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EPOR  -  erythropoietin receptor

Homo sapiens

 
 
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Disease relevance of EPOR

  • We describe a Swedish family with dominant FE in which erythrocytosis segregates with a new truncation in the negative control domain of the EPOR [1].
  • Furthermore, we found EPO and EPOR mRNAs as well as EPO protein in K562 cells, a human erythroleukemia cell line [2].
  • We also show that EPOR-T mRNA is not detected in erythroid/megakaryocytic leukemia cell lines, but is expressed in nonerythroid/nonmegakaryocytic lines, suggesting the presence of a cell type-specific system by which intron VII of the EPOR transcript is spliced [3].
  • We report basal and hypoxia-stimulated expression of EPO and its receptor, EPOR, in human breast cancer cells, and we demonstrate EPO-stimulated tyrosine phosphorylation and the proliferation of these cells in vitro [4].
  • In 50 clinical specimens of breast carcinoma, we report high levels of EPO and EPOR associated with malignant cells and tumor vasculature but not with normal breast, benign papilloma, or fibrocystic tissue [4].
  • If this finding in non-small cell lung carcinoma is a widespread phenomenon, then impaired erythropoietin receptor downregulation and degradation in tumor cells has clinical implications for those patients receiving erythropoiesis-stimulating agents for cancer-related anemia [5].
  • Anemia, however, did not appear to influence EPOR expression on leukemic cells, although children with ETV6/RUNX1-positive leukemias had a lower median hemoglobin than controls [6].
 

High impact information on EPOR

  • EPO and the EPOR are crucial in vivo for the proliferation and survival of CFU-E progenitors and their irreversible terminal differentiation [7].
  • Using EPOR mutants, phosphorylation and activation of kinase activity correlate with the induction of mitogenesis [8].
  • Two independent cDNA clones encoding the erythropoietin receptor (EPO-R) were isolated from a pXM expression library made from uninduced murine erythroleukemia (MEL) cells [9].
  • Although the MEL cell EPO-R has a single affinity with a dissociation constant of approximately 240 pM, the EPO-R cDNA, expressed in COS cells, generates both a high-affinity (30 pM) and a low-affinity (210 pM) receptor [9].
  • The Epo receptor required for Epo signaling localizes to photoreceptor cells [10].
 

Chemical compound and disease context of EPOR

 

Biological context of EPOR

  • The crystal structure of the extracellular domain of EPOR in its unliganded form at 2.4 angstrom resolution has revealed a dimer in which the individual membrane-spanning and intracellular domains would be too far apart to permit phosphorylation by JAK2 [15].
  • This unliganded EPOR dimer is formed from self-association of the same key binding site residues that interact with EPO-mimetic peptide and EPO ligands [15].
  • In other words, EPOR appeared to be dispensable for erythropoiesis [16].
  • We screened the affected individuals for EPOR gene mutations using SSCP analysis and found a C5964G mutation in exon VIII that changes tyrosine codon 426 to a translation termination codon resulting in an EPOR protein truncated by 83 amino acids [17].
  • These data demonstrate that a nonpeptide molecule is capable of inducing EPOR dimerization and mimicking the biological activities of EPO [18].
 

Anatomical context of EPOR

  • The mutant C5964G-EPOR exhibited hypersensitive EPO-dependent proliferation compared to the wild-type EPOR when tested in a murine interleukin-3-dependent myeloid cell line (FDC-P1) [17].
  • We find that EPOR is inducible by EPO in primary human endothelial cells of vein (HUVECs) and artery (HUAECs) and cells from a human bone marrow microvascular endothelial line (TrHBMEC) to a much greater extent at low oxygen tension than in room air [19].
  • Erythropoietin (EPO) and its receptor (EPOR) are required for the development of mature erythrocytes [20].
  • In addition, selected mutant proteins were expressed as full-length EPOR on the surface of COS cells and analyzed for 125I-EPO binding in receptor binding assays [21].
  • These results suggest that proinflammatory cytokines regulate expression of EPO and EPOR in human neurons, astrocytes, and microglia and further facilitate interactions among different cell types in the human CNS [22].
 

