Disease relevance of Epor

• Two recombinant retroviruses expressing EpoR(R129C), spleen focus-forming virus (SFFVc-EpoR) and myeloproliferative sarcoma virus (MPSVcEpoR), were used to infect fetal liver cells that served as a source of hematopoietic progenitors [1].
• Role of erythropoietin receptor signaling in Friend virus-induced erythroblastosis and polycythemia [2].
• Previous studies suggested that the Friend virus oncoprotein, gp55, constitutively activates the erythropoietin receptor (EPOR), causing uncontrolled erythroid proliferation [2].
• Initiation of the erythroleukemia is due to binding of the env-related glycoprotein gp55 encoded by F-SFFV to the erythropoietin receptor (EPOR) [3].
• Mice infected with SFFVcEpoR, but not a virus expressing wild type EpoR (SFFVEpoR), developed erythrocytosis and splenomegaly [4].

Psychiatry related information on Epor

• Injection of recombinant erythropoietin reduced expression of interleukin-1beta, interleukin-1beta receptor, and erythropoietin receptor genes in the brain of experimental animals and considerably increased their motor activity in the open field test [5].
• Significant differences in brain morphology and expression of cytokine IL-1 beta, type I IL-1 receptor, and erythropoietin receptor genes in brain cells were detected in (CBA x C57Bl/6)F1 mice with different initial levels of orientation and exploratory behavior [6].

High impact information on Epor

• Stat5 is rapidly activated following EpoR stimulation, but its function in erythropoiesis has been unclear since adult Stat5a-/-5b-/- mice have normal steady-state hematocrit [7].
• Compared to erythropoietin receptor-deficient mice, the phenotype of Jak2 deficiency is more severe [8].
• The JAK2-GHR and JAK2-erythropoietin receptor interactions described here and in the accompanying paper provide a molecular basis for involvement of tyrosyl phosphorylation in physiological responses to these ligands and suggest a shared signaling mechanism among members of the cytokine/hematopoietin receptor family [9].
• The activated erythropoietin receptor does not transform cultured fibroblasts, suggesting why oncogenic mutations in other members of this receptor superfamily have not been detected [10].
• A point mutation at codon 129 of the murine erythropoietin receptor (cEpoR) results in constitutive activation [10].

Chemical compound and disease context of Epor

• The EPOR can be activated, resulting in proliferation independent of EPO either by an Arg129 to Cys point mutation or by association with the Friend spleen focus-forming virus (SFFV) envelope glycoprotein gp55 [11].
• In mice expressing a phosphotyrosine-null (PY-null) Epo receptor allele (EpoR-HM), severe and persistent anemia was induced by hemolysis or 5-fluorouracil [12].
• Not only do erythroid cells express the Epo receptor (EpoR), but those from mice susceptible to SFFV-induced erythroleukemia also express a short form of the receptor tyrosine kinase Stk (sf-Stk) [13].
• Our results also demonstrate that treatment of the established murine erythroleukemia cell line HB60-5 with celecoxib results in suppression of c-Kit and erythropoietin receptor (Epo-R) phosphorylation resulting in apoptosis, likely through decreased levels of survival factors [14].

Biological context of Epor

• Protein tyrosine phosphorylation has been hypothesized to play a key role in the growth signaling induced by erythropoietin (Epo), although the Epo receptor (EpoR), a member of the cytokine receptor superfamily, lacks a tyrosine kinase domain [15].
• Nonetheless, steady-state erythropoiesis is supported effectively by EpoR alleles that are deficient in cytoplasmic phosphotyrosine sites [16].
• The aberrant EPOR transcripts containing the 3' long terminal repeat sequence were mainly expressed in F5-5 cells [17].
• Thus, it appears that EPO has the same effect on EPO-R-expressing multipotent cell proliferation as would a combination of several growth factors [18].
• These results suggest that, for downregulation of cell surface ligand occupied EPO-R and possibly for signaling receptors of the cytokine receptor superfamily in general, internalization of cell surface ligand occupied receptors may follow a pathway distinct from signaling receptors of the receptor tyrosine kinase (RTK) family [19].

Anatomical context of Epor

• The same integration upstream of the EPOR gene was also observed in other subclones and the parent cell line [17].
• Core erythropoietin receptor signals for late erythroblast development [16].
• By introducing, with a retroviral vector, a normal EPO-R cDNA into murine adult bone marrow cells, we showed that EPO is also able to induce proliferation in pluripotent progenitor cells [18].
• In the presence of EPO alone, EPO-R virus-infected bone marrow cells gave rise to mixed colonies comprising erythrocytes, granulocytes, macrophages and megakaryocytes [18].
• These results indicate that JAK1 is involved in the gp55/EPOR signaling but STAT5 is not playing an essential role in the growth of those erythroid cells [3].

