ID EPOR_HUMAN Reviewed; 508 AA. AC P19235; B2RCG4; Q15443; Q2M205; DT 01-NOV-1990, integrated into UniProtKB/Swiss-Prot. DT 01-NOV-1990, sequence version 1. DT 24-JAN-2024, entry version 245. DE RecName: Full=Erythropoietin receptor; DE Short=EPO-R; DE Flags: Precursor; GN Name=EPOR; 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 [GENOMIC DNA]. RX PubMed=2163695; RA Winkelmann J.C., Penny L.A., Deaven L.L., Forget B.G., Jenkins R.B.; RT "The gene for the human erythropoietin receptor: analysis of the coding RT sequence and assignment to chromosome 19p."; RL Blood 76:24-30(1990). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM EPOR-F). RC TISSUE=Erythroleukemia, and Fetal liver; RX PubMed=2163696; RA Jones S.S., D'Andrea A.D., Haines L.L., Wong G.G.; RT "Human erythropoietin receptor: cloning, expression, and biologic RT characterization."; RL Blood 76:31-35(1990). RN [3] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RC TISSUE=Placenta; RX PubMed=1668606; RA Noguchi C.T., Bae K.S., Chin K., Wada Y., Schechter A.N., Hankins W.D.; RT "Cloning of the human erythropoietin receptor gene."; RL Blood 78:2548-2556(1991). RN [4] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM EPOR-F). RC TISSUE=Erythroleukemia; RX PubMed=1654273; RA Ehrenman K., St John T.; RT "The erythropoietin receptor gene: cloning and identification of multiple RT transcripts in an erythroid cell line OCIM1."; RL Exp. Hematol. 19:973-977(1991). RN [5] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS EPOR-F; EPOR-S AND EPOR-T). RC TISSUE=Bone marrow, and Megakaryoblast; RX PubMed=1324524; DOI=10.1126/science.257.5073.1138; RA Nakamura Y., Komatsu N., Nakauchi H.; RT "A truncated erythropoietin receptor that fails to prevent programmed cell RT death of erythroid cells."; RL Science 257:1138-1141(1992). RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM EPOR-F). RC TISSUE=Caudate nucleus; 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 [7] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases. RN [8] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM EPOR-F). 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 [9] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-96. RC TISSUE=Placenta; RX PubMed=1668607; RA Maouche L., Tournamille C., Hattab C., Boffa G., Cartron J.-P., RA Chretien S.; RT "Cloning of the gene encoding the human erythropoietin receptor."; RL Blood 78:2557-2563(1991). RN [10] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-17. RX PubMed=1664413; DOI=10.1016/0888-7543(91)90022-7; RA Penny L.A., Forget B.G.; RT "Genomic organization of the human erythropoietin receptor gene."; RL Genomics 11:974-980(1991). RN [11] RP PARTIAL NUCLEOTIDE SEQUENCE [MRNA] (EPOR-S). RC TISSUE=Erythroid cell; RX PubMed=1657727; DOI=10.1016/0378-1119(91)90213-u; RA Todokoro K., Kuramochi S., Nagasawa T., Abe T., Ikawa Y.; RT "Isolation of a cDNA encoding a potential soluble receptor for human RT erythropoietin."; RL Gene 106:283-284(1991). RN [12] RP STAT1/STAT3 ACTIVATION, AND MUTAGENESIS OF TYR-456 AND TYR-468. RX PubMed=11756159; DOI=10.1182/blood.v99.1.102; RA Kirito K., Nakajima K., Watanabe T., Uchida M., Tanaka M., Ozawa K., RA Komatsu N.; RT "Identification of the human erythropoietin receptor region required for RT Stat1 and Stat3 activation."; RL Blood 99:102-110(2002). RN [13] RP INTERACTION WITH PTPN11. RX PubMed=7534299; DOI=10.1074/jbc.270.10.5631; RA Tauchi T., Feng G.