Associations of EPOR with chemical compounds

  • We first identified compound 1 (N-3-[2-(4-biphenyl)-6-chloro-5-methyl]indolyl-acetyl-L-lysine methyl ester) by screening the in-house chemical collection for inhibitors of EPO binding to human EPOR and then prepared compound 5, which contains eight copies of compound 1 held together by a central core [18].
  • However, this did not depend upon the presence of phosphotyrosine sites within the EPOR and was mediated by a mitogenically deficient receptor form (EPOR329) lacking cytoplasmic tyrosine residues [23].
  • We found that the 78-kDa erythropoietin receptor (EPOR), a highly modified form of the 66-kDa receptor which is abundant in HCD57 cells, was phosphorylated on serine residues without EPO stimulation [24].
  • Contiguous sections from 74 biopsies were analyzed by immunohistochemistry for EPOR and erythropoietin expression and pimonidazole binding [25].
  • We introduced tyrosine to phenylalanine substitutions in EPOR-ME, a naturally occurring, mutant human EPOR (G5881T), truncated by 110 carboxy-terminal amino acids and associated with autosomal dominantly inherited PFCP [26].
 

Physical interactions of EPOR

  • Here we show that human SOCS-3 binds to pY401 with a Kd of 9.5 microm while another EpoR tyrosine motif, pY429pY431, can also interact with SOCS-3 but with a ninefold higher affinity than we found for the previously reported motif pY401 [27].
  • In a recent paper [Philo et al. (1996), Biochemistry 38, 1681-1691] we described the formation of both 1:1 and 2:1 EPOR/EPO complexes [28].
  • Thus, GAB1 could be a scaffold protein able to couple the Epo receptor activation with the stimulation of several intracellular signaling pathways [29].
  • Therefore PFCP is presumably brought about as a result of genetic mutations which cause the loss of the SHP-1 binding site in the cytoplasmic region of EpoR [30].
  • Activation of the erythropoietin receptor caused specific DNA-binding of Stat 5b, but failed to induce reporter gene transcription [31].
 

Enzymatic interactions of EPOR

 

Regulatory relationships of EPOR

 

Other interactions of EPOR

 

