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erythropoietin receptor; EPO-R (EPOR)

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 a) LYN (putative) b) adapter protein APS c) PTPN6 (putative) d) PTPN11 e) JAK2 f) PI3 kinases, g) STAT5A/STAT5B h) SOCS3 i) CRKL (putative) - 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

Related

erythropoietin (EPO)

General

cytokine receptor glycoprotein hematopoietin receptor superfamily oligomerizing protein phosphoprotein

Properties

SIZE: entity length = 508 aa MW = 55 kD COMPARTMENT: plasma membrane MOTIF: signal sequence {1-24} cysteine residue {C52} MODIFICATION: cysteine residue {C62} cysteine residue {C62} MODIFICATION: cysteine residue {C52} N-glycosylation site {N76} cysteine residue {C91} MODIFICATION: cysteine residue {C107} cysteine residue {C107} MODIFICATION: cysteine residue {C91} phenylalanine residue {117} fibronectin type III domain or F3 module {144-240} MOTIF: WSXWS motif {233-237} transmembrane domain {251-273} box1 motif SITE: 282-290 FOR-BINDING-OF: Janus kinase (JAK) tyrosine residue {368} Tyr phosphorylation site {Y368} tyrosine residue {426} Tyr phosphorylation site {Y426} immunoreceptor tyrosine-based inhibitory motif (ITIM) {452-457} MOTIF: SOCS3 binding {454-456} tyrosine residue {454} Tyr phosphorylation site {Y454} tyrosine residue {456} Tyr phosphorylation site {Y456} Tyr phosphorylation site {Y468} tyrosine residue {485} Tyr phosphorylation site {Y485} Tyr phosphorylation site {Y489} Tyr phosphorylation site {Y504} MISC-INFO: 1/2life 40 MIN Kd [erythropoietin] 0.1 NM {HIGH-AFFINITY} Kd [erythropoietin] 0.6 NM {LOW-AFFINITY}

Database Correlations

OMIM correlations MORBIDMAP 133171 UniProt P19235 PFAM correlations Entrez Gene 2057 Kegg hsa:2057

References

  1. UniProt :accession P19235
  2. Ihle JN et al Signaling by the cytokine receptor superfamily: JAKs and STATs TIBS 19:222 1994 PMID: 8048164
  3. 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: 2174515
  4. Erythropoietin. Blood. 1991 Feb 1;77(3):419-34. Review. PMID: 1991159
  5. Taga T, Kishimoto T. Cytokine receptors and signal transduction. FASEB J. 1992 Dec;6(15):3387-96. Review. PMID: 1334470
  6. Ihle JN et al Signaling by the cytokine receptor superfamily: JAKs and STATs TIBS 19:222 1994 PMID: 8048164