Skip to main content
PMC home page
The EMBO Journal logoLink to The EMBO Journal
. 1992 Dec;11(13):4909–4915. doi: 10.1002/j.1460-2075.1992.tb05597.x

Distinct downstream signaling mechanism between erythropoietin receptor and interleukin-2 receptor.

Y Yamamura 1, Y Kageyama 1, T Matuzaki 1, M Noda 1, Y Ikawa 1
PMCID: PMC556968  PMID: 1464316

Abstract

Erythropoietin receptor (EPOR) and interleukin-2 receptor beta chain (IL-2R beta) belong to the same cytokine receptor superfamily and have highly conserved sequences in their intracellular signaling domain. However, common downstream signaling pathways of these receptors have not been demonstrated. In the present study, we introduced and expressed the murine EPOR in murine IL-2-, IL-3- and IL-5-dependent cell lines and analyzed their growth response to EPO. We found that the expression of EPOR induced EPO dependence in IL-3-dependent BAF-B03 and IL-5-dependent Y16 cells but not in IL-2-dependent CTLL-2 cells, although the EPOR-expressing CTLL-2 cell lines could bind and internalize EPO as efficiently as the BAF-B03-derived cell lines. Additional expression of AIC2B, a common signal transducer for IL-3R, IL-5R and GM-CSFR, made no difference to the EPO responsiveness of the EPOR-expressing CTLL-2 cell lines. These results suggest that the cellular components required for the transduction of EPOR signal and IL-2R signal are at least partially different, and this difference cannot be explained solely by the absence of AIC2B.

Full text

PDF
4914

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Arai K. I., Lee F., Miyajima A., Miyatake S., Arai N., Yokota T. Cytokines: coordinators of immune and inflammatory responses. Annu Rev Biochem. 1990;59:783–836. doi: 10.1146/annurev.bi.59.070190.004031. [DOI] [PubMed] [Google Scholar]
  2. Bazan J. F. Structural design and molecular evolution of a cytokine receptor superfamily. Proc Natl Acad Sci U S A. 1990 Sep;87(18):6934–6938. doi: 10.1073/pnas.87.18.6934. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Blochlinger K., Diggelmann H. Hygromycin B phosphotransferase as a selectable marker for DNA transfer experiments with higher eucaryotic cells. Mol Cell Biol. 1984 Dec;4(12):2929–2931. doi: 10.1128/mcb.4.12.2929. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Carroll M. P., Spivak J. L., McMahon M., Weich N., Rapp U. R., May W. S. Erythropoietin induces Raf-1 activation and Raf-1 is required for erythropoietin-mediated proliferation. J Biol Chem. 1991 Aug 15;266(23):14964–14969. [PubMed] [Google Scholar]
  5. Cerottini J. C., Engers H. D., Macdonald H. R., Brunner T. Generation of cytotoxic T lymphocytes in vitro. I. Response of normal and immune mouse spleen cells in mixed leukocyte cultures. J Exp Med. 1974 Sep 1;140(3):703–717. doi: 10.1084/jem.140.3.703. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Cosman D., Lyman S. D., Idzerda R. L., Beckmann M. P., Park L. S., Goodwin R. G., March C. J. A new cytokine receptor superfamily. Trends Biochem Sci. 1990 Jul;15(7):265–270. doi: 10.1016/0968-0004(90)90051-c. [DOI] [PubMed] [Google Scholar]
  7. D'Andrea A. D., Fasman G. D., Lodish H. F. A new hematopoietic growth factor receptor superfamily: structural features and implications for signal transduction. Curr Opin Cell Biol. 1990 Aug;2(4):648–651. doi: 10.1016/0955-0674(90)90106-o. [DOI] [PubMed] [Google Scholar]
  8. D'Andrea A. D., Fasman G. D., Lodish H. F. Erythropoietin receptor and interleukin-2 receptor beta chain: a new receptor family. Cell. 1989 Sep 22;58(6):1023–1024. doi: 10.1016/0092-8674(89)90499-6. [DOI] [PubMed] [Google Scholar]
