANT 198
FT /note="P -> T (in a patient with renal agenesis; unknown
FT pathological significance; prevents phosphorylation in
FT response to GDNF; dbSNP:rs76736111)"
FT /evidence="ECO:0000269|PubMed:18252215"
FT /id="VAR_044392"
FT VARIANT 231
FT /note="R -> H (in HSCR1; familial form; dbSNP:rs79661516)"
FT /id="VAR_006299"
FT VARIANT 251
FT /note="E -> K (in HSCR1; familial form; dbSNP:rs562449603)"
FT /id="VAR_006300"
FT VARIANT 278
FT /note="T -> A (in HSCR1; dbSNP:rs541929171)"
FT /evidence="ECO:0000269|PubMed:22174939"
FT /id="VAR_067104"
FT VARIANT 278
FT /note="T -> N (found in two patients with Hirschsprung
FT disease; dbSNP:rs35118262)"
FT /evidence="ECO:0000269|PubMed:17344846,
FT ECO:0000269|PubMed:22174939"
FT /id="VAR_041763"
FT VARIANT 278
FT /note="T -> P (in HSCR1)"
FT /evidence="ECO:0000269|PubMed:22174939"
FT /id="VAR_067105"
FT VARIANT 287
FT /note="R -> Q (in HSCR1; sporadic form;
FT dbSNP:rs1564491460)"
FT /id="VAR_006301"
FT VARIANT 292
FT /note="V -> M (found in patients with Hirschsprung disease;
FT unknown pathological significance; dbSNP:rs34682185)"
FT /evidence="ECO:0000269|PubMed:17344846,
FT ECO:0000269|PubMed:22174939"
FT /id="VAR_041764"
FT VARIANT 300
FT /note="D -> N (in HSCR1)"
FT /evidence="ECO:0000269|PubMed:22174939"
FT /id="VAR_067106"
FT VARIANT 313
FT /note="R -> Q (in HSCR1; dbSNP:rs77702891)"
FT /evidence="ECO:0000269|PubMed:22174939,
FT ECO:0000269|PubMed:9090527"
FT /id="VAR_009465"
FT VARIANT 316
FT /note="S -> I (in HSCR1; dbSNP:rs1060499894)"
FT /evidence="ECO:0000269|PubMed:22174939"
FT /id="VAR_067107"
FT VARIANT 330
FT /note="R -> Q (in HSCR1; dbSNP:rs80236571)"
FT /evidence="ECO:0000269|PubMed:7633441,
FT ECO:0000269|PubMed:8114939"
FT /id="VAR_006302"
FT VARIANT 339
FT /note="S -> L (in HSCR1; dbSNP:rs774829203)"
FT /evidence="ECO:0000269|PubMed:22174939"
FT /id="VAR_067108"
FT VARIANT 353
FT /note="D -> Y (in HSCR1)"
FT /evidence="ECO:0000269|PubMed:22174939"
FT /id="VAR_067109"
FT VARIANT 359
FT /note="N -> K (in HSCR1; unknown pathological
FT significance)"
FT /evidence="ECO:0000269|Ref.62"
FT /id="VAR_009466"
FT VARIANT 360
FT /note="R -> Q (in HSCR1; dbSNP:rs762472027)"
FT /evidence="ECO:0000269|PubMed:22174939"
FT /id="VAR_067110"
FT VARIANT 360
FT /note="R -> W (in HSCR1)"
FT /evidence="ECO:0000269|PubMed:10618407,
FT ECO:0000269|PubMed:16959974"
FT /id="VAR_009467"
FT VARIANT 376
FT /note="V -> A (in a patient with renal agenesis; unknown
FT pathological significance; constitutively phosphorylated;
FT expressed only the immature intracellular form)"
FT /evidence="ECO:0000269|PubMed:18252215"
FT /id="VAR_044393"
FT VARIANT 393
FT /note="F -> L (in HSCR1; familial form; dbSNP:rs78098482)"
FT /evidence="ECO:0000269|PubMed:8114939"
FT /id="VAR_006303"
FT VARIANT 394
FT /note="N -> H (in a patient with renal agenesis; unknown
FT pathological significance; prevents phosphorylation in
FT response to GDNF)"
FT /evidence="ECO:0000269|PubMed:18252215"
FT /id="VAR_044394"
