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Gene Review

Epor  -  erythropoietin receptor

Mus musculus

Synonyms: EPO-R, Erythropoietin receptor
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Disease relevance of Epor


Psychiatry related information on Epor


High impact information on Epor


Chemical compound and disease context of Epor


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


Associations of Epor with chemical compounds


Physical interactions of Epor


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


  1. Expression of a constitutively active erythropoietin receptor in primary hematopoietic progenitors abrogates erythropoietin dependence and enhances erythroid colony-forming unit, erythroid burst-forming unit, and granulocyte/macrophage progenitor growth. Pharr, P.N., Hankins, D., Hofbauer, A., Lodish, H.F., Longmore, G.D. Proc. Natl. Acad. Sci. U.S.A. (1993) [Pubmed]
  2. Role of erythropoietin receptor signaling in Friend virus-induced erythroblastosis and polycythemia. Zhang, J., Randall, M.S., Loyd, M.R., Li, W., Schweers, R.L., Persons, D.A., Rehg, J.E., Noguchi, C.T., Ihle, J.N., Ney, P.A. Blood (2006) [Pubmed]
  3. Activation of the JAK1-STAT5 pathway by binding of the Friend virus gp55 glycoprotein to the erythropoietin receptor. Yamamura, Y., Senda, H., Noda, M., Ikawa, Y. Leukemia (1997) [Pubmed]
  4. Mutation in murine erythropoietin receptor induces erythropoietin-independent erythroid proliferation in vitro, polycythemia in vivo. Longmore, G.D., Pharr, P., Lodish, H.F. Leukemia (1992) [Pubmed]
  5. Cytokine gene expression in cerebral hemispheres and behavioral reactions of (CBAxC57Bl)F1 mice. Poveshchenko, A.F., Markova, E.V., Korotkova, N.A., Yakushenko, E.V., Abramov, V.V., Kozlov, V.A. Bull. Exp. Biol. Med. (2002) [Pubmed]
  6. Immunomorphological characteristics of animals with different levels of orientation and exploratory behavior. Markova, E.V., Chernova, T.G., Fillimonov, P.N., Korotkova, N.A., Abramov, V.V., Kozlov, V.A. Bull. Exp. Biol. Med. (2004) [Pubmed]
  7. Fetal anemia and apoptosis of red cell progenitors in Stat5a-/-5b-/- mice: a direct role for Stat5 in Bcl-X(L) induction. Socolovsky, M., Fallon, A.E., Wang, S., Brugnara, C., Lodish, H.F. Cell (1999) [Pubmed]
  8. Jak2 deficiency defines an essential developmental checkpoint in definitive hematopoiesis. Neubauer, H., Cumano, A., Müller, M., Wu, H., Huffstadt, U., Pfeffer, K. Cell (1998) [Pubmed]
  9. Identification of JAK2 as a growth hormone receptor-associated tyrosine kinase. Argetsinger, L.S., Campbell, G.S., Yang, X., Witthuhn, B.A., Silvennoinen, O., Ihle, J.N., Carter-Su, C. Cell (1993) [Pubmed]
  10. An activating mutation in the murine erythropoietin receptor induces erythroleukemia in mice: a cytokine receptor superfamily oncogene. Longmore, G.D., Lodish, H.F. Cell (1991) [Pubmed]
  11. Mutations in the Trp-Ser-X-Trp-Ser motif of the erythropoietin receptor abolish processing, ligand binding, and activation of the receptor. Yoshimura, A., Zimmers, T., Neumann, D., Longmore, G., Yoshimura, Y., Lodish, H.F. J. Biol. Chem. (1992) [Pubmed]
  12. Signals for stress erythropoiesis are integrated via an erythropoietin receptor-phosphotyrosine-343-Stat5 axis. Menon, M.P., Karur, V., Bogacheva, O., Bogachev, O., Cuetara, B., Wojchowski, D.M. J. Clin. Invest. (2006) [Pubmed]
  13. Friend spleen focus-forming virus transforms rodent fibroblasts in cooperation with a short form of the receptor tyrosine kinase Stk. Nishigaki, K., Hanson, C., Jelacic, T., Thompson, D., Ruscetti, S. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  14. Phosphorylation status of c-Kit and Epo receptors, and the presence of wild-type p53 confer in vitro resistance of murine erythroleukemic cells to Celecoxib. Cervi, D., Truong, A.H., Lee, J.S., Sukhai, N., Li, Y.J., Koki, A., Ben-David, Y. Oncogene (2004) [Pubmed]
  15. Erythropoietin induces association of the JAK2 protein tyrosine kinase with the erythropoietin receptor in vivo. Miura, O., Nakamura, N., Quelle, F.W., Witthuhn, B.A., Ihle, J.N., Aoki, N. Blood (1994) [Pubmed]
  16. Core erythropoietin receptor signals for late erythroblast development. Menon, M.P., Fang, J., Wojchowski, D.M. Blood (2006) [Pubmed]
  17. Unregulated expression of the erythropoietin receptor gene caused by insertion of spleen focus-forming virus long terminal repeat in a murine erythroleukemia cell line. Hino, M., Tojo, A., Misawa, Y., Morii, H., Takaku, F., Shibuya, M. Mol. Cell. Biol. (1991) [Pubmed]
