Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

Erythropoietin Receptor

Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101844

Synonyms

 EPO-R

Historical Background

The erythropoietin receptor (EPOR) and its cognate ligand, erythropoietin (EPO), are required for maintaining adequate levels of circulating erythrocytes during embryogenesis and adulthood by promoting erythroid mitogenesis, survival, and differentiation. Before the cloning of the EPOR cDNA, radiolabeled EPO was used to demonstrate specific binding to normal erythroid progenitors, murine and human erythroleukemia cells, and cells from human fetal liver. Then in 1989, the EPOR cDNA has been cloned by transfection of recombinant plasmid pools of murine cDNA from murine erythroleukemia (MEL) cell line into COS cells. A single cDNA was isolated that confers to COS cells the ability to bind EPO (D’Andrea et al. 1989). This murine EPOR cDNA, expressed in COS cells, generates high-affinity (30 pM) and low-affinity (210 pM) receptors. In 1990, the human homologue of the murine EPOR has been isolated from an erythroleukemia line and from fetal liver (Jones et al. 1990). Both cDNA and protein sequences of the human receptor are 82% similar to the sequences of the murine receptor. Scatchard analysis of the EPO-EPOR binding revealed the presence of two receptor species having apparent dissociation constants of 30 pM and 210 pM. Also, it has been shown that approximately 200 EPORs are present on the surface of normal erythroid progenitor cells (CFUe) in the bone marrow and that this number increases to about 1000 per cell on certain cell lines. Since then, the EPOR gene has been cloned from 126 organisms.

Gene and Protein Structures

Budarf et al. (1990) mapped the human EPOR gene to 19pter-q12 by hybrid analysis of somatic cells, and the murine locus was found near the centromere of chromosome 9. This region of mouse chromosome 9 is homologous to the human 19p13 region. Using a highly informative simple sequence repetition polymorphism (PIC = 0.86) at the 5-prime end of the EPOR gene, the gene has been mapped at position 19p13.2. The coding region extends over about 6.5 kb with 7 introns whose size varies from 87 bp (exons 6 and 7) to 2.1 kbp (exon 8) (Fig. 1).
Erythropoietin Receptor, Fig. 1

Gene and transcripts of the monomer of erythropoietin receptor. The human and mouse EPOR genes have eight exons and seven introns. Exons 1–5 encode the extracellular domain; exon 6 encodes the membrane-spanning region. The cytoplasmic domain is encoded by exons 7 and 8. Three mRNAs have been identified. The full-length mRNA encodes a 507/508 amino acid peptide. The EPOR-S mRNA encodes a soluble form of the receptor. It results from an alternative splicing event introducing a stop codon before the sequence of the membrane-spanning region. The EPOR-T mRNA encodes a protein that lacks most of the cytoplasmic region except for 56 amino acids encoded by exon 7 and intron 7 (Not drawn to scale)

The human and murine genes encode a 508/507 amino acid protein, respectively. Besides the full-length mRNA, two EPOR splice variants are known (Fig. 1; Arcasoy et al. 2003; http://www.ncbi.nlm.nih.gov/gene/2057). Posttranslation modifications lead to the cleavage of the N-terminal 24-amino acid signal peptide, glycosylation, phosphorylation, and ubiquitination resulting in a mature 66–105 kDa protein. As observed in other cytokine receptors, the EPOR has a cytoplasmic domain, a single transmembrane segment, and an extracellular region with a tryptophan-serine-X-tryptophan-serine motif (Fig. 2; McCaffery et al. 1989). Crystallographic studies demonstrate that the extracellular domain exists as a dimer in the absence of EPO. Also, as member of the cytokine receptor family, EPOR presents small regions of homology with four conserved cysteines forming two disulfide bonds and a WSxWS sequence near the transmembrane region. Mutagenesis studies have identified two leucine residues at positions 240 and 241 in the transmembrane domain that are crucial for receptor dimerization. The intracellular domain is composed of two different functional regions called Box-1 and Box-2 which also exist in other cytokine receptors. The juxtamembrane region between the transmembrane domain and Box-1 contains a conserved hydrophobic motif leading to a conformationally rigid region (Constantinescu et al. 2001). The transmembrane region is responsible for the homodimerization of the receptor in response to EPO binding (Kubatzky et al. 2005). Eight tyrosines of the cytoplasmic domain can be phosphorylated and serve as an anchor site for different types of signaling molecules.
Erythropoietin Receptor, Fig. 2