FT VARIANT 394
FT /note="N -> K (in HSCR1)"
FT /evidence="ECO:0000269|PubMed:10618407"
FT /id="VAR_009468"
FT VARIANT 397
FT /note="V -> M (in HSCR1; dbSNP:rs183729115)"
FT /evidence="ECO:0000269|PubMed:22174939"
FT /id="VAR_067111"
FT VARIANT 399
FT /note="P -> L (in HSCR1; sporadic form;
FT dbSNP:rs1554818362)"
FT /evidence="ECO:0000269|PubMed:7704557"
FT /id="VAR_006304"
FT VARIANT 412
FT /note="V -> M (in HSCR1; dbSNP:rs746970700)"
FT /evidence="ECO:0000269|PubMed:22174939"
FT /id="VAR_067112"
FT VARIANT 423
FT /note="G -> R (in HSCR1; dbSNP:rs767601598)"
FT /evidence="ECO:0000269|PubMed:22174939"
FT /id="VAR_067113"
FT VARIANT 432
FT /note="A -> E (found in a patient with congenital central
FT hypoventilation syndrome; unknown pathological
FT significance; dbSNP:rs552057730)"
FT /evidence="ECO:0000269|PubMed:14566559"
FT /id="VAR_018155"
FT VARIANT 475
FT /note="R -> Q (in HSCR1; sporadic form; dbSNP:rs138624658)"
FT /id="VAR_006305"
FT VARIANT 480
FT /note="E -> K (in HSCR1; dbSNP:rs537874538)"
FT /evidence="ECO:0000269|PubMed:22174939"
FT /id="VAR_067114"
FT VARIANT 489
FT /note="D -> N (in dbSNP:rs9282834)"
FT /evidence="ECO:0000269|PubMed:14566559,
FT ECO:0000269|PubMed:17344846"
FT /id="VAR_018156"
FT VARIANT 531
FT /note="C -> CEEC (in MTC; familial form)"
FT /evidence="ECO:0000269|PubMed:10323403"
FT /id="VAR_009469"
FT VARIANT 549..550
FT /note="Missing (in HSCR1)"
FT /evidence="ECO:0000269|PubMed:22174939"
FT /id="VAR_067115"
FT VARIANT 593
FT /note="G -> E (in a colorectal cancer sample; somatic
FT mutation)"
FT /evidence="ECO:0000269|PubMed:16959974"
FT /id="VAR_035712"
FT VARIANT 595
FT /note="E -> Q (in HSCR1; dbSNP:rs1483605155)"
FT /evidence="ECO:0000269|PubMed:22174939"
FT /id="VAR_067116"
FT VARIANT 600
FT /note="R -> Q (in dbSNP:rs377767393)"
FT /evidence="ECO:0000269|PubMed:10612852"
FT /id="VAR_008966"
FT VARIANT 609
FT /note="C -> G (in MEN2A; dbSNP:rs77558292)"
FT /id="VAR_009470"
FT VARIANT 609
FT /note="C -> R (in MEN2A; dbSNP:rs77558292)"
FT /id="VAR_009471"
FT VARIANT 609
FT /note="C -> W (in HSCR1; familial form; dbSNP:rs377767396)"
FT /evidence="ECO:0000269|PubMed:7881414"
FT /id="VAR_006307"
FT VARIANT 609
FT /note="C -> Y (in MTC, MEN2A and HSCR1; familial and
FT sporadic forms; dbSNP:rs77939446)"
FT /evidence="ECO:0000269|PubMed:7633441,
FT ECO:0000269|PubMed:7849720, ECO:0000269|PubMed:9384613,
FT ECO:0000269|Ref.62"
FT /id="VAR_006306"
FT VARIANT 611
FT /note="C -> G (in MTC; familial form; dbSNP:rs377767391)"
FT /evidence="ECO:0000269|PubMed:9677065"
FT /id="VAR_009472"
FT VARIANT 611
FT /note="C -> R (in MEN2A; dbSNP:rs377767391)"
FT /id="VAR_009473"
FT VARIANT 611
FT /note="C -> S (in MEN2A; dbSNP:rs377767391)"
FT /id="VAR_009474"
FT VARIANT 611
FT /note="C -> W (in MEN2A and MTC; familial form;
FT dbSNP:rs80069458)"
FT /evidence="ECO:0000269|PubMed:8103403"
FT /id="VAR_006308"
FT VARIANT 611
FT /note="C -> Y (in MEN2A; dbSNP:rs377767397)"
FT /id="VAR_006309"
