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Protein

Erythropoietin receptor

Gene

Epor

Organism
Mus musculus (Mouse)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Receptor for erythropoietin. Mediates erythropoietin-induced erythroblast proliferation and differentiation. Upon EPO stimulation, EPOR dimerizes triggering the JAK2/STAT5 signaling cascade. In some cell types, can also activate STAT1 and STAT3. May also activate the LYN tyrosine kinase.2 Publications

Miscellaneous

Interaction with FSFFV envelope-like membrane glycoprotein gp55 leads to ligand-independent activation of EPOR and to the abnormally rapid proliferation of erythroid precursor cells.
Viral promoter integration by Friend spleen focus-forming virus (F-SFFVP) in the murine erythroleukemia cell line F5-5, results in aberrant EPOR sequences and EPOR overexpression in erythroid progenitor cells.

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sitei116Required for ligand bindingBy similarity1
Sitei425Required for STAT5/PTPN11/SOCS3 binding1

GO - Molecular functioni

GO - Biological processi

  • brain development Source: MGI
  • cardiac muscle tissue morphogenesis Source: DFLAT
  • decidualization Source: MGI
  • heart development Source: MGI
  • heart morphogenesis Source: DFLAT
  • signal transduction Source: MGI
  • vasculogenesis involved in coronary vascular morphogenesis Source: DFLAT
  • ventricular cardiac muscle tissue morphogenesis Source: DFLAT
  • viral process Source: UniProtKB-KW
  • visceral serous pericardium development Source: DFLAT

Keywordsi

Molecular functionReceptor
Biological processHost-virus interaction

Enzyme and pathway databases

SABIO-RKiP14753.

Names & Taxonomyi

Protein namesi
Recommended name:
Erythropoietin receptor
Short name:
EPO-R
Gene namesi
Name:Epor
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaMyomorphaMuroideaMuridaeMurinaeMusMus
Proteomesi
  • UP000000589 Componenti: Chromosome 9

Organism-specific databases

MGIiMGI:95408. Epor.

Subcellular locationi

Topology

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Topological domaini25 – 249ExtracellularSequence analysisAdd BLAST225
Transmembranei250 – 272HelicalSequence analysisAdd BLAST23
Topological domaini273 – 507CytoplasmicSequence analysisAdd BLAST235