Organization of the monomer of the erythropoietin receptor. EPOR homoneric protein is a class I member of the cytokine receptor family. It is a single transmembrane protein of 66 KDa with an extracellular region that includes a fibronectin type III repeat divided into two subdomains, termed D1 and D2. The D1 domain possesses four cysteine residues (bleu lines). The extracellular domain also contains a membrane proximal domain containing a WSxWS motif that creates an aromatic stack that appears to be necessary for expression and stability. The transmembrane domain (TM) contains 24 amino acids. A major feature of the cytoplasmic domain is the proline rich Box-1 motif, which together with the less-conserved distal Box-2 containing aromatic and acidic residues serves to bind the JAK2 proteins close to the cell membrane. They are involved in JAK2 kinase activation. The eight specific tyrosine residues in the cytoplasmic domain are marked by green lines. The EPOR-S is a soluble protein lacking the transmembrane and cytoplasmic domains, which is potentially an EPO antagonist. The isoform EPOR-T has a short cytoplasmic domain of 56 amino acids. It acts as a dominant-negative receptor of EPOR-mediated signaling. Also, a point mutation in the extracellular domain in which the arginine at position 129 is changed to a cysteine has been described. This leads to a receptor that is constitutively active in the absence of the ligand (Not drawn to scale)

In Xenopus laevis, the identities of the entire deduced amino acid sequences with human and murine EPOR are 33.3% and 34.2%, respectively. The sequence reveals the cysteine residues, the WSXWS motif, and two additional cysteine residues. In the cytoplasmic domain, Box-1/2 motifs are conserved. No tyrosine kinase catalytic domain exists whereas seven tyrosine residues are present. Interestingly, after the Box-2 motif, there is an insertion of 55 residues including one tyrosine that have no similar sequence related to mammalian EPOR.

Sequence identity between zebrafish EPOR and other vertebrates is relatively low: Fugu rubripes, 44%; Tetraodon nigroviridis, 41%; Xenopus laevis, 22%; Xenopus tropicalis, 22%; Mus musculus, 26%; and Homo sapiens, 27%. Despite this, the zebrafish EPOR retains key structural features. In the extracellular domain, it possesses the four highly conserved cysteine residues and the “WSxWS” domain. In the cytoplasmic domain, there are the conserved Box-1 and Box-2 domains, as well as five of eight tyrosine residues (Paffett-Lugassy et al. 2007).

Distribution of the Erythropoietin Receptor

In mouse embryos, EPOR expression begins at day 7.5 in both endothelial and primitive blood cells. An increased expression is found in the yolk sac vasculature and vitelline vessels. In Xenopus laevis, in situ hybridization studies revealed that EPOR is expressed in the ventral blood island of the developing tadpole, the site of primitive hematopoiesis, the equivalent to the mammalian yolk sac. Later, EPOR transcripts are detected in circulating blood (Yergeau et al. 2006). During zebrafish development, EPOR transcripts are detected in presumptive hematopoietic precursors, then in circulating erythrocytes, and finally only in the brain.