FT VARIANT 618
FT /note="C -> F (in MEN2A and MTC; familial form;
FT dbSNP:rs79781594)"
FT /id="VAR_006312"
FT VARIANT 618
FT /note="C -> G (in MEN2A; dbSNP:rs76262710)"
FT /evidence="ECO:0000269|PubMed:8099202"
FT /id="VAR_006310"
FT VARIANT 618
FT /note="C -> R (in MEN2A, MTC and HSCR1; dbSNP:rs76262710)"
FT /evidence="ECO:0000269|PubMed:7849720,
FT ECO:0000269|PubMed:7881414, ECO:0000269|PubMed:7915165,
FT ECO:0000269|PubMed:9259198"
FT /id="VAR_006311"
FT VARIANT 618
FT /note="C -> S (in MEN2A, HSCR1 and MTC; familial and
FT sporadic forms; dbSNP:rs79781594)"
FT /evidence="ECO:0000269|PubMed:7849720,
FT ECO:0000269|PubMed:7860065, ECO:0000269|PubMed:7915165,
FT ECO:0000269|PubMed:8103403, ECO:0000269|PubMed:9384613"
FT /id="VAR_006313"
FT VARIANT 618
FT /note="C -> Y (in MEN2A and MTC; familial form;
FT dbSNP:rs79781594)"
FT /id="VAR_006314"
FT VARIANT 620
FT /note="C -> F (in MEN2A and MTC; familial form;
FT dbSNP:rs77503355)"
FT /evidence="ECO:0000269|PubMed:7915165"
FT /id="VAR_006318"
FT VARIANT 620
FT /note="C -> G (in MEN2A and MTC; familial and sporadic
FT forms; dbSNP:rs77316810)"
FT /id="VAR_006315"
FT VARIANT 620
FT /note="C -> R (in MEN2A, MTC and HSCR1; familial and
FT sporadic forms; dbSNP:rs77316810)"
FT /evidence="ECO:0000269|PubMed:7633441,
FT ECO:0000269|PubMed:7881414, ECO:0000269|PubMed:7915165,
FT ECO:0000269|PubMed:8103403, ECO:0000269|PubMed:9090527,
FT ECO:0000269|PubMed:9384613, ECO:0000269|Ref.62"
FT /id="VAR_006316"
FT VARIANT 620
FT /note="C -> S (in MEN2A and MTC; familial form;
FT dbSNP:rs77503355)"
FT /evidence="ECO:0000269|PubMed:7849720,
FT ECO:0000269|PubMed:7860065"
FT /id="VAR_006317"
FT VARIANT 620
FT /note="C -> W (in MEN2A and HSCR1; dbSNP:rs79890926)"
FT /evidence="ECO:0000269|PubMed:9384613"
FT /id="VAR_009475"
FT VARIANT 620
FT /note="C -> Y (in MEN2A; dbSNP:rs77503355)"
FT /evidence="ECO:0000269|PubMed:8103403"
FT /id="VAR_006319"
FT VARIANT 626
FT /note="Q -> K (in HSCR1; sporadic form;
FT dbSNP:rs1255575160)"
FT /evidence="ECO:0000269|PubMed:10090908"
FT /id="VAR_009476"
FT VARIANT 630
FT /note="C -> F (in MEN2A and MTC; familial form;
FT dbSNP:rs377767405)"
FT /id="VAR_006320"
FT VARIANT 630
FT /note="C -> S (in MTC; sporadic form; dbSNP:rs377767405)"
FT /id="VAR_009477"
FT VARIANT 630
FT /note="C -> Y (in MTC; familial and sporadic forms;
FT dbSNP:rs377767405)"
FT /id="VAR_009478"
FT VARIANT 631
FT /note="D -> G (in thyroid carcinoma; somatic mutation;
FT dbSNP:rs121913308)"
FT /id="VAR_006321"
FT VARIANT 632..634
FT /note="ELC -> DVR (in MEN2A; dbSNP:rs377767408)"
FT /id="VAR_006322"
FT VARIANT 634..635
FT /note="CR -> WG (in MEN2A)"
FT /id="VAR_006329"
FT VARIANT 634
FT /note="C -> CHELC (in MEN2A)"
FT /evidence="ECO:0000269|PubMed:9097963"
FT /id="VAR_009479"
FT VARIANT 634
FT /note="C -> F (in MEN2A and pheochromocytoma;
FT dbSNP:rs75996173)"
FT /evidence="ECO:0000269|PubMed:12000816,
FT ECO:0000269|PubMed:7915165, ECO:0000269|PubMed:8099202"
FT /id="VAR_006324"