Associations of Epor with chemical compounds

• This cytoplasmic domain is also the minimal domain required for activation of JAK2, a cytosolic tyrosine kinase essential for the function of the EPO-R [19].
• Alanine scanning mutagenesis of the EpoR membrane proximal region reveals two modes of EpoR-JAK2 interaction [20].
• Zidovudine-induced blockade of the expression and function of the erythropoietin receptor [21].
• Cardiac erythropoietin receptor expression was downregulated in doxorubicin-induced cardiomyopathy but was restored by erythropoietin [22].
• Furthermore, constitutively high amounts of protein kinase activity were observed in Epo receptor complexes isolated from autonomously growing cells coexpressing the Epo receptor and the leukemogenic glycoprotein gp55 [23].

Physical interactions of Epor

• Activation of the erythropoietin receptor is not required for internalization of bound erythropoietin [19].
• Erythropoietin receptor Y479 couples to ERK1/2 activation via recruitment of phospholipase Cgamma [24].
• Erythropoietin-dependent autocrine secretion of tumor necrosis factor-alpha in hematopoietic cells modulates proliferation via MAP kinase--ERK-1/2 and does not require tyrosine docking sites in the EPO receptor [25].
• We propose that these two tyrosine residues of the erythropoietin receptor constitute docking sites for the STAT5 SH2 domain [26].

Enzymatic interactions of Epor

• A common epitope is shared by activated signal transducer and activator of transcription-5 (STAT5) and the phosphorylated erythropoietin receptor: implications for the docking model of STAT activation [27].
• However, recent studies have shown that there is a physical association between these 2 receptors and that c-kit can phosphorylate EPO-R [28].
• This appears to be due, in large part, to the specific association of PI 3-kinase with the tyrosine-phosphorylated EpR, either directly or through a 93- or 70-Kd tyrosine-phosphorylated intermediate [29].

Regulatory relationships of Epor

• Moreover, the ability of EPO to override these checkpoints in cells expressing defective EPO-R mutants could be restored by overexpression of a constitutively active Akt [30].
• Erythropoietin receptor haploinsufficiency and in vivo interplay with granulocyte-macrophage colony-stimulating factor and interleukin 3 [31].
• Through the expression of EPOR carboxyl-terminal truncation mutants in FDC-P1 cells, we presently show that an EPOR form truncated within the ExBx2 domain efficiently activates Jak2, yet is deficient in mitogenesis [32].
• These findings extend a mechanistic alignment between the EPO receptor and protein tyrosine kinase-encoding receptors that likewise activate PI3-K, and expand the importance of further defining pathways to PI3-K activation [33].
• We have shown previously that the tyrosine kinase Lyn is involved in differentiation signals emanating from an activated erythropoietin receptor [34].

Other interactions of Epor

• Wild-type signaling capacities, however, depend further upon signals provided via an EpoR/PY343/Stat5 axis [16].
• Stat1 and Stat3 activation was nominal for all EpoR forms [16].
• To determine the function of this motif, we constructed deletion and insertion mutations in this part of the EPOR and introduced them into an interleukin-3 (IL-3)-dependent hematopoietic Ba/F3 cell line [11].
• Erythropoietin receptor and interleukin-2 receptor use different downstream signaling pathways for proliferation and apoptosis-block [35].
• Given the requirement for sf-STK, we sought to establish the in vivo significance of gp55-mediated activation of the EPOR [2].

Analytical, diagnostic and therapeutic context of Epor

• Molecular cloning of F5-5-derived cDNA encoding EPOR revealed that the 5' noncoding region of the EPOR cDNA corresponds to the 3' long terminal repeat sequence of the polycythemic strain of Friend spleen focus-forming virus (F-SFFVP) [17].
• Northern (RNA) and Southern blot analyses revealed overexpression of mRNA for the EPO receptor (EPOR) and rearrangement of one of the EPOR gene alleles in F5-5 cells, respectively [17].
• Our data, obtained by electrophoretic mobility shift assays (EMSA) and reporter gene assays, show that the intracellular domain of the EPO receptor (EPOR) transmits signals leading to the activation of NF-kappaB [36].
• The immunoprecipitation data indicated the existence of a preformed V(H)-gp130 and V(L)-EpoR heterodimer in the absence of lysozyme, suggesting the crucial role of a receptor conformational change in signal triggering as well as wild-type EpoR and gp130 [37].
• In situ hybridization studies have revealed that erythropoietin-receptor (EPOR) mRNA accumulation begins in mesoderm cell masses of the developing yolk sac of the neural plate stage embryo (E7.5) before the development of morphologically recognizable erythroblasts [38].

References