UniProt functional annotation for P19235



	UniProt functional annotation for P19235

UniProt code: P19235.

Organism: Homo sapiens (Human).

Taxonomy: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.

Function: 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.

Function: Isoform EPOR-T acts as a dominant-negative receptor of EPOR- mediated signaling.

Subunit: Forms homodimers on EPO stimulation. The tyrosine- phosphorylated form interacts with several SH2 domain-containing proteins including LYN (By similarity), the adapter protein SH2B2, PTPN6 (By similarity), PTPN11, JAK2, PI3 kinases, STAT5A/B, SOCS3, CRKL (By similarity). Interacts with INPP5D/SHIP1 (By similarity). The N- terminal SH2 domain of PTPN6 binds Tyr-454 and inhibits signaling through dephosphorylation of JAK2 (By similarity). SH2B2 binding also inhibits the JAK-STAT signaling. Binding to PTPN11, preferentially through the N-terminal SH2 domain, promotes mitogenesis and phosphorylation of PTPN11 (By similarity). Binding of JAK2 (through its N-terminal) promotes cell-surface expression (By similarity). Interacts with RHEX; this interaction occurs in a erythropoietin (EPO)-dependent manner (PubMed:25092874). Interaction with the ubiquitin ligase NOSIP mediates EPO-induced cell proliferation. Interacts with ATXN2L. {ECO:0000250, ECO:0000269|PubMed:10374881, ECO:0000269|PubMed:10388848, ECO:0000269|PubMed:11784712, ECO:0000269|PubMed:12027890, ECO:0000269|PubMed:12746455, ECO:0000269|PubMed:25092874, ECO:0000269|PubMed:7534299, ECO:0000269|PubMed:9774108}.

Subcellular location: Cell membrane; Single-pass type I membrane protein.

Subcellular location: [Isoform EPOR-S]: Secreted {ECO:0000269|PubMed:11722595}. Note=Secreted and located to the cell surface.

Tissue specificity: Erythroid cells and erythroid progenitor cells. Isoform EPOR-F is the most abundant form in EPO-dependent erythroleukemia cells and in late-stage erythroid progenitors. Isoform EPOR-S and isoform EPOR-T are the predominant forms in bone marrow. Isoform EPOR-T is the most abundant from in early-stage erythroid progenitor cells.

Domain: The WSXWS motif appears to be necessary for proper protein folding and thereby efficient intracellular transport and cell-surface receptor binding.

Domain: The box 1 motif is required for JAK interaction and/or activation.

Domain: 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.

Ptm: 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-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. {ECO:0000269|PubMed:10374881}.

Ptm: 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. Ubiquitination mediates proliferation and survival of EPO-dependent cells. {ECO:0000250}.

Disease: Erythrocytosis, familial, 1 (ECYT1) [MIM:133100]: 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. {ECO:0000269|PubMed:8506290, ECO:0000269|PubMed:8608241}. Note=The disease is caused by variants affecting the gene represented in this entry.

Similarity: Belongs to the type I cytokine receptor family. Type 1 subfamily. {ECO:0000305}.

Annotations taken from UniProtKB at the EBI.


Organism:		Homo sapiens (Human).
Taxonomy:		Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.



Function:		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.



Function:		Isoform EPOR-T acts as a dominant-negative receptor of EPOR- mediated signaling.


Subunit:		Forms homodimers on EPO stimulation. The tyrosine- phosphorylated form interacts with several SH2 domain-containing proteins including LYN (By similarity), the adapter protein SH2B2, PTPN6 (By similarity), PTPN11, JAK2, PI3 kinases, STAT5A/B, SOCS3, CRKL (By similarity). Interacts with INPP5D/SHIP1 (By similarity). The N- terminal SH2 domain of PTPN6 binds Tyr-454 and inhibits signaling through dephosphorylation of JAK2 (By similarity). SH2B2 binding also inhibits the JAK-STAT signaling. Binding to PTPN11, preferentially through the N-terminal SH2 domain, promotes mitogenesis and phosphorylation of PTPN11 (By similarity). Binding of JAK2 (through its N-terminal) promotes cell-surface expression (By similarity). Interacts with RHEX; this interaction occurs in a erythropoietin (EPO)-dependent manner (PubMed:25092874). Interaction with the ubiquitin ligase NOSIP mediates EPO-induced cell proliferation. Interacts with ATXN2L. {ECO:0000250, ECO:0000269\|PubMed:10374881, ECO:0000269\|PubMed:10388848, ECO:0000269\|PubMed:11784712, ECO:0000269\|PubMed:12027890, ECO:0000269\|PubMed:12746455, ECO:0000269\|PubMed:25092874, ECO:0000269\|PubMed:7534299, ECO:0000269\|PubMed:9774108}.
Subcellular location:		Cell membrane; Single-pass type I membrane protein.
Subcellular location:		[Isoform EPOR-S]: Secreted {ECO:0000269\|PubMed:11722595}. Note=Secreted and located to the cell surface.
Tissue specificity:		Erythroid cells and erythroid progenitor cells. Isoform EPOR-F is the most abundant form in EPO-dependent erythroleukemia cells and in late-stage erythroid progenitors. Isoform EPOR-S and isoform EPOR-T are the predominant forms in bone marrow. Isoform EPOR-T is the most abundant from in early-stage erythroid progenitor cells.
Domain:		The WSXWS motif appears to be necessary for proper protein folding and thereby efficient intracellular transport and cell-surface receptor binding.
Domain:		The box 1 motif is required for JAK interaction and/or activation.
Domain:		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.
Ptm:		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-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. {ECO:0000269\|PubMed:10374881}.
Ptm:		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. Ubiquitination mediates proliferation and survival of EPO-dependent cells. {ECO:0000250}.
Disease:		Erythrocytosis, familial, 1 (ECYT1) [MIM:133100]: 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. {ECO:0000269\|PubMed:8506290, ECO:0000269\|PubMed:8608241}. Note=The disease is caused by variants affecting the gene represented in this entry.
Similarity:		Belongs to the type I cytokine receptor family. Type 1 subfamily. {ECO:0000305}.