Skip to main content
PMC home page
Journal of Virology logoLink to Journal of Virology
. 1995 Feb;69(2):856–863. doi: 10.1128/jvi.69.2.856-863.1995

Deletions in one domain of the Friend virus-encoded membrane glycoprotein overcome host range restrictions for erythroleukemia.

M E Hoatlin 1, F E Ferro Jr 1, R W Geib 1, M T Fox 1, S L Kozak 1, D Kabat 1
PMCID: PMC188652  PMID: 7815553

Abstract

Although the Friend virus-encoded membrane glycoprotein (gp55) activates erythropoietin receptors (EpoR) to cause erythroblastosis only in certain inbred strains of mice but not in other species, mutant viruses can overcome aspects of mouse resistance. Thus, mice homozygous for the resistance allele of the Fv-2 gene are unaffected by gp55 but are susceptible to mutant glycoproteins that have partial deletions in their ecotropic domains. These and other results have suggested that proteins coded for by polymorphic Fv-2 alleles might directly or indirectly interact with EpoR and that changes in gp55 can overcome this defense. A new viral mutant with an exceptionally large deletion in its ecotropic domain is now also shown to overcome Fv-2rr resistance. In all cases, the glycoproteins that activate EpoR are processed to cell surfaces as disulfide-bonded dimers. To initiate analysis of nonmurine resistances, we expressed human EpoR and mouse EpoR in the interleukin 3-dependent mouse cell line BaF3 and compared the abilities of Friend virus-encoded glycoproteins to convert these cells to growth factor independence. Human EpoR was activated in these cells by erythropoietin but was resistant to gp55. However, human EpoR was efficiently activated in these cells by the same viral mutants that overcome Fv-2rr resistance in mice. By construction and analysis of human-mouse EpoR chimeras, we obtained evidence that the cytosolic domain of human EpoR contributes to its resistance to gp55 and that this resistance is mediated by accessory cellular factors. Aspects of host resistance in both murine and nonmurine species are targeted specifically against the ecotropic domain of gp55.

Full Text

The Full Text of this article is available as a PDF (343.2 KB).