FT VARIANT 634
FT /note="C -> G (in MEN2A and pheochromocytoma;
FT dbSNP:rs75076352)"
FT /evidence="ECO:0000269|PubMed:12000816,
FT ECO:0000269|PubMed:7915165, ECO:0000269|PubMed:8099202"
FT /id="VAR_006323"
FT VARIANT 634
FT /note="C -> R (in MEN2A, pheochromocytoma and MTC; familial
FT form; also found as somatic mutation in a sporadic thyroid
FT carcinoma; dbSNP:rs75076352)"
FT /evidence="ECO:0000269|PubMed:12000816,
FT ECO:0000269|PubMed:7860065, ECO:0000269|PubMed:8103403"
FT /id="VAR_006326"
FT VARIANT 634
FT /note="C -> S (in MEN2A, pheochromocytoma and MTC; familial
FT form; dbSNP:rs75076352)"
FT /evidence="ECO:0000269|PubMed:12000816,
FT ECO:0000269|PubMed:8099202"
FT /id="VAR_006327"
FT VARIANT 634
FT /note="C -> W (in MEN2A, pheochromocytoma and MTC; familial
FT form; dbSNP:rs77709286)"
FT /evidence="ECO:0000269|PubMed:12000816"
FT /id="VAR_006328"
FT VARIANT 634
FT /note="C -> Y (in MEN2A, pheochromocytoma and MTC; familial
FT form; dbSNP:rs75996173)"
FT /evidence="ECO:0000269|PubMed:12000816,
FT ECO:0000269|PubMed:7860065, ECO:0000269|PubMed:7915165,
FT ECO:0000269|PubMed:8099202"
FT /id="VAR_006325"
FT VARIANT 636
FT /note="T -> TCRT (in MEN2A)"
FT /evidence="ECO:0000269|PubMed:9452064"
FT /id="VAR_006330"
FT VARIANT 639
FT /note="A -> G (in MTC; sporadic form)"
FT /evidence="ECO:0000269|PubMed:11692159"
FT /id="VAR_012743"
FT VARIANT 640
FT /note="A -> G (in MEN2A; dbSNP:rs78935588)"
FT /evidence="ECO:0000269|PubMed:10522989"
FT /id="VAR_009480"
FT VARIANT 641
FT /note="A -> G (in MTC; sporadic form)"
FT /evidence="ECO:0000269|PubMed:11692159"
FT /id="VAR_012744"
FT VARIANT 679
FT /note="P -> L (in HSCR1)"
FT /evidence="ECO:0000269|PubMed:22174939"
FT /id="VAR_067117"
FT VARIANT 690
FT /note="S -> P (in HSCR1; sporadic form)"
FT /id="VAR_006331"
FT VARIANT 691
FT /note="G -> S (in dbSNP:rs1799939)"
FT /evidence="ECO:0000269|PubMed:14566559,
FT ECO:0000269|PubMed:17344846, ECO:0000269|PubMed:9223675,
FT ECO:0000269|PubMed:9497256"
FT /id="VAR_006332"
FT VARIANT 694
FT /note="R -> Q (in HSCR1; dbSNP:rs141185224)"
FT /evidence="ECO:0000269|PubMed:22174939"
FT /id="VAR_067118"
FT VARIANT 749
FT /note="R -> T (in dbSNP:rs34288963)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_041765"
FT VARIANT 762
FT /note="E -> Q (in HSCR1; sporadic form)"
FT /evidence="ECO:0000269|PubMed:7704557"
FT /id="VAR_009481"
FT VARIANT 765
FT /note="S -> P (in HSCR1; dbSNP:rs75075748)"
FT /evidence="ECO:0000269|PubMed:7704557,
FT ECO:0000269|PubMed:8114938, ECO:0000269|PubMed:9043870"
FT /id="VAR_009493"
FT VARIANT 767
FT /note="S -> R (in HSCR1; sporadic form)"
FT /id="VAR_006334"
FT VARIANT 768
FT /note="E -> D (in MTC; familial and sporadic forms;
FT dbSNP:rs78014899)"
FT /evidence="ECO:0000269|PubMed:7784092,
FT ECO:0000269|PubMed:7845675, ECO:0000269|PubMed:8807338"
FT /id="VAR_006335"
FT VARIANT 778
FT /note="V -> I (in a patient with renal agenesis; unknown
FT pathological significance; constitutively phosphorylated;