In human and mouse adults, the majority of the EPOR is located on the cell surface of erythroid progenitors, erythroid burst-forming units (BFU-E), and erythroid colony-forming units (CFU-E) in the bone marrow. The EPOR is also expressed in non-hematopoietic tissues that locally produce or use EPO. It is expressed in cardiomyocytes, reproductive tract, brain, endothelial cells, and pancreatic beta cells which show biological responses following receptor activation; in skeletal muscle, EPOR protein is present in sarcolemma and capillaries and mRNA expressed in muscle fibers. In addition, both EPOR mRNA and protein are expressed in human satellite cells. In non-hematopoietic tissue, two receptor partners for EPOR have been proposed. They form heterodimer or heterotrimer that result in signaling involved in tissue protection. In a variety of cells, including microglia, cardiomyocytes, astrocytes, renal tubular and collecting duct cells, neurons, smooth muscle cells, myoblasts, retina, and vascular cells, the β-common receptor (βCR), a common β-chain subunit of the high-affinity receptor for interleukin 3 (IL3), interleukin 5 (IL5), and granulocyte–macrophage colony stimulation factor (GM-CSF2), is colocalized and interacts with the EPOR to form heterodimeric EPOR/βCR or heterotrimeric EPOR/βCR/EPOR receptors. The other partner of EPOR is the epinephrine B4 receptor (EPHB4) that forms the heterodimer EPOR/EPHB4. It has been proposed that they form novel EPOR complexes, termed NEPOR, involved in tissue protection (Fig. 3; Debeljak et al. 2014).
Erythropoietin Receptor, Fig. 3

The novel erythropoietin receptor complexes (NEPOR). In non-hematopoietic tissue, EPOR partners have been identified, including the β-common receptor (βCR) and the epinephrine B4 receptor (EPHB4). The signaling networks they generate are still not well understood. They may involve signal pathways different from those triggered by EPOR dimers (Adapted from Debeljak et al. 2014. (Not drawn to scale))

Erythropoietin Receptor and Signaling Pathways

In the cell membrane of hematopoietic cells, EPOR forms an homodimer that is activated by a single EPO ligand molecule. Unlike most other tyrosine kinase receptors, EPOR lacks an intrinsic kinase activity, requiring kinase from the Janus family of tyrosine kinase (JAK2) to trigger signaling pathways (Fig. 4).
Erythropoietin Receptor, Fig. 4

The erythropoietin receptor and signaling pathways. Activation of EPOR is initiated by the direct binding of a single EPO molecule with two membrane-spanning EPOR proteins that form homodimers. The dimer undergoes a conformational change that phosphorylate JAK2 kinase, which is constitutively associated with cytoplasmic domains of homodimers. In turn, JAK2 kinases mediate rapid phosphorylation of eight conserved tyrosine residues (of which the six most important are shown). They generate signaling pathways required for cell proliferation, survival, and differentiation. The proteins that dephosphorylate JAK2 or inhibit STAT5 and ERK pathways are indicated

The interaction between EPOR and JAK2 is initiated in the endoplasmic reticulum and promotes maturation of the receptor as well as its addressing to cell surface. Homodimerization of EPOR in response to EPO induces conformational changes in the extracellular domain of the receptor that subsequently allows the activation of two JAK2 molecules associated with the Box-1/2 motifs. JAK2 molecules are activated by autophosphorylation and in turn phosphorylate eight tyrosine residues in the cytoplasmic domain (Kubatzky et al. 2005). They serve as docking sites for several proteins, which subsequently activate the above signaling pathways (Fig. 4). The signal transducer and activator of transcription 5 (STAT5) is recruited to phosphorylated tyrosine residues at Y343 and Y401 through its Src homology 2 (SH2) domain. The STAT3 is recruited through the phosphorylated Y431. STAT3 and STAT5 are both phosphorylated, and then they homodimerize and translocate to the nucleus where they act as transcription factors. The G-protein RAS, bounded to phosphorylated tyrosine by several adaptor proteins, acts as a switch, activating both the rat sarcoma/mitogen-activated protein kinase/extracellular signal-regulated kinase (RAS/MEK/ERK) and the phosphatidylinositol 3-kinase/serine/threonine kinase (PI3K/Akt) pathways. The RAF protein kinase activates sequential phosphorylation of MEK/ERK whose ERK, the last element of the cascade, translocates into the nucleus. It activates cofactors such as the ETS transcription factor ELK-1, to transcribe target genes. The RAF/MEK/ERK pathway also is activated by protein kinase C (PKC) via phosphorylation of RAF or MEK. EPOR cytoplasmic domain also associates with the growth factor receptor protein 2 (GRB2) and the p85 α subunit of phosphatidylinositol 3 kinase (PI3K) via phosphorylated tyrosine residues at Y464 and Y429/431 or Y479, respectively. GRB2 induces the activation of ERK through the MEK pathway. The p85 regulatory subunit of PI3K induces the activation of Akt through the phosphorylation of phosphatidylinositol resulting in the activation of several transcription, translation, and regulation factors. Downstream genes, mainly BCL-xL, BCL-3, cyclin D1, c-MYC, and c-FOS, whose transcription and translation are stimulated by these pathways, impact biological functions of EPOR such as proliferation, differentiation, regulation of apoptosis, and drug resistance. In addition, Y464 and/or Y479 recruits the SH2 domain of the Src tyrosine kinase Lyn. In turn, Lyn phosphorylates the CRKL adapter protein, recruited on Y460, resulting in the augmentation of MAPK activation.