Selected References

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

  1. Amanuma H., Katori A., Obata M., Sagata N., Ikawa Y. Complete nucleotide sequence of the gene for the specific glycoprotein (gp55) of Friend spleen focus-forming virus. Proc Natl Acad Sci U S A. 1983 Jul;80(13):3913–3917. doi: 10.1073/pnas.80.13.3913. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Barber D. L., DeMartino J. C., Showers M. O., D'Andrea A. D. A dominant negative erythropoietin (EPO) receptor inhibits EPO-dependent growth and blocks F-gp55-dependent transformation. Mol Cell Biol. 1994 Apr;14(4):2257–2265. doi: 10.1128/mcb.14.4.2257. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Bestwick R. K., Hankins W. D., Kabat D. Roles of helper and defective retroviral genomes in murine erythroleukemia: studies of spleen focus-forming virus in the absence of helper. J Virol. 1985 Dec;56(3):660–664. doi: 10.1128/jvi.56.3.660-664.1985. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Bestwick R. K., Kozak S. L., Kabat D. Overcoming interference to retroviral superinfection results in amplified expression and transmission of cloned genes. Proc Natl Acad Sci U S A. 1988 Aug;85(15):5404–5408. doi: 10.1073/pnas.85.15.5404. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Casadevall N., Lacombe C., Muller O., Gisselbrecht S., Mayeux P. Multimeric structure of the membrane erythropoietin receptor of murine erythroleukemia cells (Friend cells). Cross-linking of erythropoietin with the spleen focus-forming virus envelope protein. J Biol Chem. 1991 Aug 25;266(24):16015–16020. [PubMed] [Google Scholar]
  6. Chesebro B., Miyazawa M., Britt W. J. Host genetic control of spontaneous and induced immunity to Friend murine retrovirus infection. Annu Rev Immunol. 1990;8:477–499. doi: 10.1146/annurev.iy.08.040190.002401. [DOI] [PubMed] [Google Scholar]
  7. Clark S. P., Mak T. W. Complete nucleotide sequence of an infectious clone of Friend spleen focus-forming provirus: gp55 is an envelope fusion glycoprotein. Proc Natl Acad Sci U S A. 1983 Aug;80(16):5037–5041. doi: 10.1073/pnas.80.16.5037. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Cunningham B. C., Ultsch M., De Vos A. M., Mulkerrin M. G., Clauser K. R., Wells J. A. Dimerization of the extracellular domain of the human growth hormone receptor by a single hormone molecule. Science. 1991 Nov 8;254(5033):821–825. doi: 10.1126/science.1948064. [DOI] [PubMed] [Google Scholar]
  9. Cutler R. L., Liu L., Damen J. E., Krystal G. Multiple cytokines induce the tyrosine phosphorylation of Shc and its association with Grb2 in hemopoietic cells. J Biol Chem. 1993 Oct 15;268(29):21463–21465. [PubMed] [Google Scholar]
  10. 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]
  11. 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]
  12. Damen J. E., Liu L., Cutler R. L., Krystal G. Erythropoietin stimulates the tyrosine phosphorylation of Shc and its association with Grb2 and a 145-Kd tyrosine phosphorylated protein. Blood. 1993 Oct 15;82(8):2296–2303. [PubMed] [Google Scholar]
  13. Damen J. E., Mui A. L., Puil L., Pawson T., Krystal G. Phosphatidylinositol 3-kinase associates, via its Src homology 2 domains, with the activated erythropoietin receptor. Blood. 1993 Jun 15;81(12):3204–3210. [PubMed] [Google Scholar]
  14. Dawson P. J., Rose W. M., Fieldsteel A. H. Lymphatic leukaemia in rats and mice inoculated with Friend virus. Br J Cancer. 1966 Mar;20(1):114–121. doi: 10.1038/bjc.1966.12. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Dizik M., Elliott R. W., Lilly F. Construction of a D2.B6-Fv-2r congenic mouse strain: nonlethality of the homozygous Fv-2' genotype. J Natl Cancer Inst. 1981 Apr;66(4):755–760. [PubMed] [Google Scholar]
  16. Dusanter-Fourt I., Casadevall N., Lacombe C., Muller O., Billat C., Fischer S., Mayeux P. Erythropoietin induces the tyrosine phosphorylation of its own receptor in human erythropoietin-responsive cells. J Biol Chem. 1992 May 25;267(15):10670–10675. [PubMed] [Google Scholar]
