ID   EPOR_RAT                Reviewed;         507 AA.
AC   Q07303;
DT   01-FEB-1995, integrated into UniProtKB/Swiss-Prot.
DT   01-FEB-1995, sequence version 1.
DT   24-JAN-2024, entry version 157.
DE   RecName: Full=Erythropoietin receptor;
DE            Short=EPO-R;
DE   Flags: Precursor;
GN   Name=Epor;
OS   Rattus norvegicus (Rat).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC   Murinae; Rattus.
OX   NCBI_TaxID=10116;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM EPOR-F).
RC   TISSUE=Pheochromocytoma;
RX   PubMed=7684373; DOI=10.1016/s0021-9258(18)82112-3;
RA   Masuda S., Nagao M., Takahata K., Konishi Y., Gallyas F., Tabira T.,
RA   Sasaki R.;
RT   "Functional erythropoietin receptor of the cells with neural
RT   characteristics. Comparison with receptor properties of erythroid cells.";
RL   J. Biol. Chem. 268:11208-11216(1993).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS EPOR-F AND EPOR-S).
RC   STRAIN=Long Evans;
RX   PubMed=9029168; DOI=10.1016/s0304-3835(96)04544-2;
RA   Fujita M., Takahashi R., Kitada K., Watanabe R., Kitazawa S., Ashoori F.,
RA   Liang P., Saya H., Serikawa T., Maeda S.;
RT   "Alternative splicing of the erythropoietin receptor gene correlates with
RT   erythroid differentiation in rat hematopoietic and leukemic cells.";
RL   Cancer Lett. 112:47-55(1997).
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 LYN
CC       tyrosine kinase (By similarity). {ECO:0000250}.
CC   -!- SUBUNIT: Forms homodimers on EPO stimulation. The tyrosine-
CC       phosphorylated form interacts with several SH2 domain-containing
CC       proteins including LYN, the adapter protein APS, PTPN6, PTPN11, JAK2,
CC       PI3 kinases, STAT5A/B, SOCS3 and CRKL. The N-terminal SH2 domain of
CC       PTPN6 binds Tyr-453 and inhibits signaling through dephosphorylation of
CC       JAK2. APS binding also inhibits the JAK-STAT signaling. Binding to
CC       PTPN11, preferentially through the N-terminal SH2 domain, promotes
CC       mitogenesis and phosphorylation of PTPN11. Binding of JAK2 (through its
CC       N-terminal) promotes cell-surface expression. Interaction with the
CC       ubiquitin ligase NOSIP mediates EPO-induced cell proliferation.
CC       Interacts with ATXN2L and INPP5D/SHIP1 (By similarity). {ECO:0000250}.
CC   -!- SUBCELLULAR LOCATION: Membrane; Single-pass type I membrane protein.
CC   -!- ALTERNATIVE PRODUCTS:
CC       Event=Alternative splicing; Named isoforms=2;
CC       Name=EPOR-F; Synonyms=Full-length form;
CC         IsoId=Q07303-1; Sequence=Displayed;
CC       Name=EPOR-S; Synonyms=Soluble form;
CC         IsoId=Q07303-2; Sequence=VSP_009514, VSP_009515;
CC   -!- TISSUE SPECIFICITY: Isoform EPOR-F and isoform EPOR-S are expressed in
CC       bone marrow, spleen and eythroleukemia cell lines.
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-453 is required for PTPN6
CC       interaction, Tyr-425 for PTPN11. Tyr-425 is also required for SOCS3
CC       binding, but Tyr-453/Tyr-455 motif is the preferred binding site (By
CC       similarity). {ECO:0000250}.
CC   -!- PTM: Ubiquitinated by NOSIP; appears to be either multi-
CC       monoubiquitinated or polyubiquitinated. Ubiquitination mediates
CC       proliferation and survival of EPO-dependent cells. Ubiquitination at
CC       Lys-280 mediates receptor internalization, whereas ubiquitination at
CC       Lys-452 promotes trafficking of activated receptors to the lysosomes
CC       for degradation (By similarity). {ECO:0000250}.
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; D13566; BAA02761.1; -; mRNA.