GO - Cellular componenti

Keywords - Cellular componenti

Cell membrane, Membrane, Secreted

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi153R → C: Reduced JAK2/STAT5 activation. 1 Publication1
Mutagenesisi232W → A, C, D, E, G, H, I, K, L, M, N, P, Q, R, S, T, V or Y: Loss of EPO binding. 1 Publication1
Mutagenesisi232W → F: Greatly reduced EPO binding. 1 Publication1
Mutagenesisi233S → A: Not secreted and loss of EPO binding. 2 Publications1
Mutagenesisi233S → C, D, E, F, H, I, K, L, M, N, P, Q, R, V, W or Y: Loss of EPO binding. 2 Publications1
Mutagenesisi233S → G: 50-fold less EPO binding. 2 Publications1
Mutagenesisi233S → T: 2-fold less EPO binding. 2 Publications1
Mutagenesisi234A → C, D, G, H, K, N, Q, R, S or T: No change in EPO binding. 2 Publications1
Mutagenesisi234A → E: Enhanced secretion and increased EPO binding. 2 Publications1
Mutagenesisi234A → F, I, M, W or Y: Little EPO binding. 2 Publications1
Mutagenesisi234A → L, P or V: Reduced EPO binding. 2 Publications1
Mutagenesisi235W → A, C, D, E, G, H, I, K, L, M, N, P, Q, R, S, T or V: Loss of EPO binding. 1 Publication1
Mutagenesisi235W → F: 14-fold less EPO binding. 1 Publication1
Mutagenesisi235W → Y: 100-fold less EPO binding. 1 Publication1
Mutagenesisi236S → A, C or G: Reduced EPO binding. 1 Publication1
Mutagenesisi236S → D, E, F, H, I, K, L, M, N, P, Q, R, V or W: Loss of EPO binding. 1 Publication1
Mutagenesisi236S → T: No loss of EPO binding. 1 Publication1
Mutagenesisi236S → Y: Greatly reduced EPO binding. 1 Publication1
Mutagenesisi304Q → L: Greatly reduced JAK2/STAT5 activation and some loss of mitogenic response. 2 Publications1
Mutagenesisi306W → R: No JAK2 binding nor JAK2/STAT5 activation. No EPO-induced phosphorylation. Complete loss of mitogenic response. 3 Publications1
Mutagenesisi317S → R: Slightly reduced JAK2/STAT5 activation and mitogenic response. 2 Publications1
Mutagenesisi324E → V: No change in JAK2/STAT5 activation nor mitogenic response. 2 Publications1
Mutagenesisi330L → R: Reduced JAK2/STAT5 activation. 2 Publications1
Mutagenesisi331E → A: No change in JAK2/STAT5 activation nor mitogenic response. 2 Publications1
Mutagenesisi331E → K: Reduced JAK2/STAT5 activation and mitogenic response. 2 Publications1
Mutagenesisi367Y → F: No STAT5 activation. 2 Publications1
Mutagenesisi425Y → F: No PTPN11 binding, reduced PTPN11 tyrosine phosphorylation and reduced cell proliferation. 1 Publication1
Mutagenesisi453 – 455YLY → FLF: No binding to PTPN6 SH2 domains. Enhanced JAK2 activation and cell proliferation. 1 Publication3
Mutagenesisi453Y → F: No PTPN6 binding, binds PTPN11. 2 Publications1
Mutagenesisi455Y → F: Binds to PTPN6 and PTPN11 SH2 domains. 2 Publications1
Mutagenesisi467Y → F: No loss of PTPN11 binding. 1 Publication1
Mutagenesisi484Y → F: No loss of PTPN11 binding. 1 Publication1
Mutagenesisi488Y → F: No loss of PTPN11 binding. 1 Publication1
Mutagenesisi503Y → F: No loss of PTPN11 binding. 1 Publication1

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Signal peptidei1 – 24Add BLAST24
ChainiPRO_000001086925 – 507Erythropoietin receptorAdd BLAST483

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Disulfide bondi52 ↔ 62By similarity
Glycosylationi75N-linked (GlcNAc...) asparagineSequence analysis1
Disulfide bondi90 ↔ 106By similarity
Cross-linki280Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)1 Publication
Modified residuei367Phosphotyrosine; by JAK21 Publication1
Modified residuei425Phosphotyrosine; by JAK21 Publication1
Cross-linki452Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)1 Publication
Modified residuei453Phosphotyrosine; by JAK21 Publication1
Modified residuei455Phosphotyrosine; by JAK22 Publications1
Modified residuei467Phosphotyrosine; by JAK21 Publication1
Modified residuei484Phosphotyrosine; by JAK21 Publication1
Modified residuei488Phosphotyrosine; by JAK21 Publication1
Modified residuei503Phosphotyrosine; by JAK21 Publication1
Isoform EPOR-S (identifier: P14753-2)
Glycosylationi232C-linked (Man) tryptophan1 Publication1

Post-translational modificationi

The identity of the C-linked hexose on the WXXW motif has not been determined. It is probably mannose.
On EPO stimulation, phosphorylated on C-terminal tyrosine residues by JAK2. The phosphotyrosine motifs are also recruitment sites for several SH2-containing proteins and adapter proteins which mediate cell proliferation. Phosphorylation on Tyr-453 is required for PTPN6 interaction, Tyr-425 for PTPN11. Tyr-425 is also required for SOCS3 binding, but Tyr-453/Tyr-455 motif is the preferred binding site (By similarity).By similarity
Ubiquitinated by NOSIP; appears to be either multi-monoubiquitinated or polyubiquitinated. Ubiquitination mediates proliferation and survival of EPO-dependent cells (By similarity). Ubiquitination at Lys-280 mediates receptor internalization, whereas ubiquitination at Lys-452 promotes trafficking of activated receptors to the lysosomes for degradation.By similarity1 Publication

Keywords - PTMi

Disulfide bond, Glycoprotein, Isopeptide bond, Phosphoprotein, Ubl conjugation

Proteomic databases

PaxDbiP14753.
PRIDEiP14753.

