ID RET_MOUSE Reviewed; 1115 AA. AC P35546; Q8BQ34; Q9QXH9; DT 01-JUN-1994, integrated into UniProtKB/Swiss-Prot. DT 16-AUG-2004, sequence version 2. DT 02-OCT-2024, entry version 211. DE RecName: Full=Proto-oncogene tyrosine-protein kinase receptor Ret; DE EC=2.7.10.1; 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; OS Mus musculus (Mouse). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae; OC Murinae; Mus; Mus. OX NCBI_TaxID=10090; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). RX PubMed=8455936; RA Iwamoto T., Taniguchi M., Asai N., Ohkusu K., Nakashima I., Takahashi M.; RT "cDNA cloning of mouse ret proto-oncogene and its sequence similarity to RT the cadherin superfamily."; RL Oncogene 8:1087-1091(1993). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). RA Phua C.Y.D., Too H.P.; RT "Molecular characterization of mouse neuro-2a c-ret proto-oncogene."; RL Submitted (NOV-1999) to the EMBL/GenBank/DDBJ databases. RN [3] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2). RC STRAIN=BALB/cJ; RA Wang Y.-Z., Yoong L.-F., Too H.-P.; RL Submitted (JUN-2003) to the EMBL/GenBank/DDBJ databases. RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2). RC STRAIN=C57BL/6J; TISSUE=Spinal ganglion; RX PubMed=16141072; DOI=10.1126/science.1112014; RA Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N., RA Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K., RA Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J., RA Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R., RA Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T., RA Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A., RA Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B., RA Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M., RA Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S., RA Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E., RA Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D., RA Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M., RA Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H., RA Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V., RA Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S., RA Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H., RA Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N., RA Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F., RA Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G., RA Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z., RA Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C., RA Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y., RA Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S., RA Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K., RA Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R., RA van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H., RA Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M., RA Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C., RA Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S., RA Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K., RA Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M., RA Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C., RA Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A., RA Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.; RT "The transcriptional landscape of the mammalian genome."; RL Science 309:1559-1563(2005). RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2). RC STRAIN=C57BL/6J; 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 [6] RP INTERACTION WITH GRB7 AND PLCG1. RX PubMed=8631863; DOI=10.1074/jbc.271.18.10607; RA Pandey A., Liu X., Dixon J.E., Di Fiore P.P., Dixit V.M.; RT "Direct association between the Ret receptor tyrosine kinase and the Src RT homology 2-containing adapter protein Grb7."; RL J. Biol. Chem. 271:10607-10610(1996). RN [7] RP INTERACTION WITH DOK2; DOK4 AND DOK5, PHOSPHORYLATION, AND MUTAGENESIS OF RP TYR-1063. RX PubMed=11470823; DOI=10.1083/jcb.200102032; RA Grimm J., Sachs M., Britsch S., Di Cesare S., Schwarz-Romond T., RA Alitalo K., Birchmeier W.; RT "Novel p62dok family members, dok-4 and dok-5, are substrates of the c-Ret RT receptor tyrosine kinase and mediate neuronal differentiation."; RL J. Cell Biol. 154:345-354(2001). RN [8] RP FUNCTION. RX PubMed=15242795; DOI=10.1016/j.ydbio.2004.04.025; RA Yan H., Bergner A.J., Enomoto H., Milbrandt J., Newgreen D.F., Young H.M.; RT "Neural cells in the esophagus respond to glial cell line-derived RT neurotrophic factor and neurturin, and are RET-dependent."; RL Dev. Biol. 272:118-133(2004). RN [9] RP FUNCTION IN PEYER'S PATCH ORGANOGENESIS. RX PubMed=17322904; DOI=10.1038/nature05597; RA Veiga-Fernandes H., Coles M.C., Foster K.E., Patel A., Williams A., RA Natarajan D., Barlow A., Pachnis V., Kioussis D.; RT "Tyrosine kinase receptor RET is a key regulator of Peyer's patch RT organogenesis."; RL Nature 446:547-551(2007). RN [10] RP INTERACTION WITH CD2AP AND CBLC, AND TISSUE SPECIFICITY. 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 [11] RP FUNCTION IN NOCICEPTORS REGULATION, AND DISRUPTION PHENOTYPE. RX PubMed=20237269; DOI=10.1523/jneurosci.5930-09.2010; RA Golden J.P., Hoshi M., Nassar M.A., Enomoto H., Wood J.N., Milbrandt J., RA Gereau R.W. IV, Johnson E.M. Jr., Jain S.; RT "RET signaling is required for survival and normal function of RT nonpeptidergic nociceptors."; RL J. Neurosci. 30:3983-3994(2010). RN [12] 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 [13] RP TISSUE SPECIFICITY. 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 [14] 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 [15] RP FUNCTION, AND INTERACTION WITH GFRAL. 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 [16] RP X-RAY CRYSTALLOGRAPHY (2.50 ANGSTROMS) OF 1055-1067, AND PHOSPHORYLATION AT RP TYR-1063. RX PubMed=14607833; DOI=10.1074/jbc.m311030200; RA Shi N., Ye S., Bartlam M., Yang M., Wu J., Liu Y., Sun F., Han X., Peng X., RA Qiang B., Yuan J., Rao Z.; RT "Structural basis for the specific recognition of RET by the Dok1 RT phosphotyrosine binding domain."; RL J. Biol. Chem. 279:4962-4969(2004). CC -!