EPOR_RAT
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 25-MAY-2022, entry version 150.
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}.
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DR EMBL; D13566; BAA02761.1; -; mRNA.
DR PIR; A46713; A46713.
DR AlphaFoldDB; Q07303; -.
DR SMR; Q07303; -.
DR STRING; 10116.ENSRNOP00000017369; -.
DR GlyGen; Q07303; 1 site.
DR iPTMnet; Q07303; -.
DR PhosphoSitePlus; Q07303; -.
DR PaxDb; Q07303; -.
DR UCSC; RGD:2560; rat. [Q07303-1]
DR RGD; 2560; Epor.
DR eggNOG; ENOG502RYHW; Eukaryota.
DR InParanoid; Q07303; -.
DR PhylomeDB; Q07303; -.
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:0005737; C:cytoplasm; IDA:RGD.
DR GO; GO:0009897; C:external side of plasma membrane; IDA:RGD.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0004896; F:cytokine receptor activity; IBA:GO_Central.
DR GO; GO:0004900; F:erythropoietin receptor activity; IDA:RGD.
DR GO; GO:0042802; F:identical protein binding; ISO:RGD.
DR GO; GO:0007568; P:aging; IEP: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:1903206; P:negative regulation of hydrogen peroxide-induced cell death; IMP:RGD.
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: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; -; 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 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