FT dbSNP:rs75686697)"
FT /evidence="ECO:0000269|PubMed:18252215"
FT /id="VAR_044395"
FT VARIANT 783
FT /note="N -> S (in HSCR1; dbSNP:rs587778656)"
FT /evidence="ECO:0000269|PubMed:22174939"
FT /id="VAR_067119"
FT VARIANT 790
FT /note="L -> F (in MEN2A and MTC; familial form;
FT dbSNP:rs75030001)"
FT /evidence="ECO:0000269|PubMed:9506724"
FT /id="VAR_009482"
FT VARIANT 791
FT /note="Y -> F (in HSCR1, pheochromocytoma, MTC and MEN2A;
FT familial form; dbSNP:rs77724903)"
FT /evidence="ECO:0000269|PubMed:12000816,
FT ECO:0000269|PubMed:9090527, ECO:0000269|PubMed:9506724"
FT /id="VAR_009483"
FT VARIANT 804
FT /note="V -> L (in MTC; familial form; dbSNP:rs79658334)"
FT /evidence="ECO:0000269|PubMed:7784092"
FT /id="VAR_006336"
FT VARIANT 804
FT /note="V -> M (in MTC; familial form; dbSNP:rs79658334)"
FT /evidence="ECO:0000269|PubMed:10826520,
FT ECO:0000269|PubMed:9452077"
FT /id="VAR_006337"
FT VARIANT 813
FT /note="R -> Q (in HSCR1; sporadic form;
FT dbSNP:rs1318733775)"
FT /evidence="ECO:0000269|PubMed:10090908"
FT /id="VAR_009484"
FT VARIANT 826
FT /note="Y -> S (in dbSNP:rs34617196)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_041766"
FT VARIANT 830
FT /note="G -> R (in HSCR1; dbSNP:rs200127630)"
FT /evidence="ECO:0000269|PubMed:22174939"
FT /id="VAR_067120"
FT VARIANT 844
FT /note="R -> L (in MTC; familial form; dbSNP:rs55947360)"
FT /evidence="ECO:0000269|PubMed:10826520,
FT ECO:0000269|PubMed:17344846"
FT /id="VAR_011582"
FT VARIANT 873
FT /note="R -> Q (in HSCR1; sporadic form;
FT dbSNP:rs1451004715)"
FT /id="VAR_006338"
FT VARIANT 883
FT /note="A -> F (in MEN2B; somatic mutation in sporadic
FT medullary thyroid carcinoma; requires 2 nucleotide
FT substitutions; dbSNP:rs377767429)"
FT /evidence="ECO:0000269|PubMed:9294615,
FT ECO:0000269|PubMed:9360560"
FT /id="VAR_009485"
FT VARIANT 891
FT /note="S -> A (in MTC; familial form; dbSNP:rs75234356)"
FT /evidence="ECO:0000269|PubMed:9398735"
FT /id="VAR_009486"
FT VARIANT 893
FT /note="F -> L (in HSCR1; sporadic form)"
FT /id="VAR_006339"
FT VARIANT 894
FT /note="G -> S (in a patient with renal agenesis; unknown
FT pathological significance; constitutively phosphorylated;
FT expressed only the immature intracellular form)"
FT /evidence="ECO:0000269|PubMed:18252215"
FT /id="VAR_044396"
FT VARIANT 897
FT /note="R -> Q (in HSCR1; sporadic form; dbSNP:rs76087194)"
FT /evidence="ECO:0000269|PubMed:7704557,
FT ECO:0000269|PubMed:8114938"
FT /id="VAR_006340"
FT VARIANT 907
FT /note="K -> E (in HSCR1; sporadic form; dbSNP:rs377767430)"
FT /id="VAR_006341"
FT VARIANT 907
FT /note="K -> T (in HSCR1)"
FT /evidence="ECO:0000269|PubMed:22174939"
FT /id="VAR_067121"
FT VARIANT 918
FT /note="M -> T (in MEN2B and MTC; sporadic form; somatic
FT mutation; also found in a patient with renal agenesis;
FT dbSNP:rs74799832)"
FT /evidence="ECO:0000269|PubMed:18252215,
FT ECO:0000269|PubMed:7906417, ECO:0000269|PubMed:7906866,
FT ECO:0000269|PubMed:7911697, ECO:0000269|PubMed:8595427,