- FUNCTION: Receptor tyrosine-protein kinase involved in numerous CC cellular mechanisms including cell proliferation, neuronal navigation, CC cell migration, and cell differentiation in response to glia cell line- CC derived growth family factors (GDNF, NRTN, ARTN, PSPN and GDF15) CC (PubMed:17322904, PubMed:20237269, PubMed:28846099). In contrast to CC most receptor tyrosine kinases, RET requires not only its cognate CC ligands but also coreceptors, for activation (PubMed:17322904, CC PubMed:20237269, PubMed:28846099). GDNF ligands (GDNF, NRTN, ARTN, PSPN CC and GDF15) first bind their corresponding GDNFR coreceptors (GFRA1, CC GFRA2, GFRA3, GFRA4 and GFRAL, respectively), triggering RET CC autophosphorylation and activation, leading to activation of downstream CC signaling pathways, including the MAPK- and AKT-signaling pathways CC (PubMed:17322904, PubMed:28846099). Acts as a dependence receptor via CC the GDNF-GFRA1 signaling: in the presence of the ligand GDNF in CC somatotrophs within pituitary, promotes survival and down regulates CC growth hormone (GH) production, but triggers apoptosis in absence of CC GDNF (PubMed:20237269). Required for the molecular mechanisms CC orchestration during intestine organogenesis via the ARTN-GFRA3 CC signaling: involved in the development of enteric nervous system and CC renal organogenesis during embryonic life, and promotes the formation CC of Peyer's patch-like structures, a major component of the gut- CC associated lymphoid tissue (PubMed:17322904). Mediates, through CC interaction with GDF15-receptor GFRAL, GDF15-induced cell-signaling in CC the brainstem which triggers an aversive response, characterized by CC nausea, vomiting, and/or loss of appetite in response to various CC stresses (PubMed:28846099). Modulates cell adhesion via its cleavage by CC caspase in sympathetic neurons and mediates cell migration in an CC integrin (e.g. ITGB1 and ITGB3)-dependent manner (By similarity). Also CC active in the absence of ligand, triggering apoptosis through a CC mechanism that requires receptor intracellular caspase cleavage (By CC similarity). Triggers the differentiation of rapidly adapting (RA) CC mechanoreceptors (By similarity). Involved in the development of the CC neural crest (PubMed:15242795). Regulates nociceptor survival and size CC (PubMed:20237269). Phosphorylates PTK2/FAK1 (By similarity). CC {ECO:0000250|UniProtKB:P07949, ECO:0000269|PubMed:15242795, CC ECO:0000269|PubMed:17322904, ECO:0000269|PubMed:20237269, CC ECO:0000269|PubMed:28846099}. 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 -!- COFACTOR: CC Name=Ca(2+); Xref=ChEBI:CHEBI:29108; CC Evidence={ECO:0000250|UniProtKB:P07949}; CC -!- ACTIVITY REGULATION: Repressed by withaferin A (WA). CC {ECO:0000269|PubMed:21134556}. CC -!- SUBUNIT: Phosphorylated form interacts with the PBT domain of DOK2, CC DOK4 and DOK5 (PubMed:11470823). The phosphorylated form interacts with CC PLCG1 and GRB7 (PubMed:8631863). Interacts (not phosphorylated) with CC PTK2/FAK1 (via FERM domain) (By similarity). 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 (By similarity). Interacts with AIP in the pituitary gland; this CC interaction prevents the formation of the AIP-survivin complex (By CC similarity). Interacts (inactive) with CBLC and CD2AP; dissociates upon CC activation by GDNF which increases CBLC:CD2AP interaction CC (PubMed:18753381). {ECO:0000250|UniProtKB:P07949, CC ECO:0000269|PubMed:11470823, ECO:0000269|PubMed:18753381, CC ECO:0000269|PubMed:8631863}. CC -!