Analytical, diagnostic and therapeutic context of EPOR

References

  1. Erythropoietin receptor mutations associated with familial erythrocytosis cause hypersensitivity to erythropoietin in the heterozygous state. Watowich, S.S., Xie, X., Klingmuller, U., Kere, J., Lindlof, M., Berglund, S., de la Chapelle, A. Blood (1999) [Pubmed]
  2. Human hematopoietic progenitors express erythropoietin. Stopka, T., Zivny, J.H., Stopkova, P., Prchal, J.F., Prchal, J.T. Blood (1998) [Pubmed]
  3. Selective expression of mRNA coding for the truncated form of erythropoietin receptor in hematopoietic cells and its decrease in patients with polycythemia vera. Chiba, S., Takahashi, T., Takeshita, K., Minowada, J., Yazaki, Y., Ruddle, F.H., Hirai, H. Blood (1997) [Pubmed]
  4. Erythropoietin and erythropoietin receptor expression in human cancer. Acs, G., Acs, P., Beckwith, S.M., Pitts, R.L., Clements, E., Wong, K., Verma, A. Cancer Res. (2001) [Pubmed]
  5. Impaired downregulation following erythropoietin receptor activation in non-small cell lung carcinoma. Dunlop, E.A., Maxwell, A.P., Lappin, T.R. Stem. Cells (2007) [Pubmed]
  6. Role of the erythropoietin receptor in ETV6/RUNX1-positive acute lymphoblastic leukemia. Inthal, A., Krapf, G., Beck, D., Joas, R., Kauer, M.O., Orel, L., Fuka, G., Mann, G., Panzer-Grümayer, E.R. Clin. Cancer Res. (2008) [Pubmed]
  7. Generation of committed erythroid BFU-E and CFU-E progenitors does not require erythropoietin or the erythropoietin receptor. Wu, H., Liu, X., Jaenisch, R., Lodish, H.F. Cell (1995) [Pubmed]
  8. JAK2 associates with the erythropoietin receptor and is tyrosine phosphorylated and activated following stimulation with erythropoietin. Witthuhn, B.A., Quelle, F.W., Silvennoinen, O., Yi, T., Tang, B., Miura, O., Ihle, J.N. Cell (1993) [Pubmed]
  9. Expression cloning of the murine erythropoietin receptor. D'Andrea, A.D., Lodish, H.F., Wong, G.G. Cell (1989) [Pubmed]
  10. HIF-1-induced erythropoietin in the hypoxic retina protects against light-induced retinal degeneration. Grimm, C., Wenzel, A., Groszer, M., Mayser, H., Seeliger, M., Samardzija, M., Bauer, C., Gassmann, M., Remé, C.E. Nat. Med. (2002) [Pubmed]
  11. A dominant negative erythropoietin (EPO) receptor inhibits EPO-dependent growth and blocks F-gp55-dependent transformation. Barber, D.L., DeMartino, J.C., Showers, M.O., D'Andrea, A.D. Mol. Cell. Biol. (1994) [Pubmed]
  12. Erythropoietin receptor is not a surrogate marker for tumor hypoxia and does not correlate with survival in head and neck squamous cell carcinomas. Hoogsteen, I.J., Peeters, W.J., Marres, H.A., Rijken, P.F., van den Hoogen, F.J., van der Kogel, A.J., Kaanders, J.H. Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology. (2005) [Pubmed]
  13. Increased erythropoietin-receptor expression on CD34-positive bone marrow cells from patients with chronic myeloid leukemia. Wognum, A.W., Krystal, G., Eaves, C.J., Eaves, A.C., Lansdorp, P.M. Blood (1992) [Pubmed]
  14. A CCACC motif mediates negative transcriptional regulation of the human erythropoietin receptor. Maouche, L., Lucien, N., Cartron, J.P., Chrétien, S. Eur. J. Biochem. (1995) [Pubmed]
  15. Crystallographic evidence for preformed dimers of erythropoietin receptor before ligand activation. Livnah, O., Stura, E.A., Middleton, S.A., Johnson, D.L., Jolliffe, L.K., Wilson, I.A. Science (1999) [Pubmed]
  16. Erythroid progenitors differentiate and mature in response to endogenous erythropoietin. Sato, T., Maekawa, T., Watanabe, S., Tsuji, K., Nakahata, T. J. Clin. Invest. (2000) [Pubmed]
  17. Absence of polycythemia in a child with a unique erythropoietin receptor mutation in a family with autosomal dominant primary polycythemia. Kralovics, R., Sokol, L., Prchal, J.T. J. Clin. Invest. (1998) [Pubmed]
  18. Mimicry of erythropoietin by a nonpeptide molecule. Qureshi, S.A., Kim, R.M., Konteatis, Z., Biazzo, D.E., Motamedi, H., Rodrigues, R., Boice, J.A., Calaycay, J.R., Bednarek, M.A., Griffin, P., Gao, Y.D., Chapman, K., Mark, D.F. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  19. Erythropoietin and hypoxia stimulate erythropoietin receptor and nitric oxide production by endothelial cells. Beleslin-Cokic, B.B., Cokic, V.P., Yu, X., Weksler, B.B., Schechter, A.N., Noguchi, C.T. Blood (2004) [Pubmed]
  20. Genetic evidence for an additional factor required for erythropoietin-induced signal transduction. Gaffen, S.L., Lai, S.Y., Longmore, G.D., Liu, K.D., Goldsmith, M.A. Blood (1999) [Pubmed]