  9. D'Andrea A. D., Lodish H. F., Wong G. G. Expression cloning of the murine erythropoietin receptor. Cell. 1989 Apr 21;57(2):277–285. doi: 10.1016/0092-8674(89)90965-3. [DOI] [PubMed] [Google Scholar]
  10. D'Andrea A. D., Yoshimura A., Youssoufian H., Zon L. I., Koo J. W., Lodish H. F. The cytoplasmic region of the erythropoietin receptor contains nonoverlapping positive and negative growth-regulatory domains. Mol Cell Biol. 1991 Apr;11(4):1980–1987. doi: 10.1128/mcb.11.4.1980. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Devos R., Plaetinck G., Van der Heyden J., Cornelis S., Vandekerckhove J., Fiers W., Tavernier J. Molecular basis of a high affinity murine interleukin-5 receptor. EMBO J. 1991 Aug;10(8):2133–2137. doi: 10.1002/j.1460-2075.1991.tb07747.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Erslev A. Erythropoietin coming of age. N Engl J Med. 1987 Jan 8;316(2):101–103. doi: 10.1056/NEJM198701083160207. [DOI] [PubMed] [Google Scholar]
  13. Eschbach J. W., Egrie J. C., Downing M. R., Browne J. K., Adamson J. W. Correction of the anemia of end-stage renal disease with recombinant human erythropoietin. Results of a combined phase I and II clinical trial. N Engl J Med. 1987 Jan 8;316(2):73–78. doi: 10.1056/NEJM198701083160203. [DOI] [PubMed] [Google Scholar]
  14. Ferns M. J., Hall Z. W. How many agrins does it take to make a synapse? Cell. 1992 Jul 10;70(1):1–3. doi: 10.1016/0092-8674(92)90525-h. [DOI] [PubMed] [Google Scholar]
  15. Fu X. Y. A transcription factor with SH2 and SH3 domains is directly activated by an interferon alpha-induced cytoplasmic protein tyrosine kinase(s). Cell. 1992 Jul 24;70(2):323–335. doi: 10.1016/0092-8674(92)90106-m. [DOI] [PubMed] [Google Scholar]
  16. Fujii M., Sugamura K., Sano K., Nakai M., Sugita K., Hinuma Y. High-affinity receptor-mediated internalization and degradation of interleukin 2 in human T cells. J Exp Med. 1986 Mar 1;163(3):550–562. doi: 10.1084/jem.163.3.550. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Fukunaga R., Ishizaka-Ikeda E., Pan C. X., Seto Y., Nagata S. Functional domains of the granulocyte colony-stimulating factor receptor. EMBO J. 1991 Oct;10(10):2855–2865. doi: 10.1002/j.1460-2075.1991.tb07835.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Fukunaga R., Ishizaka-Ikeda E., Seto Y., Nagata S. Expression cloning of a receptor for murine granulocyte colony-stimulating factor. Cell. 1990 Apr 20;61(2):341–350. doi: 10.1016/0092-8674(90)90814-u. [DOI] [PubMed] [Google Scholar]
  19. Gearing D. P., Comeau M. R., Friend D. J., Gimpel S. D., Thut C. J., McGourty J., Brasher K. K., King J. A., Gillis S., Mosley B. The IL-6 signal transducer, gp130: an oncostatin M receptor and affinity converter for the LIF receptor. Science. 1992 Mar 13;255(5050):1434–1437. doi: 10.1126/science.1542794. [DOI] [PubMed] [Google Scholar]
  20. Gorman D. M., Itoh N., Kitamura T., Schreurs J., Yonehara S., Yahara I., Arai K., Miyajima A. Cloning and expression of a gene encoding an interleukin 3 receptor-like protein: identification of another member of the cytokine receptor gene family. Proc Natl Acad Sci U S A. 1990 Jul;87(14):5459–5463. doi: 10.1073/pnas.87.14.5459. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Hara T., Miyajima A. Two distinct functional high affinity receptors for mouse interleukin-3 (IL-3). EMBO J. 1992 May;11(5):1875–1884. doi: 10.1002/j.1460-2075.1992.tb05239.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Hatakeyama M., Kono T., Kobayashi N., Kawahara A., Levin S. D., Perlmutter R. M., Taniguchi T. Interaction of the IL-2 receptor with the src-family kinase p56lck: identification of novel intermolecular association. Science. 1991 Jun 14;252(5012):1523–1528. doi: 10.1126/science.2047859. [DOI] [PubMed] [Google Scholar]