DR   PIR; A46713; A46713.
DR   AlphaFoldDB; Q07303; -.
DR   SMR; Q07303; -.
DR   STRING; 10116.ENSRNOP00000017369; -.
DR   GlyCosmos; Q07303; 1 site, No reported glycans.
DR   GlyGen; Q07303; 1 site.
DR   iPTMnet; Q07303; -.
DR   PhosphoSitePlus; Q07303; -.
DR   PaxDb; 10116-ENSRNOP00000017369; -.
DR   Ensembl; ENSRNOT00055021579; ENSRNOP00055017493; ENSRNOG00055012644. [Q07303-1]
DR   Ensembl; ENSRNOT00060050635; ENSRNOP00060042129; ENSRNOG00060029173. [Q07303-1]
DR   UCSC; RGD:2560; rat. [Q07303-1]
DR   AGR; RGD:2560; -.
DR   RGD; 2560; Epor.
DR   eggNOG; ENOG502RYHW; Eukaryota.
DR   InParanoid; Q07303; -.
DR   PhylomeDB; Q07303; -.
DR   Reactome; R-RNO-9006335; Signaling by Erythropoietin.
DR   Reactome; R-RNO-9027276; Erythropoietin activates Phosphoinositide-3-kinase (PI3K).
DR   Reactome; R-RNO-9027284; Erythropoietin activates RAS.
DR   PRO; PR:Q07303; -.
DR   Proteomes; UP000002494; Unplaced.
DR   GO; GO:0009986; C:cell surface; IDA:RGD.
DR   GO; GO:0009897; C:external side of plasma membrane; IDA:RGD.
DR   GO; GO:0004900; F:erythropoietin receptor activity; IDA:RGD.
DR   GO; GO:0042802; F:identical protein binding; ISO:RGD.
DR   GO; GO:0007420; P:brain development; ISO:RGD.
DR   GO; GO:1904374; P:cellular response to kainic acid; IEP:RGD.
DR   GO; GO:0019221; P:cytokine-mediated signaling pathway; IBA:GO_Central.
DR   GO; GO:0046697; P:decidualization; ISO:RGD.
DR   GO; GO:0007507; P:heart development; ISO:RGD.
DR   GO; GO:0030097; P:hemopoiesis; IBA:GO_Central.
DR   GO; GO:0043524; P:negative regulation of neuron apoptotic process; IMP:RGD.
DR   GO; GO:0045019; P:negative regulation of nitric oxide biosynthetic process; IMP:RGD.
DR   GO; GO:0008284; P:positive regulation of cell population proliferation; IMP:RGD.
DR   GO; GO:0007204; P:positive regulation of cytosolic calcium ion concentration; IDA:RGD.
DR   GO; GO:0070374; P:positive regulation of ERK1 and ERK2 cascade; IMP:RGD.
DR   GO; GO:0010976; P:positive regulation of neuron projection development; IMP:RGD.
DR   GO; GO:1901033; P:positive regulation of response to reactive oxygen species; IMP:RGD.
DR   GO; GO:0001666; P:response to hypoxia; IEP:RGD.
DR   GO; GO:0007165; P:signal transduction; ISO:RGD.
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.
PE   2: Evidence at transcript level;
KW   Alternative splicing; Disulfide bond; Glycoprotein; Isopeptide bond;
KW   Membrane; Phosphoprotein; Receptor; Reference proteome; Signal;
KW   Transmembrane; Transmembrane helix; Ubl conjugation.