-S., Shen R., Hoatlin M., Bagby G.C. Jr., Kabat D., RA Lu L., Broxmeyer H.E.; RT "Involvement of SH2-containing phosphotyrosine phosphatase Syp in RT erythropoietin receptor signal transduction pathways."; RL J. Biol. Chem. 270:5631-5635(1995). RN [14] RP LIGAND-BINDING SITE, AND MUTAGENESIS OF THR-114; SER-115; SER-116; PHE-117; RP VAL-118; LEU-120; GLU-121; ARG-165; MET-174; SER-176; HIS-177 AND ARG-179. RX PubMed=8662939; DOI=10.1074/jbc.271.24.14045; RA Middleton S.A., Johnson D.L., Jin R., McMahon F.J., Collins A., Tullai J., RA Gruninger R.H., Jolliffe L.K., Mulcahy L.S.; RT "Identification of a critical ligand binding determinant of the human RT erythropoietin receptor. Evidence for common ligand binding motifs in the RT cytokine receptor family."; RL J. Biol. Chem. 271:14045-14054(1996). RN [15] RP SUBCELLULAR LOCATION (ISOFORM EPOR-S). RX PubMed=11722595; DOI=10.1034/j.1600-0609.2001.t01-1-00446.x; RA Motohashi T., Nakamura Y., Osawa M., Hiroyama T., Iwama A., Shibuya A., RA Nakauchi H.; RT "Increased cell surface expression of C-terminal truncated erythropoietin RT receptors in polycythemia."; RL Eur. J. Haematol. 67:88-93(2001). RN [16] RP INTERACTION WITH SOCS3, AND MUTAGENESIS OF TYR-454 AND TYR-456. RX PubMed=12027890; DOI=10.1046/j.1432-1033.2002.02916.x; RA Hoertner M., Nielsch U., Mayr L.M., Heinrich P.C., Haan S.; RT "A new high affinity binding site for suppressor of cytokine signaling-3 on RT the erythropoietin receptor."; RL Eur. J. Biochem. 269:2516-2526(2002). RN [17] RP INTERACTION WITH NOSIP. RX PubMed=12746455; DOI=10.1074/jbc.m210039200; RA Friedman A.D., Nimbalkar D., Quelle F.W.; RT "Erythropoietin receptors associate with a ubiquitin ligase, p33RUL, and RT require its activity for erythropoietin-induced proliferation."; RL J. Biol. Chem. 278:26851-26861(2003). RN [18] RP PHOSPHORYLATION, AND INTERACTION WITH SH2B2. RX PubMed=10374881; DOI=10.1038/sj.leu.2401397; RA Wakioka T., Sasaki A., Mitsui K., Yokouchi M., Inoue A., Komiya S., RA Yoshimura A.; RT "APS, an adaptor protein containing pleckstrin homology (PH) and Src RT homology-2 (SH2) domains inhibits the JAK-STAT pathway in collaboration RT with c-Cbl."; RL Leukemia 13:760-767(1999). RN [19] RP INTERACTION WITH ATXN2L. RX PubMed=11784712; DOI=10.1074/jbc.m105970200; RA Meunier C.F., Bordereaux D., Porteu F., Gisselbrecht S., Chretien S., RA Courtois G.; RT "Cloning and characterization of a family of proteins associated with RT Mpl."; RL J. Biol. Chem. 277:9139-9147(2002). RN [20] RP INTERACTION WITH RHEX. RX PubMed=25092874; DOI=10.1084/jem.20130624; RA Verma R., Su S., McCrann D.J., Green J.M., Leu K., Young P.R., Schatz P.J., RA Silva J.C., Stokes M.P., Wojchowski D.M.; RT "RHEX, a novel regulator of human erythroid progenitor cell expansion and RT erythroblast development."; RL J. Exp. Med. 211:1715-1722(2014). RN [21] RP X-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS) OF 34-244. RX PubMed=8662530; DOI=10.1126/science.273.5274.464; RA Livnah O., Stura E.A., Johnson D.L., Middleton S.A., Mulcahy L.S., RA Wrighton N.C., Dower W.J., Jolliffe L.K., Wilson I.A.; RT "Functional mimicry of a protein hormone by a peptide agonist: the EPO RT receptor complex at 2.8 A."; RL Science 273:464-471(1996). RN [22] RP X-RAY CRYSTALLOGRAPHY (2.7 ANGSTROMS) OF 34-244. RX PubMed=9808045; DOI=10.1038/2965; RA Livnah O., Johnson D.L., Stura E.A., Farrell F.X., Barbone F.P., You Y., RA Liu K.D., Goldsmith M.A., He W., Krause C.D., Pestka S., Jolliffe L.K., RA Wilson I.A.; RT "An antagonist peptide-EPO receptor complex suggests that receptor RT dimerization is not sufficient for activation."; RL Nat. Struct. Biol. 5:993-1004(1998). RN [23] RP X-RAY CRYSTALLOGRAPHY (1.9 ANGSTROMS) OF 32-244 IN COMPLEX WITH EPO. RX PubMed=9774108; DOI=10.1038/26773; RA Syed R.S., Reid S.W., Li C., Cheetham J.C., Aoki K.H., Liu B., Zhan H., RA Osslund T.D., Chirino A.J., Zhang J., Finer-Moore J., Elliott S., RA Sitney K., Katz B.A., Matthews D.J., Wendoloski J.J., Egrie J., RA Stroud R.M.; RT "Efficiency of signalling through cytokine receptors depends critically on RT receptor orientation."; RL Nature 