  23. Hatakeyama M., Mori H., Doi T., Taniguchi T. A restricted cytoplasmic region of IL-2 receptor beta chain is essential for growth signal transduction but not for ligand binding and internalization. Cell. 1989 Dec 1;59(5):837–845. doi: 10.1016/0092-8674(89)90607-7. [DOI] [PubMed] [Google Scholar]
  24. Hatakeyama M., Tsudo M., Minamoto S., Kono T., Doi T., Miyata T., Miyasaka M., Taniguchi T. Interleukin-2 receptor beta chain gene: generation of three receptor forms by cloned human alpha and beta chain cDNA's. Science. 1989 May 5;244(4904):551–556. doi: 10.1126/science.2785715. [DOI] [PubMed] [Google Scholar]
  25. Hibi M., Murakami M., Saito M., Hirano T., Taga T., Kishimoto T. Molecular cloning and expression of an IL-6 signal transducer, gp130. Cell. 1990 Dec 21;63(6):1149–1157. doi: 10.1016/0092-8674(90)90411-7. [DOI] [PubMed] [Google Scholar]
  26. Itoh N., Yonehara S., Schreurs J., Gorman D. M., Maruyama K., Ishii A., Yahara I., Arai K., Miyajima A. Cloning of an interleukin-3 receptor gene: a member of a distinct receptor gene family. Science. 1990 Jan 19;247(4940):324–327. doi: 10.1126/science.2404337. [DOI] [PubMed] [Google Scholar]
  27. Jones S. S., D'Andrea A. D., Haines L. L., Wong G. G. Human erythropoietin receptor: cloning, expression, and biologic characterization. Blood. 1990 Jul 1;76(1):31–35. [PubMed] [Google Scholar]
  28. Kitamura T., Hayashida K., Sakamaki K., Yokota T., Arai K., Miyajima A. Reconstitution of functional receptors for human granulocyte/macrophage colony-stimulating factor (GM-CSF): evidence that the protein encoded by the AIC2B cDNA is a subunit of the murine GM-CSF receptor. Proc Natl Acad Sci U S A. 1991 Jun 15;88(12):5082–5086. doi: 10.1073/pnas.88.12.5082. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Kitamura T., Sato N., Arai K., Miyajima A. Expression cloning of the human IL-3 receptor cDNA reveals a shared beta subunit for the human IL-3 and GM-CSF receptors. Cell. 1991 Sep 20;66(6):1165–1174. doi: 10.1016/0092-8674(91)90039-2. [DOI] [PubMed] [Google Scholar]
  30. Kono T., Doi T., Yamada G., Hatakeyama M., Minamoto S., Tsudo M., Miyasaka M., Miyata T., Taniguchi T. Murine interleukin 2 receptor beta chain: dysregulated gene expression in lymphoma line EL-4 caused by a promoter insertion. Proc Natl Acad Sci U S A. 1990 Mar;87(5):1806–1810. doi: 10.1073/pnas.87.5.1806. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Kuramochi S., Ikawa Y., Todokoro K. Characterization of murine erythropoietin receptor genes. J Mol Biol. 1990 Dec 5;216(3):567–575. doi: 10.1016/0022-2836(90)90384-x. [DOI] [PubMed] [Google Scholar]
  32. Li J. P., Baltimore D. Mechanism of leukemogenesis induced by mink cell focus-forming murine leukemia viruses. J Virol. 1991 May;65(5):2408–2414. doi: 10.1128/jvi.65.5.2408-2414.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Li J. P., D'Andrea A. D., Lodish H. F., Baltimore D. Activation of cell growth by binding of Friend spleen focus-forming virus gp55 glycoprotein to the erythropoietin receptor. Nature. 1990 Feb 22;343(6260):762–764. doi: 10.1038/343762a0. [DOI] [PubMed] [Google Scholar]
  34. Longmore G. D., Lodish H. F. An activating mutation in the murine erythropoietin receptor induces erythroleukemia in mice: a cytokine receptor superfamily oncogene. Cell. 1991 Dec 20;67(6):1089–1102. doi: 10.1016/0092-8674(91)90286-8. [DOI] [PubMed] [Google Scholar]