FT   SIGNAL          1..24
FT                   /evidence="ECO:0000250"
FT   CHAIN           25..507
FT                   /note="Erythropoietin receptor"
FT                   /id="PRO_0000010871"
FT   TOPO_DOM        25..249
FT                   /note="Extracellular"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        250..272
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        273..507
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000255"
FT   DOMAIN          146..246
FT                   /note="Fibronectin type-III"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00316"
FT   REGION          384..423
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          466..507
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   MOTIF           232..236
FT                   /note="WSXWS motif"
FT   MOTIF           281..289
FT                   /note="Box 1 motif"
FT   MOTIF           451..456
FT                   /note="ITIM motif"
FT   COMPBIAS        396..423
FT                   /note="Polar residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   SITE            116
FT                   /note="Required for ligand binding"
FT                   /evidence="ECO:0000250"
FT   SITE            367
FT                   /note="Interaction with APS and STAT5, and activation"
FT   SITE            425
FT                   /note="Required for STAT5/PTPN11/SOCS3 binding"
FT   SITE            453
FT                   /note="Interaction with PTPN6"
FT   MOD_RES         367
FT                   /note="Phosphotyrosine; by JAK2"
FT                   /evidence="ECO:0000250|UniProtKB:P14753"
FT   MOD_RES         425
FT                   /note="Phosphotyrosine; by JAK2"
FT                   /evidence="ECO:0000250|UniProtKB:P14753"
FT   MOD_RES         453
FT                   /note="Phosphotyrosine; by JAK2"
FT                   /evidence="ECO:0000250|UniProtKB:P14753"
FT   MOD_RES         455
FT                   /note="Phosphotyrosine; by JAK2"
FT                   /evidence="ECO:0000250|UniProtKB:P14753"
FT   MOD_RES         467
FT                   /note="Phosphotyrosine; by JAK2"
FT                   /evidence="ECO:0000250|UniProtKB:P14753"
FT   MOD_RES         484
FT                   /note="Phosphotyrosine; by JAK2"
FT                   /evidence="ECO:0000250|UniProtKB:P14753"
FT   MOD_RES         488
FT                   /note="Phosphotyrosine; by JAK2"
FT                   /evidence="ECO:0000250|UniProtKB:P14753"
FT   MOD_RES         503
FT                   /note="Phosphotyrosine; by JAK2"
FT                   /evidence="ECO:0000250|UniProtKB:P14753"
FT   CARBOHYD        75
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   DISULFID        52..62
FT                   /evidence="ECO:0000250"
FT   DISULFID        90..106
FT                   /evidence="ECO:0000250"
FT   CROSSLNK        280
FT                   /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT                   G-Cter in ubiquitin)"
FT                   /evidence="ECO:0000250|UniProtKB:P14753"
FT   CROSSLNK        452
FT                   /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT                   G-Cter in ubiquitin)"
FT                   /evidence="ECO:0000250|UniProtKB:P14753"
FT   VAR_SEQ         246..265
FT                   /note="DLDPLILTLSLILVLISLLL -> GEATVPRGGGGAGPNTSKPP (in
FT                   isoform EPOR-S)"
FT                   /evidence="ECO:0000303|PubMed:9029168"
FT                   /id="VSP_009514"
FT   VAR_SEQ         266..507
FT                   /note="Missing (in isoform EPOR-S)"
FT                   /evidence="ECO:0000303|PubMed:9029168"
FT                   /id="VSP_009515"
SQ   SEQUENCE   507 AA;  55500 MW;  AC79AF22D06A7312 CRC64;
     MDQLRVARWP RVSPLCLLLA GAAWASSPSL PDPKFESKAA LLASRGSEEL LCFTQRLEDL
     VCFWEEAANS GMGFNYSFSY QLEGESRKSC RLHQAPTVRG SMRFWCSLPT ADTSSFVPLE
     LQVTEASGSP RYHRIIHINE VVLLDAPAGL LARRAEEGSH VVLRWLPPPG APMTTHIRYE
     VDVSAGNRAG GTQRVEVLEG RTECVLSNLR GGTRYTFAVR ARMAEPSFSG FWSAWSEPAS
     LLTASDLDPL ILTLSLILVL ISLLLTVLAL LSHRRALRQK IWPGIPSPEN EFEGLFTTHK
     GNFQLWLLQR DGCLWWSPSS PFPEDPPAHL EVLSERRWGV TQAGDAGAED KGPLLEPVGS
     ERAQDTYLVL DEWLLPRCPC SENLSGPGDS VDPATMDEGS ETSSCPSDLA SKPRPEGTSP
     SSFEYTILDP SSKLLCPRAL PPELPPTPPH LKYLYLVVSD SGISTDYSSG GSQGVHGDSS
     DGPYSHPYEN SLVPDTEPLR PSYVACS
//