395:511-516(1998). RN [24] RP X-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS) OF 22-249 IN COMPLEX WITH EPO. RX PubMed=10388848; DOI=10.1093/protein/12.6.505; RA Zhan H., Liu B., Reid S.W., Aoki K.H., Li C., Syed R.S., Karkaria C., RA Koe G., Sitney K., Hayenga K., Mistry F., Savel L., Dreyer M., Katz B.A., RA Schreurs J., Matthews D.J., Cheetham J.C., Egrie J., Giebel L.B., RA Stroud R.M.; RT "Engineering a soluble extracellular erythropoietin receptor (EPObp) in RT Pichia pastoris to eliminate microheterogeneity, and its complex with RT erythropoietin."; RL Protein Eng. 12:505-513(1999). RN [25] RP X-RAY CRYSTALLOGRAPHY (2.4 ANGSTROMS) OF 34-246. RX PubMed=9974392; DOI=10.1126/science.283.5404.987; RA Livnah O., Stura E.A., Middleton S.A., Johnson D.L., Jolliffe L.K., RA Wilson I.A.; RT "Crystallographic evidence for preformed dimers of erythropoietin receptor RT before ligand activation."; RL Science 283:987-990(1999). RN [26] RP INVOLVEMENT IN ECYT1. RX PubMed=8506290; DOI=10.1073/pnas.90.10.4495; RA de la Chapelle A., Traskelin A.-L., Juvonen E.; RT "Truncated erythropoietin receptor causes dominantly inherited benign human RT erythrocytosis."; RL Proc. Natl. Acad. Sci. U.S.A. 90:4495-4499(1993). RN [27] RP VARIANT SER-488. RX PubMed=8174675; RA Sokol L., Prchal J.F., D'Andrea A., Rado T.A., Prchal J.T.; RT "Mutation in the negative regulatory element of the erythropoietin receptor RT gene in a case of sporadic primary polycythemia."; RL Exp. Hematol. 22:447-453(1994). RN [28] RP VARIANT ECYT1 SER-487, AND VARIANT ERYTHROLEUKEMIA SER-487. RX PubMed=8608241; RA Le Couedic J.-P., Mitjavila M.-T., Villeval J.-L., Feger F., Gobert S., RA Mayeux P., Casadevall N., Vainchenker W.; RT "Missense mutation of the erythropoietin receptor is a rare event in human RT erythroid malignancies."; RL Blood 87:1502-1511(1996). RN [29] RP VARIANT SER-488. RX PubMed=27535533; DOI=10.1038/nature19057; RG Exome Aggregation Consortium; RA Lek M., Karczewski K.J., Minikel E.V., Samocha K.E., Banks E., Fennell T., RA O'Donnell-Luria A.H., Ware J.S., Hill A.J., Cummings B.B., Tukiainen T., RA Birnbaum D.P., Kosmicki J.A., Duncan L.E., Estrada K., Zhao F., Zou J., RA Pierce-Hoffman E., Berghout J., Cooper D.N., Deflaux N., DePristo M., RA Do R., Flannick J., Fromer M., Gauthier L., Goldstein J., Gupta N., RA Howrigan D., Kiezun A., Kurki M.I., Moonshine A.L., Natarajan P., RA Orozco L., Peloso G.M., Poplin R., Rivas M.A., Ruano-Rubio V., Rose S.A., RA Ruderfer D.M., Shakir K., Stenson P.D., Stevens C., Thomas B.P., Tiao G., RA Tusie-Luna M.T., Weisburd B., Won H.H., Yu D., Altshuler D.M., RA Ardissino D., Boehnke M., Danesh J., Donnelly S., Elosua R., Florez J.C., RA Gabriel S.B., Getz G., Glatt S.J., Hultman C.M., Kathiresan S., Laakso M., RA McCarroll S., McCarthy M.I., McGovern D., McPherson R., Neale B.M., RA Palotie A., Purcell S.M., Saleheen D., Scharf J.M., Sklar P., RA Sullivan P.F., Tuomilehto J., Tsuang M.T., Watkins H.C., Wilson J.G., RA Daly M.J., MacArthur D.G.; RT "Analysis of protein-coding genetic variation in 60,706 humans."; RL Nature 536:285-291(2016). CC -!- FUNCTION: Receptor for erythropoietin. Mediates erythropoietin-induced CC erythroblast proliferation and differentiation. Upon EPO stimulation, CC EPOR dimerizes triggering the JAK2/STAT5 signaling cascade. In some CC cell types, can also activate STAT1 and STAT3. May also activate the CC LYN tyrosine kinase. CC -!- FUNCTION: Isoform EPOR-T acts as a dominant-negative receptor of EPOR- CC mediated signaling. CC -!