In contrast to phosphorylation that activates EPOR signaling, dephosphorylation tightly downregulates EPOR activities. The SH2 domain-containing tyrosine phosphatase 1 (SHP1) binds phosphorylated Y429 and Y431 and subsequently dephosphorylates JAK2, thereby inactivating the kinase and downregulating the signaling cascade. The cytokine-inducible SH2-domain-containing protein (CIS) interacts with phosphorylated Y401. Suppressor of cytokine signaling 3 (SOCS3) interacts with phosphorylated Y401 or Y429 and Y431. CIS and SOCS3 both inhibit the activation of pathways mediated by STAT5 and ERK. Interestingly, the transcription of SOCS3 and CIS is induced by EPO, thus allowing a negative feedback loop to regulate EPOR biological functions. Also, it has been suggested that CIS may promote EPOR degradation leading to EPOR downregulation. Two other pathways of EPO-induced EPOR downregulation have been proposed. Ubiquitination of EPOR at Lys256 provokes efficient EPO-induced receptor internalization, and ubiquitination at Lys428 promotes trafficking of EPOR to the lysosomes for degradation. Therefore, ubiquitination controls EPOR downregulation, downstream signaling, and its biological functions.

Biological Functions

EPOR is mainly involved in proliferation, differentiation, and regulation of apoptosis during erythropoiesis. Erythropoiesis is a central feature of vertebrate development. Erythroid cells in vertebrates come from primitive erythropoiesis in the embryonic yolk sac or its equivalent and definitive erythropoiesis in the yolk sac or the aorta–gonad–mesonephros region, shift to the kidney, spleen, liver, or bone marrow, and last for the life span of the organism. The role of EPOR was first demonstrated in mice that do not express the EPOR. These mice have fewer primitive erythrocytes in the yolk sac blood islands and die between day 13 and 15 of gestation, owing to failure of definitive fetal liver erythropoiesis. By culturing fetal livers from embryos, the authors show that BFU-E and CFU-E progenitors were present suggesting that EPORs are not required for erythroid lineage commitment or for the proliferation and differentiation of BFU-E to CFU-E progenitors. The results reveal an essential role for EPOR in regulating definitive erythropoiesis by controlling processes such as proliferation, survival, and irreversible terminal differentiation of the late CFU-E progenitors, resulting in the formation of mature circulating red blood cells. Detailed examination of EPOR-null mouse embryos also show cardiac ventricular hypoplasia and increased apoptosis in the myocardium and brain. It has been reported that EPOR signaling regulates neural progenitor cell (NPC) differentiation and that EPOR expression levels is downregulated as NPCs terminally differentiated into mature neurons (Chen et al. 2007). Interestingly, conditional EPOR deletion in the brain leads to reduced cell proliferation in the subventricular zone where in vivo neurogenesis takes place in adult mice (Tsai et al. 2006).

In zebrafish, knockdown of the EPOR causes a decrease in primitive erythropoiesis and a complete block of definitive erythropoiesis (Paffett-Lugassy et al. 2007).

