Erythropoietin receptor
Encyclopedia
The erythropoietin receptor (EpoR) is a protein
that in humans is encoded by the EPOR gene
. EpoR is a 59 kDa
peptide
and is a member of the cytokine receptor
family. EpoR pre-exists as dimers
which upon binding of a 34 kDa ligand erythropoietin
(Epo), changes its homodimerized state. These conformational changes result in the autophosphorylation
of Jak2
kinases that are pre-associated with the receptor (i.e., EpoR does not possess intrinsic kinase activity and depends on Jak2 activity). At present, the most well-established function of EpoR is to rescue erythroid
(red blood cell) progenitors from apoptosis
.
by Jak2
and serve as docking sites for a variety of intracellular pathway activators and Stats (such as Stat5
). In addition to activating Ras/AKT and ERK/MAP kinase, phosphatidylinositol 3-kinase/AKT pathway and STAT transcription factor
s, phosphotyrosines also serve as docking sites for phosphatases that negatively affect EpoR signaling in order to prevent overactivation that may lead to such disorders as erythrocytosis. In general, the defects in the erythropoietin receptor may produce erythroleukemia
and familial erythrocytosis. Mutations in Jak2 kinases associated with EpoR can also lead to polycythemia vera.
The EpoR-HM receptor also lacks the majority of the cytoplasmic domain, and contains the tyrosine 343 that was mutated to phenylalanine, making it unsuitable for efficient Stat5 docking and activation. These mice are anemic and show poor response to hypoxic stress, such as phenylhydrazine treatment or erythropoietin injection.
. Overproduction of red blood cells increases a chance of adverse cardiovascular event, such as thrombosis and stroke.
Rarely, seemingly beneficial mutations in the EpoR may arise, where increased red blood cell number allows for improved oxygen delivery in athletic endurance events with no apparent adverse effects upon the athlete's health (as for example in the Finish athlete Eero Mäntyranta
).
Erythropoietin is necessary to maintain endothelial cells and to promote tumor angiogenesis
, hence the dysregulation of EpoR may affect the growth of certain tumors.
EpoR signaling prevents neuronal death and ischemic injury.
with:
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
that in humans is encoded by the EPOR gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
. EpoR is a 59 kDa
Atomic mass unit
The unified atomic mass unit or dalton is a unit that is used for indicating mass on an atomic or molecular scale. It is defined as one twelfth of the rest mass of an unbound neutral atom of carbon-12 in its nuclear and electronic ground state, and has a value of...
peptide
Peptide
Peptides are short polymers of amino acid monomers linked by peptide bonds. They are distinguished from proteins on the basis of size, typically containing less than 50 monomer units. The shortest peptides are dipeptides, consisting of two amino acids joined by a single peptide bond...
and is a member of the cytokine receptor
Cytokine receptor
Cytokine receptors are receptors that bind cytokines.In recent years, the cytokine receptors have come to demand the attention of more investigators than cytokines themselves, partly because of their remarkable characteristics, and partly because a deficiency of cytokine receptors has now been...
family. EpoR pre-exists as dimers
which upon binding of a 34 kDa ligand erythropoietin
Erythropoietin
Erythropoietin, or its alternatives erythropoetin or erthropoyetin or EPO, is a glycoprotein hormone that controls erythropoiesis, or red blood cell production...
(Epo), changes its homodimerized state. These conformational changes result in the autophosphorylation
Autophosphorylation
In biochemistry, autophosphorylation is the process in which a protein kinase attaches a phosphate group to itself. This usually lead to kinase activation or regulation, and phosphorylation of other kinase substrates....
of Jak2
Janus kinase 2
Janus kinase 2 is a human protein that has been implicated in signaling by members of the type II cytokine receptor family , the GM-CSF receptor family , the gp130 receptor family , and the single chain receptors...
kinases that are pre-associated with the receptor (i.e., EpoR does not possess intrinsic kinase activity and depends on Jak2 activity). At present, the most well-established function of EpoR is to rescue erythroid
Red blood cell
Red blood cells are the most common type of blood cell and the vertebrate organism's principal means of delivering oxygen to the body tissues via the blood flow through the circulatory system...
(red blood cell) progenitors from apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
.
Function and mechanism of action
The cytoplasmic domains of the EpoR contain a number of phosphotyrosines that are phosphorylatedPhosphorylation
Phosphorylation is the addition of a phosphate group to a protein or other organic molecule. Phosphorylation activates or deactivates many protein enzymes....
by Jak2
Janus kinase 2
Janus kinase 2 is a human protein that has been implicated in signaling by members of the type II cytokine receptor family , the GM-CSF receptor family , the gp130 receptor family , and the single chain receptors...
and serve as docking sites for a variety of intracellular pathway activators and Stats (such as Stat5
STAT5
STAT5 refers to two highly related proteins, STAT5A and STAT5B, which are encoded by separate genes, but are 90% identical at the amino acid level....