- SUBUNIT: Forms homodimers on EPO stimulation. The tyrosine- CC phosphorylated form interacts with several SH2 domain-containing CC proteins including LYN (By similarity), the adapter protein SH2B2, CC PTPN6 (By similarity), PTPN11, JAK2, PI3 kinases, STAT5A/B, SOCS3, CRKL CC (By similarity). Interacts with INPP5D/SHIP1 (By similarity). The N- CC terminal SH2 domain of PTPN6 binds Tyr-454 and inhibits signaling CC through dephosphorylation of JAK2 (By similarity). SH2B2 binding also CC inhibits the JAK-STAT signaling. Binding to PTPN11, preferentially CC through the N-terminal SH2 domain, promotes mitogenesis and CC phosphorylation of PTPN11 (By similarity). Binding of JAK2 (through its CC N-terminal) promotes cell-surface expression (By similarity). Interacts CC with RHEX; this interaction occurs in a erythropoietin (EPO)-dependent CC manner (PubMed:25092874). Interaction with the ubiquitin ligase NOSIP CC mediates EPO-induced cell proliferation. Interacts with ATXN2L. CC {ECO:0000250, ECO:0000269|PubMed:10374881, ECO:0000269|PubMed:10388848, CC ECO:0000269|PubMed:11784712, ECO:0000269|PubMed:12027890, CC ECO:0000269|PubMed:12746455, ECO:0000269|PubMed:25092874, CC ECO:0000269|PubMed:7534299, ECO:0000269|PubMed:9774108}. CC -!- INTERACTION: CC P19235; Q8WWM7: ATXN2L; NbExp=2; IntAct=EBI-617321, EBI-948363; CC P19235; P01588: EPO; NbExp=3; IntAct=EBI-617321, EBI-1027362; CC P19235; PRO_0000008401 [P01588]: EPO; NbExp=2; IntAct=EBI-617321, EBI-11508463; CC P19235; P19235: EPOR; NbExp=3; IntAct=EBI-617321, EBI-617321; CC P19235; P16885: PLCG2; NbExp=3; IntAct=EBI-617321, EBI-617403; CC P19235; P18031: PTPN1; NbExp=3; IntAct=EBI-617321, EBI-968788; CC P19235; P29350: PTPN6; NbExp=11; IntAct=EBI-617321, EBI-78260; CC P19235; O14508: SOCS2; NbExp=3; IntAct=EBI-617321, EBI-617737; CC P19235; Q62225: Cish; Xeno; NbExp=4; IntAct=EBI-617321, EBI-617489; CC -!- SUBCELLULAR LOCATION: Cell membrane; Single-pass type I membrane CC protein. CC -!- SUBCELLULAR LOCATION: [Isoform EPOR-S]: Secreted CC {ECO:0000269|PubMed:11722595}. Note=Secreted and located to the cell CC surface. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=3; CC Name=EPOR-F; Synonyms=Full-length form; CC IsoId=P19235-1; Sequence=Displayed; CC Name=EPOR-S; Synonyms=Soluble form; CC IsoId=P19235-2; Sequence=VSP_009508, VSP_009509; CC Name=EPOR-T; Synonyms=Truncated form; CC IsoId=P19235-3; Sequence=VSP_009510, VSP_009511; CC -!- TISSUE SPECIFICITY: Erythroid cells and erythroid progenitor cells. CC Isoform EPOR-F is the most abundant form in EPO-dependent CC erythroleukemia cells and in late-stage erythroid progenitors. Isoform CC EPOR-S and isoform EPOR-T are the predominant forms in bone marrow. CC Isoform EPOR-T is the most abundant from in early-stage erythroid CC progenitor cells. CC -!- DOMAIN: The WSXWS motif appears to be necessary for proper protein CC folding and thereby efficient intracellular transport and cell-surface CC receptor binding. CC -!- DOMAIN: The box 1 motif is required for JAK interaction and/or CC activation. CC -!- DOMAIN: Contains 1 copy of a cytoplasmic motif that is referred to as CC the immunoreceptor tyrosine-based inhibitor motif (ITIM). This motif is CC involved in modulation of cellular responses. The phosphorylated ITIM CC motif can bind the SH2 domain of several SH2-containing phosphatases. CC -!- PTM: On EPO stimulation, phosphorylated on C-terminal tyrosine residues CC by JAK2. The phosphotyrosine motifs are also recruitment sites for CC several SH2-containing proteins and adapter proteins which mediate cell CC proliferation. Phosphorylation on Tyr-454 is required for PTPN6 CC interaction, Tyr-426 for PTPN11. Tyr-426 is also required for SOCS3 CC binding, but Tyr-454/Tyr-456 motif is the preferred binding site. CC {ECO:0000269|PubMed:10374881}. CC -!- PTM: Ubiquitination at Lys-281 mediates receptor internalization, CC whereas ubiquitination at Lys-453 promotes trafficking of activated CC receptors to the lysosomes for degradation (By similarity). CC Ubiquitinated by NOSIP; appears to be either multi-monoubiquitinated or CC polyubiquitinated. Ubiquitination mediates proliferation and survival CC of EPO-dependent cells. {ECO:0000250}. CC -!