  17. Ferro F. E., Jr, Kozak S. L., Hoatlin M. E., Kabat D. Cell surface site for mitogenic interaction of erythropoietin receptors with the membrane glycoprotein encoded by Friend erythroleukemia virus. J Biol Chem. 1993 Mar 15;268(8):5741–5747. [PubMed] [Google Scholar]
  18. Geib R. W., Seaward M. B., Stevens M. L., Cho C. L., Majumdar M. RB virus: a strain of Friend virus that produces a 'Friend virus-like' disease in Fv-2rr mice. Virus Res. 1989 Oct;14(2):161–173. doi: 10.1016/0168-1702(89)90036-1. [DOI] [PubMed] [Google Scholar]
  19. Gliniak B. C., Kabat D. Leukemogenic membrane glycoprotein encoded by Friend spleen focus-forming virus: transport to cell surfaces and shedding are controlled by disulfide-bonded dimerization and by cleavage of a hydrophobic membrane anchor. J Virol. 1989 Sep;63(9):3561–3568. doi: 10.1128/jvi.63.9.3561-3568.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. He T. C., Zhuang H., Jiang N., Waterfield M. D., Wojchowski D. M. Association of the p85 regulatory subunit of phosphatidylinositol 3-kinase with an essential erythropoietin receptor subdomain. Blood. 1993 Dec 15;82(12):3530–3538. [PubMed] [Google Scholar]
  21. Hoatlin M. E., Ferro F. E., Jr, Kozak S. L., Kabat D. A Friend virus mutant encodes a small glycoprotein that causes erythroleukemia. J Virol. 1994 Jun;68(6):4053–4056. doi: 10.1128/jvi.68.6.4053-4056.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Hoatlin M. E., Kozak S. L., Lilly F., Chakraborti A., Kozak C. A., Kabat D. Activation of erythropoietin receptors by Friend viral gp55 and by erythropoietin and down-modulation by the murine Fv-2r resistance gene. Proc Natl Acad Sci U S A. 1990 Dec;87(24):9985–9989. doi: 10.1073/pnas.87.24.9985. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. 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]
  24. Kabat D. Molecular biology of Friend viral erythroleukemia. Curr Top Microbiol Immunol. 1989;148:1–42. doi: 10.1007/978-3-642-74700-7_1. [DOI] [PubMed] [Google Scholar]
  25. Kishi A., Chiba T., Sugiyama M., Machide M., Nagata Y., Amanuma H., Taira H., Katsumata T., Todokoro K. Erythropoietin receptor binds to Friend virus gp55 through other membrane components. Biochem Biophys Res Commun. 1993 May 14;192(3):1131–1138. doi: 10.1006/bbrc.1993.1534. [DOI] [PubMed] [Google Scholar]
  26. Kozak C. A. Analysis of wild-derived mice for Fv-1 and Fv-2 murine leukemia virus restriction loci: a novel wild mouse Fv-1 allele responsible for lack of host range restriction. J Virol. 1985 Aug;55(2):281–285. doi: 10.1128/jvi.55.2.281-285.1985. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Kozak S. L., Hoatlin M. E., Ferro F. E., Jr, Majumdar M. K., Geib R. W., Fox M. T., Kabat D. A Friend virus mutant that overcomes Fv-2rr host resistance encodes a small glycoprotein that dimerizes, is processed to cell surfaces, and specifically activates erythropoietin receptors. J Virol. 1993 May;67(5):2611–2620. doi: 10.1128/jvi.67.5.2611-2620.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Kozak S. L., Kabat D. Ping-pong amplification of a retroviral vector achieves high-level gene expression: human growth hormone production. J Virol. 1990 Jul;64(7):3500–3508. doi: 10.1128/jvi.64.7.3500-3508.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. 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]
  30. Li J. P., Bestwick R. K., Machida C., Kabat D. Role of a membrane glycoprotein in Friend virus erythroleukemia: nucleotide sequences of nonleukemogenic mutant and spontaneous revertant viruses. J Virol. 1986 Feb;57(2):534–538. doi: 10.1128/jvi.57.2.534-538.1986. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Li J. P., Bestwick R. K., Spiro C., Kabat D. The membrane glycoprotein of Friend spleen focus-forming virus: evidence that the cell surface component is required for pathogenesis and that it binds to a receptor. J Virol. 1987 Sep;61(9):2782–2792. doi: 10.1128/jvi.61.9.2782-2792.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. 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]
  33. Lilly F. Fv-2: identification and location of a second gene governing the spleen focus response to Friend leukemia virus in mice. J Natl Cancer Inst. 1970 Jul;45(1):163–169. [PubMed] [Google Scholar]