). In addition to activating Ras/AKT and ERK/MAP kinase, phosphatidylinositol 3-kinase/AKT pathway and STAT transcription factor
STAT protein
The STAT protein regulates many aspects of growth, survival and differentiation in cells...
s, phosphotyrosines also serve as docking sites for phosphatases that negatively affect EpoR signaling in order to prevent overactivation that may lead to such disorders as erythrocytosis. In general, the defects in the erythropoietin receptor may produce erythroleukemia
Erythroleukemia
Acute erythroid leukemia is a rare form of acute myeloid leukemia where the myeloproliferation is of erythroblastic precursors.It is defined at type "M6" under the FAB classification.-Types:...
and familial erythrocytosis. Mutations in Jak2 kinases associated with EpoR can also lead to polycythemia vera.
Erythroid survival
Primary role of EpoR is to rescue sufficient numbers of erythroid progenitors from cell death. EpoR-Stat5 signaling, together with transcriptional factor GATA-1, induces the transcription of pro-survival protein Bcl-xL. Additionally, EpoR has been implicated in suppressing expression of death receptors Fas, Trail and TNFa that negatively affect erythropoiesis.Erythroid differentiation
It is thought that erythroid differentiation is primarily dependent on the presence and induction of erythroid transcriptional factors such as GATA-1, FOG-1 and EKLF, as well as the suppression of myeloid/lymphoid transcriptional factors such as PU.1. Direct and significant effects of EpoR signaling specifically upon the induction of erythroid-specific genes such as beta-globin, have been mainly elusive. It is known that GATA-1 can induce EpoR expression. In turn, EpoR's PI3-K/AKT signaling pathway augments GATA-1 activity.Erythroid cell cycle/proliferation
Induction of proliferation by the EpoR is likely cell type-dependent. It is known that EpoR can activate mitogenic signaling pathways and can lead to cell proliferation in erythroleukemic cell lines in vitro, various non-erythroid cells, and cancer cells. So far, there is no sufficient evidence that in vivo, EpoR signaling can induce erythroid progenitors to undergo cell division, or whether Epo levels can modulate the cell cycle. EpoR signaling may still have a proliferation effect upon BFU-e progenitors, but these progenitors cannot be directly identified, isolated and studied. CFU-e progenitors enter the cell cycle at the time of GATA-1 induction and PU.1 suppression, but not due to EpoR signaling. Subsequent differentiation stages (proerythroblast to orthochromatic erythroblast) involve a decrease in cell size and eventual expulsion of the nucleus, and may be dependent upon EpoR signaling only for their survival. Furthermore, some evidence on macrocytosis in hypoxic stress (when Epo can increase 1000-fold) suggests that mitosis is actually skipped in later erythroid stages, when EpoR expression is low/absent, in order to provide emergency reserve of red blood cells as soon as possible. Together, these data suggest that EpoR in erythroid differentiation functions primarily as a survival factor, while its effect on the cell cycle (for example, rate of division and corresponding changes in the levels of cyclins and Cdk inhibitors) in vivo awaits further work. In other cell systems, however, EpoR may provide a specific proliferative signal.Commitment of multipotent progenitors to the erythroid lineage
EpoR's role in lineage commitment is currently unclear. EpoR expression can extend as far back as the hematopoietic stem cell compartment. It is unknown whether EpoR signaling plays a permissive (ie induces only survival) or an instructive (ie upregulates erythroid markers to lock progenitors to a predetermined differentiation path) role in early, multipotent progenitors in order to produce sufficient erythroblast numbers. The generation of BFU-e and CFU-e progenitors was shown to be normal in rodent embryos knocked out for either Epo or EpoR. On the other hand, in response to Epo or hypoxic stress, the number of early erythroid stages, the BFU-e and CFU-e, is well known to increase dramatically. Furthermore, signaling pathways activated by the EpoR are common to many other receptors; replacing EpoR with prolactin receptor supports erythroid survival and differentiation in vitro. Together, these data suggest that commitment to erythroid lineage likely does not happen due to EpoR's as-yet-unknown instructive function, but possibly due to its role in survival at the multipotent progenitor stages.Animal studies on Epo Receptor mutations
Mice with truncated EpoR are viable, which suggests Jak2 activity is sufficient to support basal erythropoiesis by activating the necessary pathways without phosphotyrosine docking sites being needed. EpoR-H form of EpoR truncation contains the first, and, what can be argued, the most important tyrosine 343 that serves as a docking site for the Stat5 molecule, but lacks the rest of the cytoplasmic tail. These mice exhibit elevated erythropoiesis consistent with the idea that phosphatase recruitment (and therefore the shutting down of signaling) is aberrant in these mice.The EpoR-HM receptor also lacks the majority of the cytoplasmic domain, and contains the tyrosine 343 that was mutated to phenylalanine, making it unsuitable for efficient Stat5 docking and activation. These mice are anemic and show poor response to hypoxic stress, such as phenylhydrazine treatment or erythropoietin injection.