- DISEASE: Erythrocytosis, familial, 1 (ECYT1) [MIM:133100]: An autosomal CC dominant disorder characterized by elevated hemoglobin and hematocrit, CC hypersensitivity of erythroid progenitors to erythropoietin, CC erythropoietin low serum levels, and no increase in platelets nor CC leukocytes. It has a relatively benign course and does not progress to CC leukemia. {ECO:0000269|PubMed:8506290, ECO:0000269|PubMed:8608241}. CC Note=The disease is caused by variants affecting the gene represented CC in this entry. CC -!- SIMILARITY: Belongs to the type I cytokine receptor family. Type 1 CC subfamily. {ECO:0000305}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; M60459; AAA52403.1; -; mRNA. DR EMBL; S45332; AAB23271.1; -; Genomic_DNA. DR EMBL; M34986; AAA52401.1; -; mRNA. DR EMBL; AK315097; BAG37561.1; -; mRNA. DR EMBL; CH471106; EAW84205.1; -; Genomic_DNA. DR EMBL; BC112153; AAI12154.1; -; mRNA. DR EMBL; M76595; AAA52393.1; -; Genomic_DNA. DR EMBL; M77244; AAA52392.1; -; Genomic_DNA. DR EMBL; X57282; CAA40550.1; -; mRNA. DR CCDS; CCDS12260.1; -. [P19235-1] DR PIR; A43799; ZUHUR. DR PIR; I38208; I38208. DR RefSeq; NP_000112.1; NM_000121.3. [P19235-1] DR PDB; 1CN4; X-ray; 2.80 A; A/B=25-249. DR PDB; 1EBA; X-ray; 2.70 A; A/B=34-248. DR PDB; 1EBP; X-ray; 2.80 A; A/B=34-244. DR PDB; 1EER; X-ray; 1.90 A; B/C=27-250. DR PDB; 1ERN; X-ray; 2.40 A; A/B=34-246. DR PDB; 2JIX; X-ray; 3.20 A; B/C/E=25-249. DR PDB; 2MV6; NMR; -; A=237-284. DR PDB; 4Y5V; X-ray; 2.60 A; C/F/I=32-249. DR PDB; 4Y5X; X-ray; 3.15 A; C/F/I/L=32-249. DR PDB; 4Y5Y; X-ray; 2.85 A; C/F=32-249. DR PDB; 6E2Q; X-ray; 2.65 A; M/N/O/P=273-338. DR PDB; 6MOE; X-ray; 2.09 A; C/D=32-249. DR PDB; 6MOF; X-ray; 2.89 A; B=32-249. DR PDB; 6MOH; X-ray; 3.20 A; C/D=32-249. DR PDB; 6MOI; X-ray; 2.06 A; B=32-249. DR PDB; 6MOJ; X-ray; 2.43 A; B=32-249. DR PDB; 6MOK; X-ray; 5.10 A; B=32-249. DR PDB; 6MOL; X-ray; 3.16 A; B/C=32-249. DR PDBsum; 1CN4; -. DR PDBsum; 1EBA; -. DR PDBsum; 1EBP; -. DR PDBsum; 1EER; -. DR PDBsum; 1ERN; -. DR PDBsum; 2JIX; -. DR PDBsum; 2MV6; -. DR PDBsum; 4Y5V; -. DR PDBsum; 4Y5X; -. DR PDBsum; 4Y5Y; -. DR PDBsum; 6E2Q; -. DR PDBsum; 6MOE; -. DR PDBsum; 6MOF; -. DR PDBsum; 6MOH; -. DR PDBsum; 6MOI; -. DR PDBsum; 6MOJ; -. DR PDBsum; 6MOK; -. DR PDBsum; 6MOL; -. DR AlphaFoldDB; P19235; -. DR BMRB; P19235; -. DR SMR; P19235; -. DR BioGRID; 108371; 34. DR CORUM; P19235; -. DR DIP; DIP-5732N; -. DR ELM; P19235; -. DR IntAct; P19235; 21. DR MINT; P19235; -. DR STRING; 9606.ENSP00000222139; -. DR BindingDB; P19235; -. DR ChEMBL; CHEMBL1817; -. DR DrugBank; DB00012; Darbepoetin alfa. DR DrugBank; DB07637; Dibromotyrosine. DR DrugBank; DB00016; Erythropoietin. DR DrugBank; DB09107; Methoxy polyethylene glycol-epoetin beta. DR DrugBank; DB08894; Peginesatide. DR DrugCentral; P19235; -. DR GuidetoPHARMACOLOGY; 1718; -. DR TCDB; 8.A.152.1.12; the interleukin receptor (ilr) family. DR GlyCosmos; P19235; 1 site, No reported glycans. DR GlyGen; P19235; 1 site. DR iPTMnet; P19235; -. DR PhosphoSitePlus; P19235; -. DR BioMuta; EPOR; -. DR DMDM; 119524; -. DR MassIVE; P19235; -. DR PaxDb; 9606-ENSP00000222139; -. DR PeptideAtlas; P19235; -. DR ProteomicsDB; 53638; -. [P19235-1] DR ProteomicsDB; 53640; -. [P19235-3] DR TopDownProteomics; P19235-3; -. [P19235-3] DR ABCD; P19235; 4 sequenced antibodies. DR Antibodypedia; 13130; 1126 antibodies from 37 providers. DR DNASU; 2057; -. DR Ensembl; ENST00000222139.11; ENSP00000222139.5; ENSG00000187266.14. [P19235-1] DR Ensembl; ENST00000592375.6; ENSP00000467809.2; ENSG00000187266.14. [P19235-3] DR GeneID; 2057; -. DR KEGG; hsa:2057; -. DR