  34. Machida C. A., Bestwick R. K., Boswell B. A., Kabat D. Role of a membrane glycoprotein in Friend virus-induced erythroleukemia: studies of mutant and revertant viruses. Virology. 1985 Jul 15;144(1):158–172. doi: 10.1016/0042-6822(85)90314-9. [DOI] [PubMed] [Google Scholar]
  35. Majumdar M. K., Cho C. L., Fox M. T., Eckner K. L., Kozak S., Kabat D., Geib R. W. Mutations in the env gene of friend spleen focus-forming virus overcome Fv-2r-mediated resistance to Friend virus-induced erythroleukemia. J Virol. 1992 Jun;66(6):3652–3660. doi: 10.1128/jvi.66.6.3652-3660.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Mann R., Mulligan R. C., Baltimore D. Construction of a retrovirus packaging mutant and its use to produce helper-free defective retrovirus. Cell. 1983 May;33(1):153–159. doi: 10.1016/0092-8674(83)90344-6. [DOI] [PubMed] [Google Scholar]
  37. Mathey-Prevot B., Nabel G., Palacios R., Baltimore D. Abelson virus abrogation of interleukin-3 dependence in a lymphoid cell line. Mol Cell Biol. 1986 Nov;6(11):4133–4135. doi: 10.1128/mcb.6.11.4133. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Mayeux P., Casadevall N., Lacombe C., Muller O., Tambourin P. Solubilization and hydrodynamic characteristics of the erythropoietin receptor. Evidence for a multimeric complex. Eur J Biochem. 1990 Nov 26;194(1):271–278. doi: 10.1111/j.1432-1033.1990.tb19453.x. [DOI] [PubMed] [Google Scholar]
  39. Mayeux P., Dusanter-Fourt I., Muller O., Mauduit P., Sabbah M., Druker B., Vainchenker W., Fischer S., Lacombe C., Gisselbrecht S. Erythropoietin induces the association of phosphatidylinositol 3'-kinase with a tyrosine-phosphorylated protein complex containing the erythropoietin receptor. Eur J Biochem. 1993 Sep 15;216(3):821–828. doi: 10.1111/j.1432-1033.1993.tb18203.x. [DOI] [PubMed] [Google Scholar]
  40. Miller A. D., Law M. F., Verma I. M. Generation of helper-free amphotropic retroviruses that transduce a dominant-acting, methotrexate-resistant dihydrofolate reductase gene. Mol Cell Biol. 1985 Mar;5(3):431–437. doi: 10.1128/mcb.5.3.431. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Miura O., Cleveland J. L., Ihle J. N. Inactivation of erythropoietin receptor function by point mutations in a region having homology with other cytokine receptors. Mol Cell Biol. 1993 Mar;13(3):1788–1795. doi: 10.1128/mcb.13.3.1788. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Miura O., Nakamura N., Ihle J. N., Aoki N. Erythropoietin-dependent association of phosphatidylinositol 3-kinase with tyrosine-phosphorylated erythropoietin receptor. J Biol Chem. 1994 Jan 7;269(1):614–620. [PubMed] [Google Scholar]
  43. Murray M. J., Kabat D. Genetic and sialylation sources of heterogeneity of the murine leukemia virus membrane envelope glycoproteins gp69/71. J Biol Chem. 1979 Feb 25;254(4):1340–1348. [PubMed] [Google Scholar]
  44. Nakamura Y., Komatsu N., Nakauchi H. A truncated erythropoietin receptor that fails to prevent programmed cell death of erythroid cells. Science. 1992 Aug 21;257(5073):1138–1141. doi: 10.1126/science.257.5073.1138. [DOI] [PubMed] [Google Scholar]
  45. Nakamura Y., Nakauchi H. A truncated erythropoietin receptor and cell death: a reanalysis. Science. 1994 Apr 22;264(5158):588–589. doi: 10.1126/science.8160019. [DOI] [PubMed] [Google Scholar]
  46. Ohashi H., Maruyama K., Liu Y. C., Yoshimura A. Ligand-induced activation of chimeric receptors between the erythropoietin receptor and receptor tyrosine kinases. Proc Natl Acad Sci U S A. 1994 Jan 4;91(1):158–162. doi: 10.1073/pnas.91.1.158. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Pinter A., Honnen W. J. The mature form of the Friend spleen focus-forming virus envelope protein, gp65, is efficiently secreted from cells. Virology. 1985 Jun;143(2):646–650. doi: 10.1016/0042-6822(85)90406-4. [DOI] [PubMed] [Google Scholar]