FT ECO:0000269|PubMed:8807338"
FT /id="VAR_006342"
FT VARIANT 921
FT /note="E -> K (in HSCR1; sporadic form)"
FT /id="VAR_006343"
FT VARIANT 922
FT /note="S -> F (in MTC; sporadic form; dbSNP:rs377767432)"
FT /evidence="ECO:0000269|PubMed:11692159"
FT /id="VAR_012745"
FT VARIANT 922
FT /note="S -> Y (in dbSNP:rs377767432)"
FT /evidence="ECO:0000269|PubMed:8595427"
FT /id="VAR_009487"
FT VARIANT 946
FT /note="T -> M (in MEN2B and MTC; familial form)"
FT /id="VAR_006345"
FT VARIANT 961
FT /note="F -> L (in HSCR1)"
FT /evidence="ECO:0000269|PubMed:22174939"
FT /id="VAR_067122"
FT VARIANT 972
FT /note="R -> G (in HSCR1; familial form; dbSNP:rs76534745)"
FT /evidence="ECO:0000269|PubMed:7704557,
FT ECO:0000269|PubMed:8114938"
FT /id="VAR_006346"
FT VARIANT 973
FT /note="P -> L (in HSCR1; familial form)"
FT /evidence="ECO:0000269|PubMed:7704557"
FT /id="VAR_006347"
FT VARIANT 980
FT /note="M -> T (in HSCR1; sporadic form)"
FT /id="VAR_006348"
FT VARIANT 982
FT /note="R -> C (in dbSNP:rs17158558)"
FT /evidence="ECO:0000269|PubMed:14566559,
FT ECO:0000269|PubMed:15489334, ECO:0000269|PubMed:17344846,
FT ECO:0000269|PubMed:7633441, ECO:0000269|PubMed:9760196"
FT /id="VAR_006349"
FT VARIANT 1039
FT /note="P -> L (in HSCR1; dbSNP:rs79853121)"
FT /evidence="ECO:0000269|PubMed:9497256"
FT /id="VAR_018157"
FT VARIANT 1039
FT /note="P -> Q (in dbSNP:rs79853121)"
FT /id="VAR_009488"
FT VARIANT 1049
FT /note="P -> L (in a patient with renal agenesis; unknown
FT pathological significance; prevents phosphorylation in
FT response to GDNF; dbSNP:rs1490712863)"
FT /evidence="ECO:0000269|PubMed:18252215"
FT /id="VAR_044397"
FT VARIANT 1052
FT /note="L -> V (in HSCR1; dbSNP:rs1564501947)"
FT /evidence="ECO:0000269|PubMed:22174939"
FT /id="VAR_067123"
FT VARIANT 1059
FT /note="Missing (in HSCR1)"
FT /evidence="ECO:0000269|PubMed:10484767, ECO:0000269|Ref.62"
FT /id="VAR_009489"
FT VARIANT 1061
FT /note="L -> P (in HSCR1; dbSNP:rs536486113)"
FT /evidence="ECO:0000269|PubMed:10484767, ECO:0000269|Ref.62"
FT /id="VAR_009490"
FT VARIANT 1062
FT /note="Y -> C (in HSCR1; dbSNP:rs587778659)"
FT /evidence="ECO:0000269|PubMed:22174939"
FT /id="VAR_067124"
FT VARIANT 1064
FT /note="M -> T (in HSCR1; familial form; dbSNP:rs149513065)"
FT /evidence="ECO:0000269|PubMed:22174939"
FT /id="VAR_009491"
FT VARIANT 1067
FT /note="P -> S (in a patient with renal agenesis; unknown
FT pathological significance; prevents phosphorylation in
FT response to GDNF; dbSNP:rs775583354)"
FT /evidence="ECO:0000269|PubMed:18252215"
FT /id="VAR_044398"
FT VARIANT 1112
FT /note="F -> Y (in a bladder transitional cell carcinoma
FT sample; somatic mutation)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_041767"
FT MUTAGEN 707
FT /note="D->N: Impaired cleavage by caspase-3 and loss of
FT induced cell death."
FT /evidence="ECO:0000269|PubMed:21357690"
FT MUTAGEN 708..1114
FT /note="Missing: Loss of induced cell death, but increased
FT cell aggregation."