MANE-Select; ENST00000222139.11; ENSP00000222139.5; NM_000121.4; NP_000112.1. DR UCSC; uc002mrj.3; human. [P19235-1] DR AGR; HGNC:3416; -. DR CTD; 2057; -. DR DisGeNET; 2057; -. DR GeneCards; EPOR; -. DR GeneReviews; EPOR; -. DR HGNC; HGNC:3416; EPOR. DR HPA; ENSG00000187266; Low tissue specificity. DR MalaCards; EPOR; -. DR MIM; 133100; phenotype. DR MIM; 133171; gene. DR neXtProt; NX_P19235; -. DR OpenTargets; ENSG00000187266; -. DR Orphanet; 90042; Primary familial polycythemia. DR PharmGKB; PA27834; -. DR VEuPathDB; HostDB:ENSG00000187266; -. DR eggNOG; ENOG502RYHW; Eukaryota. DR GeneTree; ENSGT00940000160315; -. DR HOGENOM; CLU_041434_0_0_1; -. DR InParanoid; P19235; -. DR OMA; ERCWGTM; -. DR OrthoDB; 5360031at2759; -. DR PhylomeDB; P19235; -. DR TreeFam; TF336573; -. DR PathwayCommons; P19235; -. DR Reactome; R-HSA-9006335; Signaling by Erythropoietin. DR Reactome; R-HSA-9027276; Erythropoietin activates Phosphoinositide-3-kinase (PI3K). DR Reactome; R-HSA-9027277; Erythropoietin activates Phospholipase C gamma (PLCG). DR Reactome; R-HSA-9027283; Erythropoietin activates STAT5. DR Reactome; R-HSA-9027284; Erythropoietin activates RAS. DR SignaLink; P19235; -. DR SIGNOR; P19235; -. DR BioGRID-ORCS; 2057; 18 hits in 1166 CRISPR screens. DR ChiTaRS; EPOR; human. DR EvolutionaryTrace; P19235; -. DR GeneWiki; Erythropoietin_receptor; -. DR GenomeRNAi; 2057; -. DR Pharos; P19235; Tclin. DR PRO; PR:P19235; -. DR Proteomes; UP000005640; Chromosome 19. DR RNAct; P19235; Protein. DR Bgee; ENSG00000187266; Expressed in type B pancreatic cell and 186 other cell types or tissues. DR ExpressionAtlas; P19235; baseline and differential. DR GO; GO:0009897; C:external side of plasma membrane; IBA:GO_Central. DR GO; GO:0005576; C:extracellular region; IEA:UniProtKB-SubCell. DR GO; GO:0016607; C:nuclear speck; IDA:HPA. DR GO; GO:0005886; C:plasma membrane; IDA:HPA. DR GO; GO:0004900; F:erythropoietin receptor activity; IDA:UniProtKB. DR GO; GO:0042802; F:identical protein binding; IPI:IntAct. DR GO; GO:0007420; P:brain development; IEA:Ensembl. DR GO; GO:0019221; P:cytokine-mediated signaling pathway; IBA:GO_Central. DR GO; GO:0046697; P:decidualization; IEA:Ensembl. DR GO; GO:0007507; P:heart development; IEA:Ensembl. DR GO; GO:0030097; P:hemopoiesis; IBA:GO_Central. DR GO; GO:0008284; P:positive regulation of cell population proliferation; IBA:GO_Central. DR GO; GO:0007165; P:signal transduction; NAS:ProtInc. DR CDD; cd00063; FN3; 1. DR Gene3D; 2.60.40.10; Immunoglobulins; 2. DR InterPro; IPR009167; Erythropoietin_rcpt. DR InterPro; IPR003961; FN3_dom. DR InterPro; IPR036116; FN3_sf. DR InterPro; IPR015152; Growth/epo_recpt_lig-bind. DR InterPro; IPR013783; Ig-like_fold. DR InterPro; IPR003528; Long_hematopoietin_rcpt_CS. DR PANTHER; PTHR23037; CYTOKINE RECEPTOR; 1. DR PANTHER; PTHR23037:SF28; ERYTHROPOIETIN RECEPTOR; 1. DR Pfam; PF09067; EpoR_lig-bind; 1. DR Pfam; PF00041; fn3; 1. DR PIRSF; PIRSF001959; EPO_receptor; 1. DR SMART; SM00060; FN3; 1. DR SUPFAM; SSF49265; Fibronectin type III; 2. DR PROSITE; PS50853; FN3; 1. DR PROSITE; PS01352; HEMATOPO_REC_L_F1; 1. DR Genevisible; P19235; HS. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; Cell membrane; KW Congenital erythrocytosis; Disease variant; Disulfide bond; Glycoprotein; KW Isopeptide bond; Membrane; Phosphoprotein; Receptor; Reference proteome; KW Secreted; Signal; Transmembrane; Transmembrane helix; Ubl conjugation. FT SIGNAL 1..24 FT CHAIN 25..508 FT /note="Erythropoietin receptor" FT /id="PRO_0000010868" FT TOPO_DOM 25..250 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 251..273 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 274..508 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT DOMAIN 147..247 FT /note="Fibronectin type-III" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00316" FT