PTM databases

iPTMnetiP14753.
PhosphoSitePlusiP14753.

Expressioni

Tissue specificityi

Expressed in relatively mature erythroid progenitor cells and in EPO-responsive erythroleukemia cells.

Gene expression databases

BgeeiENSMUSG00000006235.
CleanExiMM_EPOR.
ExpressionAtlasiP14753. baseline and differential.
GenevisibleiP14753. MM.

Interactioni

Subunit structurei

Forms homodimers on EPO stimulation. The tyrosine-phosphorylated form interacts with several SH2 domain-containing proteins including LYN, the adapter protein APS, PTPN6, PTPN11, JAK2, PI3 kinases, STAT5A/B, SOCS3 and CRKL. The N-terminal SH2 domain of PTPN6 binds Tyr-453 and inhibits signaling through dephosphorylation of JAK2. APS binding also inhibits the JAK-STAT signaling. Binding to PTPN11, preferentially through the N-terminal SH2 domain, promotes mitogenesis and phosphorylation of PTPN11. Binding of JAK2 (through its N-terminal) promotes cell-surface expression. Interaction with the ubiquitin ligase NOSIP mediates EPO-induced cell proliferation. Interacts with ATXN2L (By similarity). Forms heterooligomers with friend spleen focus-forming virus (FSFFV) gp55, probably via their respective transmembrane domains. Interacts with INPP5D/SHIP1.By similarity10 Publications

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sitei367Interaction with APS and STAT5, and activation1
Sitei453Interaction with PTPN61

Binary interactionsi

Show more details

GO - Molecular functioni

Protein-protein interaction databases

BioGridi199488. 3 interactors.
DIPiDIP-657N.
IntActiP14753. 10 interactors.
MINTiMINT-1348473.
STRINGi10090.ENSMUSP00000006397.

Structurei

Secondary structure

1507
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Helixi239 – 243Combined sources5
Turni244 – 246Combined sources3
Helixi249 – 281Combined sources33

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
2MXBNMR-A236-283[»]
ProteinModelPortaliP14753.
SMRiP14753.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini146 – 246Fibronectin type-IIIPROSITE-ProRule annotationAdd BLAST101

Motif

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Motifi232 – 236WSXWS motif5
Motifi281 – 289Box 1 motif9
Motifi451 – 456ITIM motif6

Domaini

The WSXWS motif appears to be necessary for proper protein folding and thereby efficient intracellular transport and cell-surface receptor binding.
The box 1 motif is required for JAK interaction and/or activation.

Sequence similaritiesi

Keywords - Domaini

Signal, Transmembrane, Transmembrane helix

Phylogenomic databases

eggNOGiENOG410IFGH. Eukaryota.
ENOG4111PGS. LUCA.
GeneTreeiENSGT00840000129885.
HOGENOMiHOG000059639.
HOVERGENiHBG005595.
InParanoidiP14753.
KOiK05079.
OMAiVGSEHAQ.
OrthoDBiEOG091G0AK8.
PhylomeDBiP14753.
TreeFamiTF336573.

Family and domain databases

CDDicd00063. FN3. 1 hit.
Gene3Di2.60.40.10. 2 hits.
InterProiView protein in InterPro
IPR009167. Erythropoietin_rcpt.
IPR003961. FN3_dom.
IPR015152. Growth/epo_recpt_lig-bind.
IPR013783. Ig-like_fold.
IPR003528. Long_hematopoietin_rcpt_CS.
PANTHERiPTHR23037:SF38. PTHR23037:SF38. 1 hit.
PfamiView protein in Pfam
PF09067. EpoR_lig-bind. 1 hit.
PF00041. fn3. 1 hit.
PIRSFiPIRSF001959. EPO_receptor. 1 hit.
SMARTiView protein in SMART
SM00060. FN3. 1 hit.
SUPFAMiSSF49265. SSF49265. 2 hits.
PROSITEiView protein in PROSITE
PS50853. FN3. 1 hit.
PS01352. HEMATOPO_REC_L_F1. 1 hit.