  48. Pryciak P. M., Varmus H. E. Fv-1 restriction and its effects on murine leukemia virus integration in vivo and in vitro. J Virol. 1992 Oct;66(10):5959–5966. doi: 10.1128/jvi.66.10.5959-5966.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Ruscetti S., Davis L., Feild J., Oliff A. Friend murine leukemia virus-induced leukemia is associated with the formation of mink cell focus-inducing viruses and is blocked in mice expressing endogenous mink cell focus-inducing xenotropic viral envelope genes. J Exp Med. 1981 Sep 1;154(3):907–920. doi: 10.1084/jem.154.3.907. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Ruta M., Clarke S., Boswell B., Kabat D. Heterogeneous metabolism and subcellular localization of a potentially leukemogenic membrane glycoprotein encoded by Friend erythroleukemia virus. Isolation of viral and cellular processing mutants. J Biol Chem. 1982 Jan 10;257(1):126–134. [PubMed] [Google Scholar]
  51. Ruta M., Kabat D. Plasma membrane glycoproteins encoded by cloned Rauscher and Friend spleen focus-forming viruses. J Virol. 1980 Sep;35(3):844–853. doi: 10.1128/jvi.35.3.844-853.1980. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Sakamaki K., Miyajima I., Kitamura T., Miyajima A. Critical cytoplasmic domains of the common beta subunit of the human GM-CSF, IL-3 and IL-5 receptors for growth signal transduction and tyrosine phosphorylation. EMBO J. 1992 Oct;11(10):3541–3549. doi: 10.1002/j.1460-2075.1992.tb05437.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. Shibuya T., Niho Y., Mak T. W. Erythroleukemia induction by Friend leukemia virus. A host gene locus controlling early anemia or polycythemia and the rate of proliferation of late erythroid cells. J Exp Med. 1982 Aug 1;156(2):398–414. doi: 10.1084/jem.156.2.398. [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Showers M. O., DeMartino J. C., Saito Y., D'Andrea A. D. Fusion of the erythropoietin receptor and the Friend spleen focus-forming virus gp55 glycoprotein transforms a factor-dependent hematopoietic cell line. Mol Cell Biol. 1993 Feb;13(2):739–748. doi: 10.1128/mcb.13.2.739. [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. Silver J. E., Fredrickson T. N. Susceptibility to Friend helper virus leukemias in CXB recombinant inbred mice. J Exp Med. 1983 Nov 1;158(5):1693–1702. doi: 10.1084/jem.158.5.1693. [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. Steeves R. A., Mirand E. A., Bulba A., Trudel P. J. Spleen foci and polycythemia in C57B1 mice infected with host-adapted Friend leukemia virus. Int J Cancer. 1970 May 15;5(3):346–356. doi: 10.1002/ijc.2910050307. [DOI] [PubMed] [Google Scholar]
  57. 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]
  58. Witthuhn B. A., Quelle F. W., Silvennoinen O., Yi T., Tang B., Miura O., Ihle J. N. JAK2 associates with the erythropoietin receptor and is tyrosine phosphorylated and activated following stimulation with erythropoietin. Cell. 1993 Jul 30;74(2):227–236. doi: 10.1016/0092-8674(93)90414-l. [DOI] [PubMed] [Google Scholar]
  59. Wolff L., Ruscetti S. Malignant transformation of erythroid cells in vivo by introduction of a nonreplicating retrovirus vector. Science. 1985 Jun 28;228(4707):1549–1552. doi: 10.1126/science.2990034. [DOI] [PubMed] [Google Scholar]
  60. Wolff L., Scolnick E., Ruscetti S. Envelope gene of the Friend spleen focus-forming virus: deletion and insertions in 3' gp70/p15E-encoding region have resulted in unique features in the primary structure of its protein product. Proc Natl Acad Sci U S A. 1983 Aug;80(15):4718–4722. doi: 10.1073/pnas.80.15.4718. [DOI] [PMC free article] [PubMed] [Google Scholar]
  61. 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]
  62. Yoshimura A., Longmore G., Lodish H. F. Point mutation in the exoplasmic domain of the erythropoietin receptor resulting in hormone-independent activation and tumorigenicity. Nature. 1990 Dec 13;348(6302):647–649. doi: 10.1038/348647a0. [DOI] [PubMed] [Google Scholar]
  63. 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]
  64. de Vos A. M., Ultsch M., Kossiakoff A. A. Human growth hormone and extracellular domain of its receptor: crystal structure of the complex. Science. 1992 Jan 17;255(5042):306–312. doi: 10.1126/science.1549776. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Virology are provided here courtesy of American Society for Microbiology (ASM)

RESOURCES