EPOR
Domain
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.
Contains 1 copy of a cytoplasmic motif that is referred to as the immunoreceptor tyrosine-based inhibitor motif (ITIM). This motif is involved in modulation of cellular responses. The phosphorylated ITIM motif can bind the SH2 domain of several SH2-containing phosphatases.
Function
Receptor for erythropoietin, which mediates erythropoietin-induced erythroblast proliferation and differentiation (PubMed:10388848, PubMed:2163695, PubMed:2163696, PubMed:8662939, PubMed:9774108). Upon EPO stimulation, EPOR dimerizes triggering the JAK2/STAT5 signaling cascade (By similarity). In some cell types, can also activate STAT1 and STAT3 (PubMed:11756159). May also activate the LYN tyrosine kinase (By similarity).
Isoform EPOR-T
Acts as a dominant-negative receptor of EPOR-mediated signaling.
Involvement in disease
Erythrocytosis, familial, 1
ECYT1
An autosomal dominant disorder characterized by elevated hemoglobin and hematocrit, hypersensitivity of erythroid progenitors to erythropoietin, erythropoietin low serum levels, and no increase in platelets nor leukocytes. It has a relatively benign course and does not progress to leukemia.
None
The disease is caused by variants affecting the gene represented in this entry.
Post-translational modifications
On EPO stimulation, phosphorylated on C-terminal tyrosine residues by JAK2 (PubMed:11781573). The phosphotyrosine motifs are also recruitment sites for several SH2-containing proteins and adapter proteins which mediate cell proliferation (PubMed:10374881). Phosphorylation on Tyr-454 is required for PTPN6 interaction, Tyr-426 for PTPN11 (By similarity). Tyr-426 is also required for SOCS3 binding, but Tyr-454/Tyr-456 motif is the preferred binding site (PubMed:12027890).
Ubiquitinated by the ECS(SOCS2) complex following ligand-binding and phosphorylation by JAK2, leading to its degradation by the proteasome (PubMed:11781573, PubMed:31182716). Regulation by the ECS(SOCS2) complex acts as a negative feedback loop of erythropoietin-mediated signaling pathway (PubMed:11781573). Ubiquitination at Lys-281 mediates receptor internalization, whereas ubiquitination at Lys-453 promotes trafficking of activated receptors to the lysosomes for degradation (By similarity). Ubiquitinated by NOSIP; appears to be either multi-monoubiquitinated or polyubiquitinated (PubMed:12746455). Ubiquitination mediates proliferation and survival of EPO-dependent cells (By similarity).
Sequence Similarities
Belongs to the type I cytokine receptor family. Type 1 subfamily.
Tissue Specificity
Erythroid cells and erythroid progenitor cells.
Isoform EPOR-F
Isoform EPOR-F is the most abundant form in EPO-dependent erythroleukemia cells and in late-stage erythroid progenitors.
Isoform EPOR-S
Isoform EPOR-S and isoform EPOR-T are the predominant forms in bone marrow.
Isoform EPOR-T
Isoform EPOR-S and isoform EPOR-T are the predominant forms in bone marrow (PubMed:1324524). Isoform EPOR-T is the most abundant from in early-stage erythroid progenitor cells (PubMed:1324524).
Cellular localization
- Cell membrane
- Single-pass type I membrane protein
- Isoform EPOR-S
- Secreted
- Secreted and located to the cell surface.
Alternative names
Erythropoietin receptor, EPO-R, EPOR