FT /evidence="ECO:0000269|PubMed:21357690"
FT MUTAGEN 758
FT /note="K->R: Loss of kinase activity. No effect on
FT interaction with and dissociation from CBLC and CD2AP."
FT /evidence="ECO:0000269|PubMed:18753381,
FT ECO:0000269|PubMed:21357690"
FT MUTAGEN 1062
FT /note="Y->F: Abolishes GFRAL-mediated MAPK1/MAPK2
FT phosphorylation."
FT /evidence="ECO:0000269|PubMed:28953886"
FT CONFLICT 647
FT /note="I -> V (in Ref. 6; AAA36786)"
FT /evidence="ECO:0000305"
FT CONFLICT 664
FT /note="A -> S (in Ref. 1; BAF84496)"
FT /evidence="ECO:0000305"
FT CONFLICT 750
FT /note="A -> G (in Ref. 9; AAA36524)"
FT /evidence="ECO:0000305"
FT CONFLICT 904
FT /note="S -> P (in Ref. 6; AAA36786)"
FT /evidence="ECO:0000305"
FT STRAND 30..32
FT /evidence="ECO:0007829|PDB:2X2U"
FT STRAND 34..41
FT /evidence="ECO:0007829|PDB:2X2U"
FT STRAND 49..52
FT /evidence="ECO:0007829|PDB:2X2U"
FT STRAND 70..73
FT /evidence="ECO:0007829|PDB:2X2U"
FT HELIX 75..77
FT /evidence="ECO:0007829|PDB:2X2U"
FT STRAND 79..82
FT /evidence="ECO:0007829|PDB:2X2U"
FT STRAND 85..88
FT /evidence="ECO:0007829|PDB:2X2U"
FT TURN 90..92
FT /evidence="ECO:0007829|PDB:2X2U"
FT STRAND 94..99
FT /evidence="ECO:0007829|PDB:2X2U"
FT HELIX 103..111
FT /evidence="ECO:0007829|PDB:2X2U"
FT STRAND 120..126
FT /evidence="ECO:0007829|PDB:2X2U"
FT TURN 139..141
FT /evidence="ECO:0007829|PDB:2X2U"
FT STRAND 142..152
FT /evidence="ECO:0007829|PDB:2X2U"
FT HELIX 157..159
FT /evidence="ECO:0007829|PDB:2X2U"
FT HELIX 162..166
FT /evidence="ECO:0007829|PDB:2X2U"
FT STRAND 174..178
FT /evidence="ECO:0007829|PDB:2X2U"
FT STRAND 184..187
FT /evidence="ECO:0007829|PDB:2X2U"
FT HELIX 191..196
FT /evidence="ECO:0007829|PDB:2X2U"
FT STRAND 202..208
FT /evidence="ECO:0007829|PDB:2X2U"
FT STRAND 212..215
FT /evidence="ECO:0007829|PDB:2X2U"
FT STRAND 222..227
FT /evidence="ECO:0007829|PDB:2X2U"
FT TURN 231..233
FT /evidence="ECO:0007829|PDB:2X2U"
FT STRAND 235..245
FT /evidence="ECO:0007829|PDB:2X2U"
FT STRAND 252..263
FT /evidence="ECO:0007829|PDB:2X2U"
FT HELIX 705..710
FT /evidence="ECO:0007829|PDB:7DUA"
FT TURN 715..717
FT /evidence="ECO:0007829|PDB:7DUA"
FT HELIX 721..723
FT /evidence="ECO:0007829|PDB:7DUA"
FT STRAND 724..733
FT /evidence="ECO:0007829|PDB:7DUA"
FT STRAND 736..744
FT /evidence="ECO:0007829|PDB:7DUA"
FT HELIX 746..748
FT /evidence="ECO:0007829|PDB:6NEC"
FT STRAND 751..759
FT /evidence="ECO:0007829|PDB:7DUA"
FT HELIX 766..781
FT /evidence="ECO:0007829|PDB:7DUA"
