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Erythropoietin receptor

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Title: Erythropoietin receptor  
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Erythropoietin receptor

Erythropoietin receptor
Dimeric states of te EPO receptor ,,
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols  ; EPO-R
External IDs ChEMBL: GeneCards:
RNA expression pattern
Orthologs
Species Human Mouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)
RefSeq (protein)
Location (UCSC)
PubMed search

The erythropoietin receptor (EpoR) is a protein that in humans is encoded by the EPOR gene.[1] EpoR is a 59 kDa peptide and is a member of the cytokine receptor family. EpoR pre-exists as dimers [2] 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).[3][4] At present, the most well-established function of EpoR is to rescue erythroid (red blood cell) progenitors from apoptosis.[1]

Contents

  • Function and mechanism of action 1
    • Erythroid survival 1.1
    • Erythroid differentiation 1.2
    • Erythroid cell cycle/proliferation 1.3
    • Commitment of multipotent progenitors to the erythroid lineage 1.4
  • Animal studies on Epo Receptor mutations 2
  • Clinical significance 3
  • Interactions 4
  • References 5
  • Further reading 6
  • External links 7

Function and mechanism of action

Murine Epo Receptor truncations and known functions. Erythroid differentiation depends on transcriptional regulator GATA1. EpoR is thought to contribute to differentiation via multiple signaling pathways including the STAT5 pathway. In erythropoiesis, EpoR is best known for inducing survival of progenitors.

The cytoplasmic domains of the EpoR contain a number of phosphotyrosines that are phosphorylated 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 factors, 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.[5]

Erythroid survival

Primary role of EpoR is to rescue sufficient numbers of erythroid progenitors from cell death.[6] EpoR-Stat5 signaling, together with transcriptional factor GATA-1, induces the transcription of pro-survival protein Bcl-xL.[7] Additionally, EpoR has been implicated in suppressing expression of death receptors Fas, Trail and TNFa that negatively affect erythropoiesis.[8][9][10]

Based on current evidence, it is still unknown whether Epo/EpoR directly cause "proliferation and differentiation" of erythroid progenitors in vivo, although such direct effects have been described based on in vitro work.

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.[11] 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.[12] In turn, EpoR's PI3-K/AKT signaling pathway augments GATA-1 activity.[13]

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.[6] 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 in a developmental manner rather than due to EpoR signaling.[14] Subsequent differentiation stages (proerythroblast to orthochromatic erythroblast) involve a decrease in cell size and eventual expulsion of the nucleus, and are likely dependent upon EpoR signaling only for their survival. In addition, 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.[15][16] Such data, though sometimes circumstantial, argue that there is limited capacity to proliferate specifically in response to Epo (and not other factors). 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.[17] It is unknown whether EpoR signaling plays a permissive (i.e. induces only survival) or an instructive (i.e. upregulates erythroid markers to lock progenitors to a predetermined differentiation path) role in early, multipotent progenitors in order to produce sufficient erythroblast numbers. Current publications in the field suggest that it is primarily permissive. The generation of BFU-e and CFU-e progenitors was shown to be normal in rodent embryos knocked out for either Epo or EpoR.[18] An argument against such lack of requirement is that in response to Epo or hypoxic stress, the number of early erythroid stages, the BFU-e and CFU-e, increases dramatically. However, it is unclear if it is an instructive signal or, again, a permissive signal. One additional point is that signaling pathways activated by the EpoR are common to many other receptors; replacing EpoR with prolactin receptor supports erythroid survival and differentiation in vitro.[19][20] 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[21] 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.[21]

Clinical significance

Defects in the erythropoietin receptor may produce erythroleukemia and familial erythrocytosis.[1] 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).[22]

Erythropoietin is necessary to maintain endothelial cells and to promote tumor angiogenesis, hence the dysregulation of EpoR may affect the growth of certain tumors.[23][24]

EpoR signaling prevents neuronal death[25] and ischemic injury.[26]

Interactions

Erythropoietin receptor has been shown to interact with:

