EPOR_HUMAN
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 03-AUG-2022, entry version 237.
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}.
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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 GlyGen; P19235; 1 site.
DR iPTMnet; P19235; -.
DR PhosphoSitePlus; P19235; -.
DR BioMuta; EPOR; -.
DR DMDM; 119524; -.
DR MassIVE; P19235; -.
DR PaxDb; P19235; -.
DR PeptideAtlas; P19235; -.
DR PRIDE; 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; 975 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 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; APRYHRI; -.
DR OrthoDB; 1442632at2759; -.
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 1082 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 184 other tissues.
DR ExpressionAtlas; P19235; baseline and differential.
DR Genevisible; P19235; HS.
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:0005887; C:integral component of plasma membrane; TAS:ProtInc.
DR GO; GO:0016607; C:nuclear speck; IDA:HPA.
DR GO; GO:0005886; C:plasma membrane; IDA:HPA.
DR GO; GO:0004896; F:cytokine receptor activity; IBA:GO_Central.
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; -; 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:SF28; PTHR23037:SF28; 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; SSF49265; 2.
DR PROSITE; PS50853; FN3; 1.
DR PROSITE; PS01352; HEMATOPO_REC_L_F1; 1.
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