REGION 454..456 FT /note="Required for high-affinity SOCS3 binding" FT REGION 467..494 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT MOTIF 233..237 FT /note="WSXWS motif" FT MOTIF 282..290 FT /note="Box 1 motif" FT MOTIF 452..457 FT /note="ITIM motif" FT COMPBIAS 467..488 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT SITE 117 FT /note="Required for ligand binding" FT SITE 368 FT /note="Interaction with APS and STAT5, and activation" FT /evidence="ECO:0000250" FT SITE 426 FT /note="Required for STAT5/PTPN11/SOCS3 binding" FT /evidence="ECO:0000250" FT SITE 454 FT /note="Interaction with PTPN6" FT /evidence="ECO:0000250" FT SITE 456 FT /note="Required for STAT1/STAT3 activation" FT SITE 485 FT /note="Required for CrkL binding" FT /evidence="ECO:0000250" FT MOD_RES 368 FT /note="Phosphotyrosine; by JAK2" FT /evidence="ECO:0000250|UniProtKB:P14753" FT MOD_RES 426 FT /note="Phosphotyrosine; by JAK2" FT /evidence="ECO:0000250|UniProtKB:P14753" FT MOD_RES 454 FT /note="Phosphotyrosine; by JAK2" FT /evidence="ECO:0000250|UniProtKB:P14753" FT MOD_RES 456 FT /note="Phosphotyrosine; by JAK2" FT /evidence="ECO:0000250|UniProtKB:P14753" FT MOD_RES 468 FT /note="Phosphotyrosine; by JAK2" FT /evidence="ECO:0000250|UniProtKB:P14753" FT MOD_RES 485 FT /note="Phosphotyrosine; by JAK2" FT /evidence="ECO:0000250|UniProtKB:P14753" FT MOD_RES 489 FT /note="Phosphotyrosine; by JAK2" FT /evidence="ECO:0000250|UniProtKB:P14753" FT MOD_RES 504 FT /note="Phosphotyrosine; by JAK2" FT /evidence="ECO:0000250|UniProtKB:P14753" FT CARBOHYD 76 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT DISULFID 52..62 FT DISULFID 91..107 FT CROSSLNK 281 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin)" FT /evidence="ECO:0000250|UniProtKB:P14753" FT CROSSLNK 453 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin)" FT /evidence="ECO:0000250|UniProtKB:P14753" FT VAR_SEQ 196..241 FT /note="VEILEGRTECVLSNLRGRTRYTFAVRARMAEPSFGGFWSAWSEPVS -> GT FT VFLSPDWLSSTRARPHVIYFCLLRVPRPDSAPRWRSWRAAPSVC (in isoform FT EPOR-S)" FT /evidence="ECO:0000303|PubMed:1324524" FT /id="VSP_009508" FT VAR_SEQ 242..508 FT /note="Missing (in isoform EPOR-S)" FT /evidence="ECO:0000303|PubMed:1324524" FT /id="VSP_009509" FT VAR_SEQ 306..328 FT /note="LWLYQNDGCLWWSPCTPFTEDPP -> VGGLVVPSVPGLPCFLQPNCRPL FT (in isoform EPOR-T)" FT /evidence="ECO:0000303|PubMed:1324524" FT /id="VSP_009510" FT VAR_SEQ 329..508 FT /note="Missing (in isoform EPOR-T)" FT /evidence="ECO:0000303|PubMed:1324524" FT /id="VSP_009511" FT VARIANT 380 FT /note="P -> A (in dbSNP:rs35423344)" FT /id="VAR_033919" FT VARIANT 487 FT /note="N -> S (in ECYT1 and erythroleukemia; FT dbSNP:rs62638745)" FT /evidence="ECO:0000269|PubMed:8608241" FT /id="VAR_027372" FT VARIANT 488 FT /note="P -> S (in dbSNP:rs142094773)" FT /evidence="ECO:0000269|PubMed:27535533, FT ECO:0000269|PubMed:8174675" FT /id="VAR_027373" FT MUTAGEN 114 FT /note="T->A: Little effect on EPO binding." FT /evidence="ECO:0000269|PubMed:8662939" FT MUTAGEN 115 FT /note="S->A: Little effect on EPO binding." FT /evidence="ECO:0000269|PubMed:8662939" FT MUTAGEN 116 FT /note="S->A: 10-fold reduction in EPO binding." FT /evidence="ECO:0000269|PubMed:8662939" FT MUTAGEN 117 FT /note="F->A,L: Greatly reduced EPO binding." FT /evidence="ECO:0000269|PubMed:8662939" FT MUTAGEN 117 FT /note="F->W: 60-fold reduction in EPO binding." FT /evidence="ECO:0000269|PubMed:8662939" FT MUTAGEN 117 FT /note="F->Y: 8-fold reduction in EPO binding." FT /evidence="ECO:0000269|PubMed:8662939" FT MUTAGEN 118 FT /note="V->A: 16-fold reduction in EPO binding." FT /evidence="ECO:0000269|PubMed:8662939" FT MUTAGEN 120 FT /note="L->A: Some reduction in EPO binding." FT /evidence="ECO:0000269|PubMed:8662939" FT MUTAGEN 121 FT /note="E->A: Little effect on EPO