References

  1. ^ a b c "Entrez Gene: EPOR erythropoietin receptor". 
  2. ^ Livnah O, Stura EA, Middleton SA, Johnson DL, Jolliffe LK, Wilson IA. (February 1999). "Crystallographic evidence for preformed dimers of erythropoietin receptor before ligand activation.". Science 283 (5404): 987–90.  
  3. ^ Youssoufian H, Longmore G, Neumann D, Yoshimura A, Lodish HF (May 1993). "Structure, function, and activation of the erythropoietin receptor". Blood 81 (9): 2223–36.  
  4. ^ Wilson IA, Jolliffe LK (December 1999). "The structure, organization, activation and plasticity of the erythropoietin receptor". Curr. Opin. Struct. Biol. 9 (6): 696–704.  
  5. ^ James C, Ugo V, Le Couédic JP, Staerk J, Delhommeau F, Lacout C, Garçon L, Raslova H, Berger R, Bennaceur-Griscelli A, Villeval JL, Constantinescu SN, Casadevall N, Vainchenker W (April 2005). "A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera". Nature 434 (7037): 1144–8.  
  6. ^ a b Koury MJ, Bondurant MC (April 1990). "Erythropoietin retards DNA breakdown and prevents programmed death in erythroid progenitor cells". Science 248 (4953): 378–81.  
  7. ^ Socolovsky M, Fallon AE, Wang S, Brugnara C, Lodish HF (July 1999). "Fetal anemia and apoptosis of red cell progenitors in Stat5a-/-5b-/- mice: a direct role for Stat5 in Bcl-X(L) induction". Cell 98 (2): 181–91.  
  8. ^ De Maria R, Testa U, Luchetti L, Zeuner A, Stassi G, Pelosi E, Riccioni R, Felli N, Samoggia P, Peschle C (February 1999). "Apoptotic role of Fas/Fas ligand system in the regulation of erythropoiesis". Blood 93 (3): 796–803.  
  9. ^ Liu Y, Pop R, Sadegh C, Brugnara C, Haase VH, Socolovsky M (July 2006). "Suppression of Fas-FasL coexpression by erythropoietin mediates erythroblast expansion during the erythropoietic stress response in vivo". Blood 108 (1): 123–33.  
  10. ^ Felli N, Pedini F, Zeuner A, Petrucci E, Testa U, Conticello C, Biffoni M, Di Cataldo A, Winkles JA, Peschle C, De Maria R (August 2005). "Multiple members of the TNF superfamily contribute to IFN-gamma-mediated inhibition of erythropoiesis". J. Immunol. 175 (3): 1464–72.  
  11. ^ Cantor AB, Orkin SH (May 2002). "Transcriptional regulation of erythropoiesis: an affair involving multiple partners". Oncogene 21 (21): 3368–76.  
  12. ^ Zon LI, Youssoufian H, Mather C, Lodish HF, Orkin SH (December 1991). "Activation of the erythropoietin receptor promoter by transcription factor GATA-1". Proc. Natl. Acad. Sci. U.S.A. 88 (23): 10638–41.  
  13. ^ Zhao W, Kitidis C, Fleming MD, Lodish HF, Ghaffari S (February 2006). "Erythropoietin stimulates phosphorylation and activation of GATA-1 via the PI3-kinase/AKT signaling pathway". Blood 107 (3): 907–15.  
  14. ^ Pop R, Shearstone JR, Shen Q, Liu Y, Hallstrom K, Koulnis M, Gribnau J, Socolovsky M (2010). "A key commitment step in erythropoiesis is synchronized with the cell cycle clock through mutual inhibition between PU.1 and S-phase progression". PLoS Biol. 8 (9): e1000484.  
  15. ^ Seno S, Miyahara M, Asakura H, Ochi O, Matsuoka K, Toyama T (November 1964). "macrocytosis resulting from early denucleation of erythroid precursors". Blood 24: 582–93.  
  16. ^ Borsook H, Lingrel JB, Scaro JL, Millette RL (October 1962). "Synthesis of haemoglobin in relation to the maturation of erythroid cells". Nature 196 (4852): 347–50.  
  17. ^ Forsberg EC, Serwold T, Kogan S, Weissman IL, Passegué E (July 2006). "New evidence supporting megakaryocyte-erythrocyte potential of flk2/flt3+ multipotent hematopoietic progenitors". Cell 126 (2): 415–26.  
  18. ^ Wu H, Liu X, Jaenisch R, Lodish HF (October 1995). "Generation of committed erythroid BFU-E and CFU-E progenitors does not require erythropoietin or the erythropoietin receptor". Cell 83 (1): 59–67.  
  19. ^ Socolovsky M, Fallon AE, Lodish HF (September 1998). "The prolactin receptor rescues EpoR-/- erythroid progenitors and replaces EpoR in a synergistic interaction with c-kit". Blood 92 (5): 1491–6.  
  20. ^ Socolovsky M, Dusanter-Fourt I, Lodish HF (May 1997). "The prolactin receptor and severely truncated erythropoietin receptors support differentiation of erythroid progenitors". J. Biol. Chem. 272 (22): 14009–12.  
  21. ^ a b Zang H, Sato K, Nakajima H, McKay C, Ney PA, Ihle JN (June 2001). "The distal region and receptor tyrosines of the Epo receptor are non-essential for in vivo erythropoiesis.". EMBO J 20 (12): 3156–66.  
  22. ^ de la Chapelle A, Träskelin AL, Juvonen E (May 1993). "Truncated erythropoietin receptor causes dominantly inherited benign human erythrocytosis". Proc. Natl. Acad. Sci. U.S.A. 90 (10): 4495–9.  
  23. ^ Farrell F, Lee A (2004). "The erythropoietin receptor and its expression in tumor cells and other tissues". Oncologist. 9 Suppl 5: 18–30.  
  24. ^ Jelkmann W, Bohlius J, Hallek M, Sytkowski AJ (July 2008). "The erythropoietin receptor in normal and cancer tissues". Crit. Rev. Oncol. Hematol. 67 (1): 39–61.  
  25. ^ Morishita E, Masuda S, Nagao M, Yasuda Y, Sasaki R (January 1997). "Erythropoietin receptor is expressed in rat hippocampal and cerebral cortical neurons, and erythropoietin prevents in vitro glutamate-induced neuronal death". Neuroscience 76 (1): 105–16.  
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Further reading

  • Zhu Y, D'Andrea AD (1999). "The molecular physiology of erythropoietin and the erythropoietin receptor.". Curr. Opin. Hematol. 1 (2): 113–8.  
  • Lacombe C, Mayeux P (1998). "Biology of erythropoietin.". Haematologica 83 (8): 724–32.  
  • Bonifacino JS (2002). "Quality control of receptor-kinase signaling complexes.". Dev. Cell 2 (1): 1–2.  
  • Takeshita A, Shinjo K, Naito K; et al. (2003). "Erythropoietin receptor in myelodysplastic syndrome and leukemia.". Leuk. Lymphoma 43 (2): 261–4.  
  • Kralovics R, Skoda RC (2005). "Molecular pathogenesis of Philadelphia chromosome negative myeloproliferative disorders.". Blood Rev. 19 (1): 1–13.  
  • Madeddu P, Emanueli C (2007). "Switching on reparative angiogenesis: essential role of the vascular erythropoietin receptor.". Circ. Res. 100 (5): 599–601.  

External links

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