In adults, the main function of the EPO is the regulation of erythropoiesis by binding and activating EPOR on the surface of erythroid progenitor and precursor cells in the bone marrow. The responses of hematopoietic cells to EPO depend, at least partly, on the extent of EPOR expression. EPOR expresses at low levels on early erythroid progenitor cells (i.e., BFU-E); its expression then increases during erythroid differentiation by the CFU-E stage and is downregulated during late erythropoiesis, so that reticulocytes and mature red blood cells do not express EPOR.

The discovery of EPOR expression in a number of non-hematopoietic tissues suggests that the effects of EPOR activation extend beyond regulation of erythropoiesis and provides support for the various biological functions of EPO-EPOR. EPOR signaling promotes endothelial cell proliferation, tissue protection, and especially amelioration of neuronal recovery from injury (Brines and Cerami 2006). It also promotes endothelial cell and smooth muscle cell protection and cardiomyocyte survival after ischemia–reperfusion injury. These cytoprotective effects of EPOR signaling appear to require nanomolar concentrations of EPO that are not normally reached in plasma, whereas only low picomolar concentrations are required for erythropoiesis. Such differential binding affinities allow specific activation of erythroid and non-erythroid EPOR, preventing cross talk between the erythropoietic and cytoprotective effects of EPO.

EPOR signaling has protective effects on cardiac as well as vascular tissues, by either preventing apoptosis of cardiac myocytes, smooth muscle cells, and endothelial cells or by increasing endothelial production of nitric oxide. Accumulating experimental evidence suggests that EPOR signaling contributes to cardiomyocyte survival after ischemia-reperfusion injury. The EPO-induced cardioprotection was at least partly related to apoptosis inhibition and augmented cardiomyocyte survival, mediated by activating EPOR and/or EPOR/βCR complex (Xu et al. 2009). Moreover, numerous studies provided the evidence of EPOR localization in endothelial cells. It was therefore suggested that EPOR signaling was involved in increased angiogenesis in vascular system and survival of endothelial cells (Teng et al. 2011). Overall current evidence suggests that the vascular protective effects of EPOR signaling are dependent on nitric oxide (NO) production through increased of endothelial nitric oxide synthase (eNOS) phosphorylation via activation of the EPOR in endothelial cells, mediated by JAK2 activation and then PI3K and Akt phosphorylation (Satoh et al. 2006). This EPOR signaling increase in NO production improves the endothelium-dependent relaxation of arteries and then contributes to prevent cardiovascular disorders.

Because EPOR expression persists in the human brain after birth and throughout adulthood, EPOR signaling has been suggested to play a specific role in the brain. Using different animal models, it has been shown that exogenous EPO administration attenuated brain damage related to several tissue injuries during hypoxia/ischemia, after brain trauma, and neurotoxic and excitotoxic insults (Ogunshola and Bogdanova 2013). After binding with EPOR and/or EPOR/βCR, the cerebrovascular protective effects of EPOR activation involve several signaling pathways that contribute to explain the decreased excitatory amino acid release, inhibition of apoptosis, and stimulation of neurogenesis and angiogenesis. These cerebrovascular protective effects of EPOR signaling may appear to be mediated by NO production via activation of the Akt/eNOS signaling pathway and by inhibition of inducible nitric oxide synthase (iNOS) activity, preventing the formation of NO excess. Moreover, previous studies demonstrated the crucial role of endogenous EPO/EPOR on the mobilization, recruitment, and activation of endothelial progenitor cells, which in turn may contribute to vascular repair and neovascularization (Heeschen et al. 2003).

Erythropoietin Receptor and Pathologies

Mutations in the EPOR result in primary familial and congenital polycythemia (PFCP). PFCP, also known as familial erythrocytosis, is an inherited hematological disorder affecting bone marrow progenitor cells of the erythroid lineage. It is characterized by elevated hematocrit and hemoglobin levels or an increased red cell mass. It is also characterized by an hypersensitivity of erythroid progenitors to EPO and low serum levels of EPO. It is caused by uncontrolled red blood cell production. The phenotype is associated with normal leukocyte and thrombocyte counts, absence of splenomegaly, and lack of progression to clonal bone marrow disorders and leukemia (Bento et al. 2016). Actually, more than 22 EPOR mutations associated with PFCP phenotype have been described within exon 8 which encodes the C-terminal domain of the protein. Eighteen are frameshift mutations leading to a truncation of 59–84 amino acids in the C-terminal region (Bento et al. 2016). Also, in a kindred with autosomal dominantly inherited familial erythrocytosis, a nonsense mutation has been reported. It affects codon 399 in exon 8 leading to an EPOR peptide that is truncated by 110 amino acids at its C-terminal region (Arcasoy et al. 2003). Other EPOR mutations in PFCP have been found to be generated by insertion, deletion, or duplication (see Table 2 in Huang et al. 2010).