- INTERACTION: CC P35546; P97785: Gfra1; NbExp=2; IntAct=EBI-2480800, EBI-5549349; CC P35546-2; Q60629: Epha5; NbExp=5; IntAct=EBI-5548911, EBI-1267609; CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000250|UniProtKB:P07949}; CC Single-pass type I membrane protein. Endosome membrane CC {ECO:0000250|UniProtKB:P07949}; Single-pass type I membrane protein CC {ECO:0000250|UniProtKB:P07949}. Note=Predominantly located on the CC plasma membrane. In the presence of SORL1 and GFRA1, directed to CC endosomes. {ECO:0000250|UniProtKB:P07949}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=2; CC Name=1; Synonyms=Ret51; CC IsoId=P35546-1; Sequence=Displayed; CC Name=2; Synonyms=Ret9; CC IsoId=P35546-2; Sequence=VSP_011304; CC -!- TISSUE SPECIFICITY: Expressed in peripheral nerve cells, hematopoietic CC cells and podocytes (PubMed:18753381). Expressed in the brainstem, CC restricted to cells in the area postrema and the immediately adjacent CC region of the nucleus tractus solitarius (PubMed:28953886). CC {ECO:0000269|PubMed:18753381, ECO:0000269|PubMed:28953886}. CC -!- PTM: Autophosphorylated on C-terminal tyrosine residues upon ligand CC stimulation. {ECO:0000250|UniProtKB:P07949}. 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 (By similarity). {ECO:0000250|UniProtKB:P07949}. CC -!- DISRUPTION PHENOTYPE: Exclusive loss in nociceptors results in a CC reduction in nociceptor number and size with a reduced epidermal CC innervation, but increased sensitivity to cold and increased formalin- CC induced pain. {ECO:0000269|PubMed:20237269}. 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 --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; X67812; CAA48013.1; -; mRNA. DR EMBL; AF209436; AAF21033.1; -; mRNA. DR EMBL; AY326397; AAP88379.1; -; mRNA. DR EMBL; AK051633; BAC34699.1; -; mRNA. DR EMBL; BC059012; AAH59012.1; -; mRNA. DR CCDS; CCDS20470.1; -. [P35546-1] DR CCDS; CCDS39608.1; -. [P35546-2] DR PIR; I48735; S29926. DR RefSeq; NP_001074249.1; NM_001080780.1. [P35546-2] DR RefSeq; NP_033076.2; NM_009050.2. [P35546-1] DR PDB; 1UEF; X-ray; 2.50 A; C/D=1055-1067. DR PDBsum; 1UEF; -. DR AlphaFoldDB; P35546; -. DR SMR; P35546; -. DR BioGRID; 202865; 23. DR CORUM; P35546; -. DR ELM; P35546; -. DR IntAct; P35546; 12. DR MINT; P35546; -. DR STRING; 10090.ENSMUSP00000032201; -. DR BindingDB; P35546; -. DR ChEMBL; CHEMBL2034799; -. DR GlyCosmos; P35546; 12 sites, No reported glycans. DR GlyGen; P35546; 13 sites, 1 O-linked glycan (1 site). DR iPTMnet; P35546; -. DR PhosphoSitePlus; P35546; -. DR PaxDb; 10090-ENSMUSP00000032201; -. DR ProteomicsDB; 253117; -. [P35546-1] DR ProteomicsDB; 253118; -. [P35546-2] DR Antibodypedia; 1904; 1392 antibodies from 41 providers. DR DNASU; 19713; -. DR Ensembl; ENSMUST00000032201.8; ENSMUSP00000032201.6; ENSMUSG00000030110.14. [P35546-1] DR Ensembl; ENSMUST00000088790.9; ENSMUSP00000086169.4; ENSMUSG00000030110.14. [P35546-2] DR GeneID; 19713; -. DR KEGG; mmu:19713; -. DR UCSC; uc009dlm.1; mouse. [P35546-1] DR UCSC; uc009dln.1; mouse. [P35546-2] DR AGR; MGI:97902; -. DR CTD; 5979; -. DR MGI; MGI:97902; Ret. DR VEuPathDB; HostDB:ENSMUSG00000030110; -. DR eggNOG; KOG0200; Eukaryota. DR GeneTree; ENSGT00940000158499; -. DR HOGENOM; CLU_009530_0_0_1; -. DR InParanoid; P35546; -. DR OMA; CDVVENQ; -. DR OrthoDB; 