Clinical significance
Defects in the erythropoietin receptor may produce erythroleukemia and familial erythrocytosisPolycythemia
Polycythemia is a disease state in which the proportion of blood volume that is occupied by red blood cells increases...
. Overproduction of red blood cells increases a chance of adverse cardiovascular event, such as thrombosis and stroke.
Rarely, seemingly beneficial mutations in the EpoR may arise, where increased red blood cell number allows for improved oxygen delivery in athletic endurance events with no apparent adverse effects upon the athlete's health (as for example in the Finish athlete Eero Mäntyranta
Eero Mäntyranta
Eero Antero Mäntyranta is a former Finnish skier and multiple Olympic Champion. With his seven medals from four Winter Olympics, he is one of the most successful skiers Finland has ever produced....
).
Erythropoietin is necessary to maintain endothelial cells and to promote tumor angiogenesis
Angiogenesis
Angiogenesis is the physiological process involving the growth of new blood vessels from pre-existing vessels. Though there has been some debate over terminology, vasculogenesis is the term used for spontaneous blood-vessel formation, and intussusception is the term for the formation of new blood...
, hence the dysregulation of EpoR may affect the growth of certain tumors.
EpoR signaling prevents neuronal death and ischemic injury.
Interactions
Erythropoietin receptor has been shown to interactProtein-protein interaction
Protein–protein interactions occur when two or more proteins bind together, often to carry out their biological function. Many of the most important molecular processes in the cell such as DNA replication are carried out by large molecular machines that are built from a large number of protein...
with:
- CRKLCRKLCrk-like protein is a protein that in humans is encoded by the CRKL gene.CrkL together with Crk participates in the Reelin signaling cascade downstream of DAB1.-Interactions:...
, - ErythropoietinErythropoietinErythropoietin, or its alternatives erythropoetin or erthropoyetin or EPO, is a glycoprotein hormone that controls erythropoiesis, or red blood cell production...
, - Grb2Grb2Growth factor receptor-bound protein 2 also known as Grb2 is an adaptor protein involved in signal transduction/cell communication. In humans, the GRB2 protein is encoded by the GRB2 gene....
, - Janus kinase 2Janus kinase 2Janus kinase 2 is a human protein that has been implicated in signaling by members of the type II cytokine receptor family , the GM-CSF receptor family , the gp130 receptor family , and the single chain receptors...
, - LYNLYNTyrosine-protein kinase Lyn is a protein that in humans is encoded in humans by the LYN gene.Lyn is a member of the Src family of protein tyrosine kinases, which is mainly expressed in hematopoietic cells, in neural tissues liver, and adipose tissue. In various hematopoietic cells, Lyn has emerged...
, - PIK3R1PIK3R1Phosphatidylinositol 3-kinase regulatory subunit alpha is an enzyme that in humans is encoded by the PIK3R1 gene.-Interactions:PIK3R1 has been shown to interact with EPH receptor A2, KHDRBS1, Lymphocyte cytosolic protein 2, Janus kinase 2, GAB2, CD117, BCAR1, CD28, SHB, EZR, PIK3CD, GAB1, HRAS,...
, - PTPN6PTPN6Tyrosine-protein phosphatase non-receptor type 6 is an enzyme that in humans is encoded by the PTPN6 gene.Also known as Src homology region 2 domain-containing phosphatase-1 .-Interactions:...
, - SOCS2SOCS2Suppressor of cytokine signaling 2 is a protein that in humans is encoded by the SOCS2 gene.This gene encodes a member of the STAT-induced STAT inhibitor , also known as suppressor of cytokine signalling , family. SSI family members are cytokine-inducible negative regulators of cytokine signaling...
, - SOCS3SOCS3Suppressor of cytokine signaling 3 is a protein that in humans is encoded by the SOCS3 gene.-Interactions:SOCS3 has been shown to interact with PTPN11, Glycoprotein 130, Erythropoietin receptor, Janus kinase 2, RAS p21 protein activator 1 and Insulin-like growth factor 1 receptor.-Regulation:There...
, and - STAT5ASTAT5ASignal transducer and activator of transcription 5A is a protein that in humans is encoded by the STAT5A gene. STAT5A orthologs have been identified in several placentals for which complete genome data are available.-Interactions:...
.