FT STRAND 790..794
FT /evidence="ECO:0007829|PDB:7DUA"
FT STRAND 796..798
FT /evidence="ECO:0007829|PDB:7DUA"
FT STRAND 801..805
FT /evidence="ECO:0007829|PDB:7DUA"
FT HELIX 812..819
FT /evidence="ECO:0007829|PDB:7DUA"
FT STRAND 822..826
FT /evidence="ECO:0007829|PDB:7DUA"
FT STRAND 844..846
FT /evidence="ECO:0007829|PDB:6NJA"
FT HELIX 848..867
FT /evidence="ECO:0007829|PDB:7DUA"
FT HELIX 877..879
FT /evidence="ECO:0007829|PDB:7DUA"
FT STRAND 880..883
FT /evidence="ECO:0007829|PDB:7DUA"
FT HELIX 884..886
FT /evidence="ECO:0007829|PDB:7DUA"
FT STRAND 887..890
FT /evidence="ECO:0007829|PDB:7DUA"
FT HELIX 893..895
FT /evidence="ECO:0007829|PDB:7JU5"
FT TURN 900..902
FT /evidence="ECO:0007829|PDB:7DUA"
FT HELIX 915..917
FT /evidence="ECO:0007829|PDB:7DUA"
FT HELIX 920..925
FT /evidence="ECO:0007829|PDB:7DUA"
FT HELIX 930..945
FT /evidence="ECO:0007829|PDB:7DUA"
FT HELIX 957..959
FT /evidence="ECO:0007829|PDB:7DUA"
FT HELIX 960..965
FT /evidence="ECO:0007829|PDB:7DUA"
FT HELIX 978..987
FT /evidence="ECO:0007829|PDB:7DUA"
FT HELIX 992..994
FT /evidence="ECO:0007829|PDB:7DUA"
FT HELIX 998..1010
FT /evidence="ECO:0007829|PDB:7DUA"
SQ SEQUENCE 1114 AA; 124319 MW; A3DA0CE01A19A441 CRC64;
MAKATSGAAG LRLLLLLLLP LLGKVALGLY FSRDAYWEKL YVDQAAGTPL LYVHALRDAP
EEVPSFRLGQ HLYGTYRTRL HENNWICIQE DTGLLYLNRS LDHSSWEKLS VRNRGFPLLT
VYLKVFLSPT SLREGECQWP GCARVYFSFF NTSFPACSSL KPRELCFPET RPSFRIRENR
PPGTFHQFRL LPVQFLCPNI SVAYRLLEGE GLPFRCAPDS LEVSTRWALD REQREKYELV
AVCTVHAGAR EEVVMVPFPV TVYDEDDSAP TFPAGVDTAS AVVEFKRKED TVVATLRVFD
ADVVPASGEL VRRYTSTLLP GDTWAQQTFR VEHWPNETSV QANGSFVRAT VHDYRLVLNR
NLSISENRTM QLAVLVNDSD FQGPGAGVLL LHFNVSVLPV SLHLPSTYSL SVSRRARRFA
QIGKVCVENC QAFSGINVQY KLHSSGANCS TLGVVTSAED TSGILFVNDT KALRRPKCAE
LHYMVVATDQ QTSRQAQAQL LVTVEGSYVA EEAGCPLSCA VSKRRLECEE CGGLGSPTGR
CEWRQGDGKG ITRNFSTCSP STKTCPDGHC DVVETQDINI CPQDCLRGSI VGGHEPGEPR
GIKAGYGTCN CFPEEEKCFC EPEDIQDPLC DELCRTVIAA AVLFSFIVSV LLSAFCIHCY
HKFAHKPPIS SAEMTFRRPA QAFPVSYSSS GARRPSLDSM ENQVSVDAFK ILEDPKWEFP
RKNLVLGKTL GEGEFGKVVK ATAFHLKGRA GYTTVAVKML KENASPSELR DLLSEFNVLK
QVNHPHVIKL YGACSQDGPL LLIVEYAKYG SLRGFLRESR KVGPGYLGSG GSRNSSSLDH
PDERALTMGD LISFAWQISQ GMQYLAEMKL VHRDLAARNI LVAEGRKMKI SDFGLSRDVY
EEDSYVKRSQ GRIPVKWMAI ESLFDHIYTT QSDVWSFGVL LWEIVTLGGN PYPGIPPERL
FNLLKTGHRM ERPDNCSEEM YRLMLQCWKQ EPDKRPVFAD ISKDLEKMMV KRRDYLDLAA
STPSDSLIYD DGLSEEETPL VDCNNAPLPR ALPSTWIENK LYGMSDPNWP GESPVPLTRA
DGTNTGFPRY PNDSVYANWM LSPSAAKLMD TFDS