1614410at2759; -. DR PhylomeDB; P35546; -. DR TreeFam; TF317640; -. DR BRENDA; 2.7.10.1; 3474. DR Reactome; R-MMU-5673001; RAF/MAP kinase cascade. DR Reactome; R-MMU-8853659; RET signaling. DR BioGRID-ORCS; 19713; 3 hits in 80 CRISPR screens. DR ChiTaRS; Ret; mouse. DR EvolutionaryTrace; P35546; -. DR PRO; PR:P35546; -. DR Proteomes; UP000000589; Chromosome 6. DR RNAct; P35546; protein. DR Bgee; ENSMUSG00000030110; Expressed in ventral tegmental area and 207 other cell types or tissues. DR GO; GO:0030424; C:axon; ISO:MGI. DR GO; GO:0030425; C:dendrite; ISO:MGI. DR GO; GO:0005769; C:early endosome; ISO:MGI. DR GO; GO:0010008; C:endosome membrane; IEA:UniProtKB-SubCell. DR GO; GO:0043025; C:neuronal cell body; ISO:MGI. DR GO; GO:0005886; C:plasma membrane; ISS:UniProtKB. DR GO; GO:0098797; C:plasma membrane protein complex; IEA:Ensembl. DR GO; GO:0043235; C:receptor complex; ISO:MGI. DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW. DR GO; GO:0005509; F:calcium ion binding; IEA:Ensembl. DR GO; GO:0004714; F:transmembrane receptor protein tyrosine kinase activity; IDA:UniProtKB. DR GO; GO:0009653; P:anatomical structure morphogenesis; TAS:MGI. DR GO; GO:0007169; P:cell surface receptor protein tyrosine kinase signaling pathway; IGI:MGI. DR GO; GO:0071300; P:cellular response to retinoic acid; IEA:Ensembl. DR GO; GO:0001838; P:embryonic epithelial tube formation; IGI:MGI. DR GO; GO:0048484; P:enteric nervous system development; IMP:MGI. DR GO; GO:0035860; P:glial cell-derived neurotrophic factor receptor signaling pathway; ISS:UniProtKB. DR GO; GO:0007156; P:homophilic cell adhesion via plasma membrane adhesion molecules; IEA:InterPro. DR GO; GO:0060384; P:innervation; ISO:MGI. DR GO; GO:0000165; P:MAPK cascade; IGI:MGI. DR GO; GO:0033619; P:membrane protein proteolysis; IEA:Ensembl. DR GO; GO:0007399; P:nervous system development; IMP:MGI. DR GO; GO:0001755; P:neural crest cell migration; IMP:MGI. DR GO; GO:0007158; P:neuron cell-cell adhesion; IDA:UniProtKB. DR GO; GO:0030182; P:neuron differentiation; IMP:MGI. DR GO; GO:0042551; P:neuron maturation; IMP:MGI. DR GO; GO:0061146; P:Peyer's patch morphogenesis; IMP:UniProtKB. DR GO; GO:0033630; P:positive regulation of cell adhesion mediated by integrin; IEA:Ensembl. DR GO; GO:0030335; P:positive regulation of cell migration; IEA:Ensembl. DR GO; GO:0045793; P:positive regulation of cell size; IMP:MGI. DR GO; GO:0045893; P:positive regulation of DNA-templated transcription; IMP:UniProtKB. DR GO; GO:0010628; P:positive regulation of gene expression; IMP:MGI. DR GO; GO:0043410; P:positive regulation of MAPK cascade; ISS:UniProtKB. DR GO; GO:0072300; P:positive regulation of metanephric glomerulus development; IMP:UniProtKB. DR GO; GO:0014042; P:positive regulation of neuron maturation; ISO:MGI. DR GO; GO:0010976; P:positive regulation of neuron projection development; IEA:Ensembl. DR GO; GO:0033141; P:positive regulation of peptidyl-serine phosphorylation of STAT protein; IMP:MGI. DR GO; GO:0051897; P:positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction; ISS:UniProtKB. DR GO; GO:0050770; P:regulation of axonogenesis; IMP:MGI. DR GO; GO:0048265; P:response to pain; IMP: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:0035799; P:ureter maturation; IMP:MGI. DR GO; GO:0001657; P:ureteric bud development; IMP:MGI. DR CDD; cd11304; Cadherin_repeat; 2. DR CDD; cd05045; PTKc_RET; 1. DR Gene3D; 2.60.40.60; Cadherins; 2. DR Gene3D; 1.10.510.10; Transferase(Phosphotransferase) domain 1; 1. DR IDEAL; IID50274; -. 