Sequences (2)i

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

This entry describes 2 isoformsi produced by alternative splicing. AlignAdd to basket

Note: Additional isoforms seem to exist.
Isoform EPOR-F (identifier: P14753-1) [UniParc]FASTAAdd to basket
Also known as: Membrane-bound form

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

« Hide

        10         20         30         40         50
MDKLRVPLWP RVGPLCLLLA GAAWAPSPSL PDPKFESKAA LLASRGSEEL
60 70 80 90 100
LCFTQRLEDL VCFWEEAASS GMDFNYSFSY QLEGESRKSC SLHQAPTVRG
110 120 130 140 150
SVRFWCSLPT ADTSSFVPLE LQVTEASGSP RYHRIIHINE VVLLDAPAGL
160 170 180 190 200
LARRAEEGSH VVLRWLPPPG APMTTHIRYE VDVSAGNRAG GTQRVEVLEG
210 220 230 240 250
RTECVLSNLR GGTRYTFAVR ARMAEPSFSG FWSAWSEPAS LLTASDLDPL
260 270 280 290 300
ILTLSLILVL ISLLLTVLAL LSHRRTLQQK IWPGIPSPES EFEGLFTTHK
310 320 330 340 350
GNFQLWLLQR DGCLWWSPGS SFPEDPPAHL EVLSEPRWAV TQAGDPGADD
360 370 380 390 400
EGPLLEPVGS EHAQDTYLVL DKWLLPRTPC SENLSGPGGS VDPVTMDEAS
410 420 430 440 450
ETSSCPSDLA SKPRPEGTSP SSFEYTILDP SSQLLCPRAL PPELPPTPPH
460 470 480 490 500
LKYLYLVVSD SGISTDYSSG GSQGVHGDSS DGPYSHPYEN SLVPDSEPLH

PGYVACS
Length:507
Mass (Da):55,194
Last modified:April 1, 1990 - v1
Checksum:i067657A2E26451CA
GO
Isoform EPOR-S (identifier: P14753-2) [UniParc]FASTAAdd to basket
Also known as: Soluble form

The sequence of this isoform differs from the canonical sequence as follows:
     246-265: DLDPLILTLSLILVLISLLL → GEALVPRGAGGAGPNTRQTP
     266-507: Missing.

Show »
Length:265
Mass (Da):28,798
Checksum:i3368CF30E673F5CC
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti291E → D in AAB20029 (PubMed:1656233).Curated1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_009512246 – 265DLDPL…ISLLL → GEALVPRGAGGAGPNTRQTP in isoform EPOR-S. CuratedAdd BLAST20
Alternative sequenceiVSP_009513266 – 507Missing in isoform EPOR-S. CuratedAdd BLAST242

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
J04843 mRNA. Translation: AAA37571.1.
X53081 Genomic DNA. Translation: CAA37248.1.
S59388 mRNA. Translation: AAB20029.2.
BC003953 mRNA. Translation: AAH03953.1.
BC046282 mRNA. Translation: AAH46282.1.
M38133 Genomic DNA. Translation: AAA37572.1.
M62360 Genomic DNA. Translation: AAA37582.1.
CCDSiCCDS22915.1. [P14753-1]
PIRiA41686. A32385.
S14081.
RefSeqiNP_034279.3. NM_010149.3. [P14753-1]
UniGeneiMm.2653.

Genome annotation databases

EnsembliENSMUST00000006397; ENSMUSP00000006397; ENSMUSG00000006235. [P14753-1]
GeneIDi13857.
KEGGimmu:13857.
UCSCiuc009ond.1. mouse. [P14753-1]
uc009one.1. mouse. [P14753-2]

Keywords - Coding sequence diversityi

Alternative splicing

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.

Entry informationi

Entry nameiEPOR_MOUSE
AccessioniPrimary (citable) accession number: P14753
Secondary accession number(s): Q63852
Entry historyiIntegrated into UniProtKB/Swiss-Prot: April 1, 1990
Last sequence update: April 1, 1990
Last modified: June 7, 2017
This is version 182 of the entry and version 1 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome

Documents

  1. MGD cross-references
    Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
  2. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  3. SIMILARITY comments
    Index of protein domains and families