Several studies have reported EPOR expression in primary cancers as well as in tumor cell lines such as non-small cell lung cancer, head and neck squamous cell carcinoma, renal cell carcinoma, breast, prostate and gastric carcinomas, solid tumors of nervous system, tumors of female reproductive organs, and malignant melanoma (see Table 1 in Hardee et al. 2006). EPOR signaling may contribute to the growth and survival of these cells and not only enhance but also attenuate the resistance of cancer cells to different therapies. This is why today the role of EPOR signaling in tumor cells remains controversial (Szenajch et al. 2010).

In acute lymphoblastic leukemia, where chromosomal rearrangements are a hallmark, four different rearrangements of the EPOR have been described. They result in its cytoplasmic-tail truncation at residues similar to those mutated in PFCP. These rearrangements provoke the stabilization of EPOR and its hypersensitivity to EPO and heighten the activation of STAT5/3 signaling (Iacobucci et al. 2016).

Animal Models of Human Erythropoietin Receptor Pathologies

A mouse model of PFCP has been generated by replacing the murine EPOR with a truncated human EPOR that has been identified in PFCP patients. Within 3–6 weeks of age, the mice develop polycythemia. They show increased hematocrit and elevated hemoglobin concentrations, thus mimicking the human phenotype. This animal model can be used to investigate EPOR function in erythroid tissue as well as in non-erythropoietic tissues that express EPOR.

Summary

The EPOR is a member of the cytokine receptor family. The main role of EPOR and its ligand EPO is to maintain adequate levels of circulating erythrocytes during embryogenesis and adulthood inducing erythroid proliferation, differentiation, and survival. The EPOR gene has been cloned and mapped in humans on chromosome 19p13.2. EPOR has a cytoplasmic domain, a single transmembrane segment, and an extracellular region. As in cytokine receptors, the intracellular domain possesses the proline rich Box-1 motif, which together with the less-conserved distal Box-2 containing aromatic and acidic residues serves to bind the JAK2 proteins close to the cell membrane. The transmembrane part of the protein is responsible for receptor homodimerization in response to EPO. The homodimer allows the activation by autophosphorylation of JAK2 and by consequence the phosphorylation of eight tyrosines in the cytoplasmic domain. They constitute docking sites for several cytoplasmic proteins and activate signaling pathways. EPOR is present in hematopoietic tissues of embryos and adults where it promotes proliferation, differentiation, and regulation of apoptosis during erythropoiesis. In adults, EPOR is also expressed on numerous non-erythropoietic cells, associated with βCR or epinephrine B4 receptors to form heterodimer/trimers named NEPOR. The signaling pathways they generate, though still not well understood, lead to protective effects for tissues which express them. Mutations in human EPOR and chromosomal rearrangements are responsible of pathologies such as erythrocytosis and lymphoblastic leukemia. EPOR gene expression is widespread in both human cancer cell lines and in primary tumors. Although evidence from many experiments supports an effect of EPOR signaling on cell growth enhancement in tumor cell lines, further investigation is necessary to clarify the relationship among functional EPOR expression and EPOR signaling pathways in cell growth and survival in human tumors.

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Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Laboratoire de Biologie du développementSorbonne Universités, UPMC Universités Paris 06, CNRS, Institut de Biologie Paris Seine (LBD – IBPS)ParisFrance
  2. 2.Agence Française de Lutte contre le DopageParisFrance
  3. 3.Laboratoire Hypoxie et PoumonsSorbonne Paris cité Universités Paris 13Bobigny CedexFrance