erythropoietin receptor; EPO-R (EPOR)
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Function
- receptor for erythropoietin
- mediates erythropoietin-induced erythroblast proliferation & differentiation
- upon EPO stimulation, EPOR dimerizes triggering the JAK2/STAT5 signaling cascade.
- in some cell types, can also activate STAT1 & STAT3
- may also activate the LYN tyrosine kinase
- isoform EPOR-T, missing the cytoplasmic tail, acts as a dominant-negative receptor of EPOR-mediated signaling
- forms homodimers on EPO stimulation
- Tyr-phosphorylated form interacts with several SH2 domain- containing proteins including
- interacts with INPP5D/SHIP1
- N-terminal SH2 domain of PTPN6 binds Tyr-454 & inhibits signaling through dephosphorylation of JAK2 (putative)
- APS binding also inhibits the JAK-STAT signaling
- binding to PTPN11, preferentially through the N-terminal SH2 domain, promotes mitogenesis & phosphorylation of PTPN11 (putative)
- binding of JAK2 (through its N-terminal) promotes cell-surface expression (putative)
- interaction with the ubiquitin ligase NOSIP mediates EPO-induced cell proliferation
- interacts with ATXN2L
- on EPO stimulation, phosphorylated on C-terminal Tyr by JAK2
- the phospho-Tyr motifs are recruitment sites for several SH2-containing proteins & adapter proteins which mediate cell proliferation
- phosphorylation on Tyr-454 is required for PTPN6 interaction, Tyr-426 for PTPN11.
- Tyr-426 is also required for SOCS3 binding, but Tyr-454/Tyr-456 motif is the preferred binding site
- ubiquitinated by NOSIP; appears to be either multi- monoubiquitinated or polyubiquitinated
- ubiquitination mediates proliferation & survival of EPO-dependent cells
Structure
- the WSXWS motif appears to be necessary for proper protein folding, efficient intracellular transport & cell- surface receptor binding
- the box 1 motif is required for JAK interaction &/or activation
- contains 1 copy of a cytoplasmic motif that is referred to as the immunoreceptor tyrosine-based inhibitor motif (ITIM)
- phosphorylated ITIM motif can bind the SH2 domain of several SH2-containing phosphatases
- belongs to the type I cytokine receptor family, type 1 subfamily
- contains 1 fibronectin F3 module
Compartment
- cell membrane
- isoform EPOR-S: secreted
- secreted & located to the cell surface
Alternative splicing
named isoforms=3
Expression
- erythroid cells & erythroid progenitor cells.
- isoform EPOR-F is the most abundant form in EPO-dependent erythroleukemia cells & in late-stage erythroid progenitors
- isoform EPOR-S & isoform EPOR-T are the predominant forms in bone marrow
- isoform EPOR-T is the most abundant from in early-stage erythroid progenitor cells
Pathology
- defects in EPOR are the cause of erythrocytosis familial type-1
More general terms
- hematopoietin receptor superfamily
- cytokine receptor
- glycoprotein
- phosphoprotein
- oligomerizing protein
Additional terms
References
- ↑ UniProt http://www.uniprot.org/uniprot/P19235.html
- ↑ Ihle JN et al Signaling by the cytokine receptor superfamily: JAKs and STATs TIBS 19:222 1994 PMID: https://www.ncbi.nlm.nih.gov/pubmed/8048164
- ↑ Yoshimura A, Longmore G, Lodish HF. Point mutation in the exoplasmic domain of the erythropoietin receptor resulting in hormone-independent activation and tumorigenicity. Nature. 1990 Dec 13;348(6302):647-9. PMID: https://www.ncbi.nlm.nih.gov/pubmed/2174515
- ↑ Erythropoietin. Blood. 1991 Feb 1;77(3):419-34. Review. PMID: https://www.ncbi.nlm.nih.gov/pubmed/1991159
- ↑ Taga T, Kishimoto T. Cytokine receptors and signal transduction. FASEB J. 1992 Dec;6(15):3387-96. Review. PMID: https://www.ncbi.nlm.nih.gov/pubmed/1334470
- ↑ Ihle JN et al Signaling by the cytokine receptor superfamily: JAKs and STATs TIBS 19:222 1994 PMID: https://www.ncbi.nlm.nih.gov/pubmed/8048164