  35. Miller A. D., Rosman G. J. Improved retroviral vectors for gene transfer and expression. Biotechniques. 1989 Oct;7(9):980-2, 984-6, 989-90. [PMC free article] [PubMed] [Google Scholar]
  36. Miura O., D'Andrea A., Kabat D., Ihle J. N. Induction of tyrosine phosphorylation by the erythropoietin receptor correlates with mitogenesis. Mol Cell Biol. 1991 Oct;11(10):4895–4902. doi: 10.1128/mcb.11.10.4895. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Mori H., Barsoumian E. L., Hatakeyama M., Taniguchi T. Signal transduction by interleukin 2 receptor beta chain: importance of the structural integrity as revealed by site-directed mutagenesis and generation of chimeric receptors. Int Immunol. 1991 Feb;3(2):149–156. doi: 10.1093/intimm/3.2.149. [DOI] [PubMed] [Google Scholar]
  38. Mosley B., Beckmann M. P., March C. J., Idzerda R. L., Gimpel S. D., VandenBos T., Friend D., Alpert A., Anderson D., Jackson J. The murine interleukin-4 receptor: molecular cloning and characterization of secreted and membrane bound forms. Cell. 1989 Oct 20;59(2):335–348. doi: 10.1016/0092-8674(89)90295-x. [DOI] [PubMed] [Google Scholar]
  39. Murakami M., Narazaki M., Hibi M., Yawata H., Yasukawa K., Hamaguchi M., Taga T., Kishimoto T. Critical cytoplasmic region of the interleukin 6 signal transducer gp130 is conserved in the cytokine receptor family. Proc Natl Acad Sci U S A. 1991 Dec 15;88(24):11349–11353. doi: 10.1073/pnas.88.24.11349. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Nicola N. A., Metcalf D. Subunit promiscuity among hemopoietic growth factor receptors. Cell. 1991 Oct 4;67(1):1–4. doi: 10.1016/0092-8674(91)90564-f. [DOI] [PubMed] [Google Scholar]
  41. Quelle D. E., Wojchowski D. M. Localized cytosolic domains of the erythropoietin receptor regulate growth signaling and down-modulate responsiveness to granulocyte-macrophage colony-stimulating factor. Proc Natl Acad Sci U S A. 1991 Jun 1;88(11):4801–4805. doi: 10.1073/pnas.88.11.4801. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Quelle F. W., Wojchowski D. M. Proliferative action of erythropoietin is associated with rapid protein tyrosine phosphorylation in responsive B6SUt.EP cells. J Biol Chem. 1991 Jan 5;266(1):609–614. [PubMed] [Google Scholar]
  43. Robb R. J., Greene W. C. Internalization of interleukin 2 is mediated by the beta chain of the high-affinity interleukin 2 receptor. J Exp Med. 1987 Apr 1;165(4):1201–1206. doi: 10.1084/jem.165.4.1201. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Sawyer S. T., Krantz S. B., Goldwasser E. Binding and receptor-mediated endocytosis of erythropoietin in Friend virus-infected erythroid cells. J Biol Chem. 1987 Apr 25;262(12):5554–5562. [PubMed] [Google Scholar]
  45. Sawyer S. T., Krantz S. B., Luna J. Identification of the receptor for erythropoietin by cross-linking to Friend virus-infected erythroid cells. Proc Natl Acad Sci U S A. 1987 Jun;84(11):3690–3694. doi: 10.1073/pnas.84.11.3690. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Spivak J. L., Pham T., Isaacs M., Hankins W. D. Erythropoietin is both a mitogen and a survival factor. Blood. 1991 Mar 15;77(6):1228–1233. [PubMed] [Google Scholar]
  47. Takaki S., Mita S., Kitamura T., Yonehara S., Yamaguchi N., Tominaga A., Miyajima A., Takatsu K. Identification of the second subunit of the murine interleukin-5 receptor: interleukin-3 receptor-like protein, AIC2B is a component of the high affinity interleukin-5 receptor. EMBO J. 1991 Oct;10(10):2833–2838. doi: 10.1002/j.1460-2075.1991.tb07832.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Takeshita T., Asao H., Ohtani K., Ishii N., Kumaki S., Tanaka N., Munakata H., Nakamura M., Sugamura K. Cloning of the gamma chain of the human IL-2 receptor. Science. 1992 Jul 17;257(5068):379–382. doi: 10.1126/science.1631559. [DOI] [PubMed] [Google Scholar]