binding." FT /evidence="ECO:0000269|PubMed:8662939" FT MUTAGEN 165 FT /note="R->A: Little effect on EPO binding." FT /evidence="ECO:0000269|PubMed:8662939" FT MUTAGEN 174 FT /note="M->A: Little effect on EPO binding." FT /evidence="ECO:0000269|PubMed:8662939" FT MUTAGEN 176 FT /note="S->A: 16-fold reduction in EPO binding." FT /evidence="ECO:0000269|PubMed:8662939" FT MUTAGEN 177 FT /note="H->A: Little effect on EPO binding." FT /evidence="ECO:0000269|PubMed:8662939" FT MUTAGEN 179 FT /note="R->A: Little effect on EPO binding." FT /evidence="ECO:0000269|PubMed:8662939" FT MUTAGEN 454 FT /note="Y->F: Some loss of SOCS3 binding." FT /evidence="ECO:0000269|PubMed:12027890" FT MUTAGEN 456 FT /note="Y->F: Inhibition of STAT1/STAT3 activity. No effect FT on STAT5 activity. Some loss of SOCS3 binding." FT /evidence="ECO:0000269|PubMed:11756159, FT ECO:0000269|PubMed:12027890" FT MUTAGEN 468 FT /note="Y->F: No effect on STAT1/STAT3 nor STAT5 activity." FT /evidence="ECO:0000269|PubMed:11756159" FT CONFLICT 102 FT /note="A -> R (in Ref. 1; no nucleotide entry)" FT /evidence="ECO:0000305" FT CONFLICT 189..190 FT /note="GA -> RP (in Ref. 1; no nucleotide entry)" FT /evidence="ECO:0000305" FT CONFLICT 244 FT /note="T -> E (in Ref. 1; no nucleotide entry)" FT /evidence="ECO:0000305" FT HELIX 33..45 FT /evidence="ECO:0007829|PDB:1EER" FT STRAND 47..49 FT /evidence="ECO:0007829|PDB:4Y5Y" FT STRAND 51..58 FT /evidence="ECO:0007829|PDB:1EER" FT STRAND 61..67 FT /evidence="ECO:0007829|PDB:1EER" FT STRAND 76..83 FT /evidence="ECO:0007829|PDB:1EER" FT STRAND 84..86 FT /evidence="ECO:0007829|PDB:6MOF" FT STRAND 89..91 FT /evidence="ECO:0007829|PDB:1EER" FT STRAND 93..98 FT /evidence="ECO:0007829|PDB:1EER" FT TURN 99..101 FT /evidence="ECO:0007829|PDB:1EER" FT STRAND 102..108 FT /evidence="ECO:0007829|PDB:1EER" FT HELIX 111..113 FT /evidence="ECO:0007829|PDB:1EER" FT STRAND 116..118 FT /evidence="ECO:0007829|PDB:1EER" FT STRAND 120..126 FT /evidence="ECO:0007829|PDB:1EER" FT TURN 127..129 FT /evidence="ECO:0007829|PDB:1CN4" FT STRAND 131..137 FT /evidence="ECO:0007829|PDB:1EER" FT HELIX 139..141 FT /evidence="ECO:0007829|PDB:1EER" FT STRAND 142..144 FT /evidence="ECO:0007829|PDB:1EER" FT STRAND 149..155 FT /evidence="ECO:0007829|PDB:1EER" FT STRAND 157..160 FT /evidence="ECO:0007829|PDB:6MOJ" FT STRAND 162..167 FT /evidence="ECO:0007829|PDB:1EER" FT STRAND 169..171 FT /evidence="ECO:0007829|PDB:1ERN" FT HELIX 175..177 FT /evidence="ECO:0007829|PDB:1EER" FT STRAND 178..185 FT /evidence="ECO:0007829|PDB:1EER" FT STRAND 188..190 FT /evidence="ECO:0007829|PDB:1EER" FT STRAND 195..198 FT /evidence="ECO:0007829|PDB:1EER" FT STRAND 204..207 FT /evidence="ECO:0007829|PDB:1EER" FT STRAND 212..224 FT /evidence="ECO:0007829|PDB:1EER" FT TURN 226..228 FT /evidence="ECO:0007829|PDB:1EER" FT STRAND 240..244 FT /evidence="ECO:0007829|PDB:1EER" FT TURN 245..247 FT /evidence="ECO:0007829|PDB:2MV6" FT HELIX 250..282 FT /evidence="ECO:0007829|PDB:2MV6" FT HELIX 289..293 FT /evidence="ECO:0007829|PDB:6E2Q" FT TURN 294..299 FT /evidence="ECO:0007829|PDB:6E2Q" FT HELIX 304..311 FT /evidence="ECO:0007829|PDB:6E2Q" FT STRAND 316..320 FT /evidence="ECO:0007829|PDB:6E2Q" SQ SEQUENCE 508 AA; 55065 MW; F9F326E162E9512A CRC64; MDHLGASLWP QVGSLCLLLA GAAWAPPPNL PDPKFESKAA LLAARGPEEL LCFTERLEDL VCFWEEAASA GVGPGNYSFS YQLEDEPWKL CRLHQAPTAR GAVRFWCSLP TADTSSFVPL ELRVTAASGA PRYHRVIHIN EVVLLDAPVG LVARLADESG HVVLRWLPPP ETPMTSHIRY EVDVSAGNGA GSVQRVEILE GRTECVLSNL RGRTRYTFAV RARMAEPSFG GFWSAWSEPV SLLTPSDLDP LILTLSLILV VILVLLTVLA LLSHRRALKQ KIWPGIPSPE SEFEGLFTTH KGNFQLWLYQ NDGCLWWSPC TPFTEDPPAS LEVLSERCWG TMQAVEPGTD DEGPLLEPVG SEHAQDTYLV LDKWLLPRNP PSEDLPGPGG SVDIVAMDEG SEASSCSSAL ASKPSPEGAS AASFEYTILD PSSQLLRPWT LCPELPPTPP HLKYLYLVVS DSGISTDYSS GDSQGAQGGL SDGPYSNPYE NSLIPAAEPL PPSYVACS //