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; IPR050122; RTK. 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 PANTHER; PTHR24416:SF485; PROTO-ONCOGENE TYROSINE-PROTEIN KINASE RECEPTOR RET; 1. DR PANTHER; PTHR24416; TYROSINE-PROTEIN KINASE RECEPTOR; 1. 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 Pfam; PF22540; RET_CRD; 1. DR PIRSF; PIRSF000631; TyrPK_receptor_Ret; 1. DR PRINTS; PR00109; TYRKINASE. DR SMART; SM00219; TyrKc; 1. DR SUPFAM; SSF49313; Cadherin-like; 1. DR SUPFAM; SSF56112; Protein kinase-like (PK-like); 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; Calcium; Cell adhesion; KW Cell membrane; Disulfide bond; Endosome; Glycoprotein; Kinase; Membrane; KW Metal-binding; Nucleotide-binding; Phosphoprotein; Proto-oncogene; KW Receptor; Reference proteome; Signal; Transferase; Transmembrane; KW Transmembrane helix; Tyrosine-protein kinase. FT SIGNAL 1..28 FT /evidence="ECO:0000255" FT CHAIN 29..1115 FT /note="Proto-oncogene tyrosine-protein kinase receptor Ret" FT /id="PRO_0000024451" FT CHAIN 29..708 FT /note="Extracellular cell-membrane anchored RET cadherin FT 120 kDa fragment" FT /evidence="ECO:0000250|UniProtKB:P07949" FT /id="PRO_0000415294" FT CHAIN 709..1018 FT /note="Soluble RET kinase fragment" FT /evidence="ECO:0000250|UniProtKB:P07949" FT /id="PRO_0000415295" FT TOPO_DOM 29..637 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 638..659 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 660..1115 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT DOMAIN 168..273 FT /note="Cadherin" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00043" FT DOMAIN 725..1017 FT /note="Protein kinase" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159" FT REGION 29..153 FT /note="Cadherin-like region 1 (CLD1)" FT /evidence="ECO:0000250|UniProtKB:P07949" FT REGION 266..380 FT /note="Cadherin-like region 3 (CLD3)" FT /evidence="ECO:0000250|UniProtKB:P07949" FT REGION 407..508 FT /note="Cadherin-like region 4 (CLD4)" FT /evidence="ECO:0000250|UniProtKB:P07949" FT ACT_SITE 875 FT /note="Proton acceptor" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159, FT ECO:0000255|PROSITE-ProRule:PRU10028" FT BINDING 178 FT /ligand="Ca(2+)" FT /ligand_id="ChEBI:CHEBI:29108" FT /ligand_label="1" FT /evidence="ECO:0000250|UniProtKB:P07949" FT BINDING 179 FT /ligand="Ca(2+)" FT /ligand_id="ChEBI:CHEBI:29108" FT /ligand_label="1" FT /evidence="ECO:0000250|UniProtKB:P07949" FT BINDING 230 FT /ligand="Ca(2+)" FT /ligand_id="ChEBI:CHEBI:29108" FT /ligand_label="1" FT /evidence="ECO:0000250|UniProtKB:P07949" FT BINDING 232 FT /ligand="Ca(2+)" FT /ligand_id="ChEBI:CHEBI:29108" FT /ligand_label="1" FT /evidence="ECO:0000250|UniProtKB:P07949" FT BINDING 232 FT /ligand="Ca(2+)" FT /ligand_id="ChEBI:CHEBI:29108" FT /ligand_label="2" FT /evidence="ECO:0000250|UniProtKB:P07949" FT BINDING 265 FT /ligand="Ca(2+)" FT /ligand_id="ChEBI:CHEBI:29108" FT /ligand_label="2" FT /evidence="ECO:0000250|UniProtKB:P07949" FT BINDING 266 FT /ligand="Ca(2+)" FT /ligand_id="ChEBI:CHEBI:29108" FT /ligand_label="2" FT /evidence="ECO:0000250|UniProtKB:P07949" FT BINDING 267 FT /ligand="Ca(2+)" FT /ligand_id="ChEBI:CHEBI:29108" FT /ligand_label="3" FT /evidence="ECO:0000250|UniProtKB:P07949" FT BINDING 268 FT /ligand="Ca(2+)" FT /ligand_id="ChEBI:CHEBI:29108" FT /ligand_label="2" FT /evidence="ECO:0000250|UniProtKB:P07949" FT BINDING 268 FT /ligand="Ca(2+)" FT /ligand_id="ChEBI:CHEBI:29108" FT /ligand_label="4" FT /evidence="ECO:0000250|UniProtKB:P07949" FT BINDING 269 FT /ligand="Ca(2+)" FT /ligand_id="ChEBI:CHEBI:29108" FT /ligand_label="3" FT /evidence="ECO:0000250|UniProtKB:P07949" FT BINDING 301 FT /ligand="Ca(2+)" FT /ligand_id="ChEBI:CHEBI:29108" FT /ligand_label="3" FT /evidence="ECO:0000250|UniProtKB:P07949" FT BINDING 303 FT /ligand="Ca(2+)" FT /ligand_id="ChEBI:CHEBI:29108" FT /ligand_label="2" FT /evidence="ECO:0000250|UniProtKB:P07949" FT BINDING 303 FT /ligand="Ca(2+)" FT /ligand_id="ChEBI:CHEBI:29108" FT /ligand_label="3" FT /evidence="ECO:0000250|UniProtKB:P07949" FT BINDING 379 FT /ligand="Ca(2+)" FT /ligand_id="ChEBI:CHEBI:29108" FT /ligand_label="3" FT /evidence="ECO:0000250|UniProtKB:P07949" FT BINDING 566 FT /ligand="Ca(2+)" FT /ligand_id="ChEBI:CHEBI:29108" FT /ligand_label="4" FT /evidence="ECO:0000250|UniProtKB:P07949" FT BINDING 567 FT /ligand="Ca(2+)" FT /ligand_id="ChEBI:CHEBI:29108" FT /ligand_label="4" FT /evidence="ECO:0000250|UniProtKB:P07949" FT BINDING 569 FT /ligand="Ca(2+)" FT /ligand_id="ChEBI:CHEBI:29108" FT /ligand_label="4" FT /evidence="ECO:0000250|UniProtKB:P07949" FT BINDING 571 FT /ligand="Ca(2+)" FT /ligand_id="ChEBI:CHEBI:29108" FT /ligand_label="4" FT /evidence="ECO:0000250|UniProtKB:P07949" FT BINDING 576 FT /ligand="Ca(2+)" FT /ligand_id="ChEBI:CHEBI:29108" FT /ligand_label="4" FT /evidence="ECO:0000250|UniProtKB:P07949" FT BINDING 586 FT /ligand="Ca(2+)" FT /ligand_id="ChEBI:CHEBI:29108" FT /ligand_label="4" FT /evidence="ECO:0000250|UniProtKB:P07949" FT BINDING 731..739 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159" FT BINDING 759 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159" FT SITE 708..709 FT /note="Cleavage; by caspase-3" FT /evidence="ECO:0000250|UniProtKB:P07949" FT SITE 1018..1019 FT /note="Cleavage; by caspase-3" FT /evidence="ECO:0000250|UniProtKB:P07949" FT MOD_RES 688 FT /note="Phosphotyrosine; by autocatalysis" FT /evidence="ECO:0000250|UniProtKB:P07949" FT MOD_RES 697 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:P07949" FT MOD_RES 807 FT /note="Phosphotyrosine; by autocatalysis" FT /evidence="ECO:0000250|UniProtKB:P07949" FT MOD_RES 810 FT /note="Phosphotyrosine; by autocatalysis" FT /evidence="ECO:0000250|UniProtKB:P07949" FT MOD_RES 827 FT /note="Phosphotyrosine; by autocatalysis" FT /evidence="ECO:0000250|UniProtKB:P07949" FT MOD_RES 901 FT /note="Phosphotyrosine; by autocatalysis" FT /evidence="ECO:0000250|UniProtKB:P07949" FT MOD_RES 906 FT /note="Phosphotyrosine; by autocatalysis" FT /evidence="ECO:0000250|UniProtKB:P07949" FT MOD_RES 982 FT /note="Phosphotyrosine; by autocatalysis" FT /evidence="ECO:0000250|UniProtKB:P07949" FT MOD_RES 1016 FT /note="Phosphotyrosine; by autocatalysis" FT /evidence="ECO:0000250|UniProtKB:P07949" FT MOD_RES 1030 FT /note="Phosphotyrosine; by autocatalysis" FT /evidence="ECO:0000250|UniProtKB:P07949" FT MOD_RES 1063 FT /note="Phosphotyrosine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:14607833" FT MOD_RES 1091 FT /note="Phosphotyrosine; by autocatalysis" FT /evidence="ECO:0000250|UniProtKB:P07949" FT MOD_RES 1097 FT /note="Phosphotyrosine; by autocatalysis" FT /evidence="ECO:0000250|UniProtKB:P07949" FT CARBOHYD 89 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" 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:0000250" FT CARBOHYD 156 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 199 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 345 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 360 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 378 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 396 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 450 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 470 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 556 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 689 FT /note="O-linked (GlcNAc) serine" FT /evidence="ECO:0000250|UniProtKB:P07949" FT DISULFID 137..142 FT /evidence="ECO:0000250|UniProtKB:P07949" FT DISULFID 157..197 FT /evidence="ECO:0000250|UniProtKB:P07949" FT DISULFID 166..243 FT /evidence="ECO:0000250|UniProtKB:P07949" FT VAR_SEQ 1065..1115 FT /note="MSDPNWPGESPVPLTRADGTSTGFPRYANDSVYANWMVSPSAAKLMDTFDS FT -> RISHAFTRF (in isoform 2)" FT /evidence="ECO:0000303|PubMed:15489334, FT ECO:0000303|PubMed:16141072, ECO:0000303|Ref.3" FT /id="VSP_011304" FT MUTAGEN 1063 FT /note="Y->F: Abolishes interaction with DOK proteins." FT /evidence="ECO:0000269|PubMed:11470823" FT CONFLICT 174 FT /note="F -> S (in Ref. 1; CAA48013)" FT /evidence="ECO:0000305" FT STRAND 1057..1059 FT /evidence="ECO:0007829|PDB:1UEF" FT TURN 1061..1064 FT /evidence="ECO:0007829|PDB:1UEF" SQ SEQUENCE 1115 AA; 123874 MW; A5CF1EF45A640413 CRC64; MAKATSGAAG LGLKLILLLP LLGEAPLGLY FSRDAYWERL YVDQPAGTPL LYVHALRDAP GEVPSFRLGQ HLYGVYRTRL HENDWIRINE TTGLLYLNQS LDHSSWEQLS IRNGGFPLLT IFLQVFLGST AQREGECHWP GCTRVYFSFI NDTFPNCSSF KAQDLCIPET AVSFRVRENR PPGTFYHFHM LPVQFLCPNI SVKYSLLGGD SLPFRCDPDC LEVSTRWALD RELREKYVLE ALCIVAGPGA NKETVTLSFP VTVYDEDDSA PTFSGGVGTA SAVVEFKRKE GTVVATLQVF DADVVPASGE LVRRYTNTLL SGDSWAQQTF RVEHSPIETL VQVNNNSVRA TMHNYKLILN RSLSISESRV LQLAVLVNDS DFQGPGAGGI LVLHFNVSVL PVTLNLPRAY SFPVNKRARR YAQIGKVCVE NCQEFSGVSI QYKLQPSSIN CTALGVVTSP EDTSGTLFVN DTEALRRPEC TKLQYTVVAT DRQTRRQTQA SLVVTVEGTS ITEEVGCPKS CAVNKRRPEC EECGGLGSPT GRCEWRQGDG KGITRNFSTC SPSTRTCPDG HCDAVESRDA NICPQDCLRA DIVGGHERGE RQGIKAGYGI CNCFPDEKKC FCEPEDSQGP LCDALCRTII TAALFSLIIS ILLSIFCVCH HHKHGHKPPI ASAEMTFCRP AQGFPISYSS SGTRRPSLDS TENQVPVDSF KIPEDPKWEF PRKNLVLGKT LGEGEFGKVV KATAFRLKGR AGYTTVAVKM LKENASQSEL RDLLSEFNLL KQVNHPHVIK LYGACSQDGP LLLIVEYAKY GSLRGFLRDS RKIGPAYVSG GGSRNSSSLD HPDERVLTMG DLISFAWQIS RGMQYLAEMK LVHRDLAARN ILVAEGRKMK ISDFGLSRDV YEEDSYVKKS KGRIPVKWMA IESLFDHIYT TQSDVWSFGV LLWEIVTLGG NPYPGIPPER LFNLLKTGHR MERPDNCSEE MYRLMLQCWK QEPDKRPVFA DISKDLEKMM VKSRDYLDLA ASTPSDSLLY DDGLSEEETP LVDCNNAPLP RSLPSTWIEN KLYGMSDPNW PGESPVPLTR ADGTSTGFPR YANDSVYANW MVSPSAAKLM DTFDS //