  49. Todokoro K., Kanazawa S., Amanuma H., Ikawa Y. Characterization of erythropoietin receptor on erythropoietin-unresponsive mouse erythroleukemia cells. Biochim Biophys Acta. 1988 Aug 18;943(2):326–330. doi: 10.1016/0005-2736(88)90564-0. [DOI] [PubMed] [Google Scholar]
  50. Todokoro K., Kanazawa S., Amanuma H., Ikawa Y. Specific binding of erythropoietin to its receptor on responsive mouse erythroleukemia cells. Proc Natl Acad Sci U S A. 1987 Jun;84(12):4126–4130. doi: 10.1073/pnas.84.12.4126. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Todokoro K., Watson R. J., Higo H., Amanuma H., Kuramochi S., Yanagisawa H., Ikawa Y. Down-regulation of c-myb gene expression is a prerequisite for erythropoietin-induced erythroid differentiation. Proc Natl Acad Sci U S A. 1988 Dec;85(23):8900–8904. doi: 10.1073/pnas.85.23.8900. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Tominaga A., Mita S., Kikuchi Y., Hitoshi Y., Takatsu K., Nishikawa S., Ogawa M. Establishment of IL-5-dependent early B cell lines by long-term bone marrow cultures. Growth Factors. 1989;1(2):135–146. doi: 10.3109/08977198909029123. [DOI] [PubMed] [Google Scholar]
  53. Velazquez L., Fellous M., Stark G. R., Pellegrini S. A protein tyrosine kinase in the interferon alpha/beta signaling pathway. Cell. 1992 Jul 24;70(2):313–322. doi: 10.1016/0092-8674(92)90105-l. [DOI] [PubMed] [Google Scholar]
  54. Watowich S. S., Yoshimura A., Longmore G. D., Hilton D. J., Yoshimura Y., Lodish H. F. Homodimerization and constitutive activation of the erythropoietin receptor. Proc Natl Acad Sci U S A. 1992 Mar 15;89(6):2140–2144. doi: 10.1073/pnas.89.6.2140. [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. Weissman A. M., Harford J. B., Svetlik P. B., Leonard W. L., Depper J. M., Waldmann T. A., Greene W. C., Klausner R. D. Only high-affinity receptors for interleukin 2 mediate internalization of ligand. Proc Natl Acad Sci U S A. 1986 Mar;83(5):1463–1466. doi: 10.1073/pnas.83.5.1463. [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. Yonehara S., Ishii A., Yonehara M., Koyasu S., Miyajima A., Schreurs J., Arai K., Yahara I. Identification of a cell surface 105 kd protein (Aic-2 antigen) which binds interleukin-3. Int Immunol. 1990;2(2):143–150. doi: 10.1093/intimm/2.2.143. [DOI] [PubMed] [Google Scholar]
  57. Yoshimura A., D'Andrea A. D., Lodish H. F. Friend spleen focus-forming virus glycoprotein gp55 interacts with the erythropoietin receptor in the endoplasmic reticulum and affects receptor metabolism. Proc Natl Acad Sci U S A. 1990 Jun;87(11):4139–4143. doi: 10.1073/pnas.87.11.4139. [DOI] [PMC free article] [PubMed] [Google Scholar]
  58. Yoshimura A., Lodish H. F. In vitro phosphorylation of the erythropoietin receptor and an associated protein, pp130. Mol Cell Biol. 1992 Feb;12(2):706–715. doi: 10.1128/mcb.12.2.706. [DOI] [PMC free article] [PubMed] [Google Scholar]
  59. Zon L. I., Moreau J. F., Koo J. W., Mathey-Prevot B., D'Andrea A. D. The erythropoietin receptor transmembrane region is necessary for activation by the Friend spleen focus-forming virus gp55 glycoprotein. Mol Cell Biol. 1992 Jul;12(7):2949–2957. doi: 10.1128/mcb.12.7.2949. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from The EMBO Journal are provided here courtesy of Nature Publishing Group

RESOURCES