  18. Murine pluripotent hematopoietic progenitors constitutively expressing a normal erythropoietin receptor proliferate in response to erythropoietin without preferential erythroid cell differentiation. Dubart, A., Feger, F., Lacout, C., Goncalves, F., Vainchenker, W., Dumenil, D. Mol. Cell. Biol. (1994) [Pubmed]
  19. Activation of the erythropoietin receptor is not required for internalization of bound erythropoietin. Beckman, D.L., Lin, L.L., Quinones, M.E., Longmore, G.D. Blood (1999) [Pubmed]
  20. The N-terminal domain of Janus kinase 2 is required for Golgi processing and cell surface expression of erythropoietin receptor. Huang, L.J., Constantinescu, S.N., Lodish, H.F. Mol. Cell (2001) [Pubmed]
  21. Zidovudine-induced blockade of the expression and function of the erythropoietin receptor. Gogu, S.R., Malter, J.S., Agrawal, K.C. Biochem. Pharmacol. (1992) [Pubmed]
  22. Preventive effect of erythropoietin on cardiac dysfunction in doxorubicin-induced cardiomyopathy. Li, L., Takemura, G., Li, Y., Miyata, S., Esaki, M., Okada, H., Kanamori, H., Khai, N.C., Maruyama, R., Ogino, A., Minatoguchi, S., Fujiwara, T., Fujiwara, H. Circulation (2006) [Pubmed]
  23. Association of the erythropoietin receptor with protein tyrosine kinase activity. Linnekin, D., Evans, G.A., D'Andrea, A., Farrar, W.L. Proc. Natl. Acad. Sci. U.S.A. (1992) [Pubmed]
  24. Erythropoietin receptor Y479 couples to ERK1/2 activation via recruitment of phospholipase Cgamma. Halupa, A., Chohan, M., Stickle, N.H., Beattie, B.K., Miller, B.A., Barber, D.L. Exp. Cell Res. (2005) [Pubmed]
  25. 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. Chen, J., Jacobs-Helber, S.M., Barber, D.L., Sawyer, S.T. Exp. Cell Res. (2004) [Pubmed]
  26. Identification of tyrosine residues within the intracellular domain of the erythropoietin receptor crucial for STAT5 activation. Gobert, S., Chretien, S., Gouilleux, F., Muller, O., Pallard, C., Dusanter-Fourt, I., Groner, B., Lacombe, C., Gisselbrecht, S., Mayeux, P. EMBO J. (1996) [Pubmed]
  27. 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. Barber, D.L., Beattie, B.K., Mason, J.M., Nguyen, M.H., Yoakim, M., Neel, B.G., D'Andrea, A.D., Frank, D.A. Blood (2001) [Pubmed]
  28. Residual erythroid progenitors in W/W mice respond to erythropoietin in the absence of steel factor signals. Pharr, P.N., Hofbauer, A., Worthington, R.E., Longmore, G.D. Int. J. Hematol. (2000) [Pubmed]
  29. Phosphatidylinositol 3-kinase associates, via its Src homology 2 domains, with the activated erythropoietin receptor. Damen, J.E., Mui, A.L., Puil, L., Pawson, T., Krystal, G. Blood (1993) [Pubmed]
  30. DNA damage-induced cell-cycle arrest of hematopoietic cells is overridden by activation of the PI-3 kinase/Akt signaling pathway. Henry, M.K., Lynch, J.T., Eapen, A.K., Quelle, F.W. Blood (2001) [Pubmed]
  31. Erythropoietin receptor haploinsufficiency and in vivo interplay with granulocyte-macrophage colony-stimulating factor and interleukin 3. Jegalian, A.G., Acurio, A., Dranoff, G., Wu, H. Blood (2002) [Pubmed]
  32. The extended box 2 subdomain of erythropoietin receptor is nonessential for Jak2 activation yet critical for efficient mitogenesis in FDC-ER cells. He, T.C., Jiang, N., Zhuang, H., Quelle, D.E., Wojchowski, D.M. J. Biol. Chem. (1994) [Pubmed]
  33. Association of the p85 regulatory subunit of phosphatidylinositol 3-kinase with an essential erythropoietin receptor subdomain. He, T.C., Zhuang, H., Jiang, N., Waterfield, M.D., Wojchowski, D.M. Blood (1993) [Pubmed]
  34. Thyroid hormone receptor-interacting protein 1 modulates cytokine and nuclear hormone signaling in erythroid cells. Ingley, E., Chappell, D., Poon, S.Y., Sarna, M.K., Beaumont, J.G., Williams, J.H., Stillitano, J.P., Tsai, S., Leedman, P.J., Tilbrook, P.A., Klinken, S.P. J. Biol. Chem. (2001) [Pubmed]
  35. Erythropoietin receptor and interleukin-2 receptor use different downstream signaling pathways for proliferation and apoptosis-block. Yamamura, Y., Noda, M., Ikawa, Y. Leukemia (1994) [Pubmed]
  36. Activation of the transcription factor NF-kappaB by the erythropoietin receptor: structural requirements and biological significance. Bittorf, T., Büchse, T., Sasse, T., Jaster, R., Brock, J. Cell. Signal. (2001) [Pubmed]
  37. A growth signal with an artificially induced erythropoietin receptor-gp130 cytoplasmic domain heterodimer. Kawahara, M., Ueda, H., Tsumoto, K., Kumagai, I., Mahoney, W., Nagamune, T. J. Biochem. (2001) [Pubmed]
  38. Erythropoietin-receptor expression and function during the initiation of murine yolk sac erythropoiesis. McGann, J.K., Silver, L., Liesveld, J., Palis, J. Exp. Hematol. (1997) [Pubmed]
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