  21. Mutagenesis studies of the human erythropoietin receptor. Establishment of structure-function relationships. Barbone, F.P., Middleton, S.A., Johnson, D.L., McMahon, F.J., Tullai, J., Gruninger, R.H., Schilling, A.E., Jolliffe, L.K., Mulcahy, L.S. J. Biol. Chem. (1997) [Pubmed]
  22. Erythropoietin and erythropoietin receptors in human CNS neurons, astrocytes, microglia, and oligodendrocytes grown in culture. Nagai, A., Nakagawa, E., Choi, H.B., Hatori, K., Kobayashi, S., Kim, S.U. J. Neuropathol. Exp. Neurol. (2001) [Pubmed]
  23. Erythropoietin-induced recruitment of Shc via a receptor phosphotyrosine-independent, Jak2-associated pathway. He, T.C., Jiang, N., Zhuang, H., Wojchowski, D.M. J. Biol. Chem. (1995) [Pubmed]
  24. Association of JAK2 and STAT5 with erythropoietin receptors. Role of receptor phosphorylation in erythropoietin signal transduction. Sawyer, S.T., Penta, K. J. Biol. Chem. (1996) [Pubmed]
  25. Erythropoietin and erythropoietin receptor expression in head and neck cancer: relationship to tumor hypoxia. Arcasoy, M.O., Amin, K., Chou, S.C., Haroon, Z.A., Varia, M., Raleigh, J.A. Clin. Cancer Res. (2005) [Pubmed]
  26. Erythropoietin hypersensitivity in primary familial and congenital polycythemia: role of tyrosines Y285 and Y344 in erythropoietin receptor cytoplasmic domain. Arcasoy, M.O., Karayal, A.F. Biochim. Biophys. Acta (2005) [Pubmed]
  27. A new high affinity binding site for suppressor of cytokine signaling-3 on the erythropoietin receptor. Hörtner, M., Nielsch, U., Mayr, L.M., Heinrich, P.C., Haan, S. Eur. J. Biochem. (2002) [Pubmed]
  28. Changes in conformation and stability upon formation of complexes of erythropoietin (EPO) and soluble EPO receptor. Narhi, L.O., Aoki, K.H., Philo, J.S., Arakawa, T. J. Protein Chem. (1997) [Pubmed]
  29. Erythropoietin induces the tyrosine phosphorylation of GAB1 and its association with SHC, SHP2, SHIP, and phosphatidylinositol 3-kinase. Lecoq-Lafon, C., Verdier, F., Fichelson, S., Chrétien, S., Gisselbrecht, S., Lacombe, C., Mayeux, P. Blood (1999) [Pubmed]
  30. Primary familial polycythaemia associated with a novel point mutation in the erythropoietin receptor. Furukawa, T., Narita, M., Sakaue, M., Otsuka, T., Kuroha, T., Masuko, M., Azegami, T., Kishi, K., Takahashi, M., Utsumi, J., Koike, T., Aizawa, Y. Br. J. Haematol. (1997) [Pubmed]
  31. Activation of Stat 5b in erythroid progenitors correlates with the ability of ErbB to induce sustained cell proliferation. Mellitzer, G., Wessely, O., Decker, T., Meinke, A., Hayman, M.J., Beug, H. Proc. Natl. Acad. Sci. U.S.A. (1996) [Pubmed]
  32. Erythropoietin-dependent association of phosphatidylinositol 3-kinase with tyrosine-phosphorylated erythropoietin receptor. Miura, O., Nakamura, N., Ihle, J.N., Aoki, N. J. Biol. Chem. (1994) [Pubmed]
  33. The erythropoietin receptor. Mulcahy, L. Semin. Oncol. (2001) [Pubmed]
  34. Thrombopoietin has a differentiative effect on late-stage human erythropoiesis. Liu, W., Wang, M., Tang, D.C., Ding, I., Rodgers, G.P. Br. J. Haematol. (1999) [Pubmed]
  35. Multiple tyrosine residues in the cytosolic domain of the erythropoietin receptor promote activation of STAT5. Klingmüller, U., Bergelson, S., Hsiao, J.G., Lodish, H.F. Proc. Natl. Acad. Sci. U.S.A. (1996) [Pubmed]
  36. Identification of the human erythropoietin receptor region required for Stat1 and Stat3 activation. Kirito, K., Nakajima, K., Watanabe, T., Uchida, M., Tanaka, M., Ozawa, K., Komatsu, N. Blood (2002) [Pubmed]
  37. Src directly tyrosine-phosphorylates STAT5 on its activation site and is involved in erythropoietin-induced signaling pathway. Okutani, Y., Kitanaka, A., Tanaka, T., Kamano, H., Ohnishi, H., Kubota, Y., Ishida, T., Takahara, J. Oncogene (2001) [Pubmed]
  38. Activation of the mitogen-activated protein kinases Erk1/2 by erythropoietin receptor via a G(i )protein beta gamma-subunit-initiated pathway. Guillard, C., Chrétien, S., Pelus, A.S., Porteu, F., Muller, O., Mayeux, P., Duprez, V. J. Biol. Chem. (2003) [Pubmed]
  39. Expression of erythropoietin receptor splice variants in human cancer. Arcasoy, M.O., Jiang, X., Haroon, Z.A. Biochem. Biophys. Res. Commun. (2003) [Pubmed]
  40. The erythropoietin receptor gene is not linked with the polycythemia phenotype in a family with autosomal dominant primary polycythemia. Kralovics, R., Sokol, L., Broxson, E.H., Prchal, J.T. Proc. Assoc. Am. Physicians (1997) [Pubmed]
  41. Effect of erythropoietin axotomy-induced apoptosis in rat retinal ganglion cells. Weishaupt, J.H., Rohde, G., Pölking, E., Siren, A.L., Ehrenreich, H., Bähr, M. Invest. Ophthalmol. Vis. Sci. (2004) [Pubmed]
 
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