Skip to main content
Journal of Virology logoLink to Journal of Virology
. 1994 Jun;68(6):3582–3592. doi: 10.1128/jvi.68.6.3582-3592.1994

Specific interaction between the bovine papillomavirus E5 transforming protein and the beta receptor for platelet-derived growth factor in stably transformed and acutely transfected cells.

L Petti 1, D DiMaio 1
PMCID: PMC236862  PMID: 8189497

Abstract

The E5 protein of bovine papillomavirus is a 44-amino-acid membrane protein which induces morphologic and tumorigenic transformation of fibroblasts. We previously showed that the E5 protein activates and forms a complex with the endogenous beta receptor for platelet-derived growth factor (PDGF) in transformed rodent fibroblasts and that the PDGF beta receptor can mediate tumorigenic transformation by the E5 protein in a heterologous cell system. Other workers have identified the receptor for epidermal growth factor (EGF) as a potential target of the E5 protein in NIH 3T3 cells. Here, we investigate the specificity of the interaction of the E5 protein with various growth factor receptors, with particular emphasis on the PDGF beta receptor and the EGF receptor. Under conditions where both the PDGF beta receptor and the EGF receptor are stably expressed in E5-transformed mouse and bovine fibroblasts and in E5-transformed epithelial cells, the E5 protein specifically forms a complex with and activates the PDGF receptor and not the EGF receptor. Under conditions of transient overexpression in COS cells, the E5 protein has the potential to associate with several growth factor receptors, including the EGF receptor. However, upon coexpression of PDGF beta receptors and EGF receptors in COS cells, the E5 protein preferentially forms a complex with the PDGF receptor. Therefore, we conclude that the PDGF beta receptor is the primary target for the E5 protein in a variety of cell types, including bovine fibroblasts.

Full text

PDF
3582

Images in this article

Selected References

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

  1. Bargmann C. I., Hung M. C., Weinberg R. A. Multiple independent activations of the neu oncogene by a point mutation altering the transmembrane domain of p185. Cell. 1986 Jun 6;45(5):649–657. doi: 10.1016/0092-8674(86)90779-8. [DOI] [PubMed] [Google Scholar]
  2. Bergman P., Ustav M., Sedman J., Moreno-Lopéz J., Vennström B., Pettersson U. The E5 gene of bovine papillomavirus type 1 is sufficient for complete oncogenic transformation of mouse fibroblasts. Oncogene. 1988 May;2(5):453–459. [PubMed] [Google Scholar]
  3. Burkhardt A., DiMaio D., Schlegel R. Genetic and biochemical definition of the bovine papillomavirus E5 transforming protein. EMBO J. 1987 Aug;6(8):2381–2385. doi: 10.1002/j.1460-2075.1987.tb02515.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Burkhardt A., Willingham M., Gay C., Jeang K. T., Schlegel R. The E5 oncoprotein of bovine papillomavirus is oriented asymmetrically in Golgi and plasma membranes. Virology. 1989 May;170(1):334–339. doi: 10.1016/0042-6822(89)90391-7. [DOI] [PubMed] [Google Scholar]
  5. Burnett S., Jareborg N., DiMaio D. Localization of bovine papillomavirus type 1 E5 protein to transformed basal keratinocytes and permissive differentiated cells in fibropapilloma tissue. Proc Natl Acad Sci U S A. 1992 Jun 15;89(12):5665–5669. doi: 10.1073/pnas.89.12.5665. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Cao H., Bangalore L., Dompé C., Bormann B. J., Stern D. F. An extra cysteine proximal to the transmembrane domain induces differential cross-linking of p185neu and p185neu. J Biol Chem. 1992 Oct 5;267(28):20489–20492. [PubMed] [Google Scholar]
  7. Claesson-Welsh L., Eriksson A., Morén A., Severinsson L., Ek B., Ostman A., Betsholtz C., Heldin C. H. cDNA cloning and expression of a human platelet-derived growth factor (PDGF) receptor specific for B-chain-containing PDGF molecules. Mol Cell Biol. 1988 Aug;8(8):3476–3486. doi: 10.1128/mcb.8.8.3476. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Cohen B. D., Goldstein D. J., Rutledge L., Vass W. C., Lowy D. R., Schlegel R., Schiller J. T. Transformation-specific interaction of the bovine papillomavirus E5 oncoprotein with the platelet-derived growth factor receptor transmembrane domain and the epidermal growth factor receptor cytoplasmic domain. J Virol. 1993 Sep;67(9):5303–5311. doi: 10.1128/jvi.67.9.5303-5311.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Cohen B. D., Lowy D. R., Schiller J. T. The conserved C-terminal domain of the bovine papillomavirus E5 oncoprotein can associate with an alpha-adaptin-like molecule: a possible link between growth factor receptors and viral transformation. Mol Cell Biol. 1993 Oct;13(10):6462–6468. doi: 10.1128/mcb.13.10.6462. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. DiMaio D., Guralski D., Schiller J. T. Translation of open reading frame E5 of bovine papillomavirus is required for its transforming activity. Proc Natl Acad Sci U S A. 1986 Mar;83(6):1797–1801. doi: 10.1073/pnas.83.6.1797. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Escobedo J. A., Keating M. T., Ives H. E., Williams L. T. Platelet-derived growth factor receptors expressed by cDNA transfection couple to a diverse group of cellular responses associated with cell proliferation. J Biol Chem. 1988 Jan 25;263(3):1482–1487. [PubMed] [Google Scholar]
  12. Franchini G., Mulloy J. C., Koralnik I. J., Lo Monico A., Sparkowski J. J., Andresson T., Goldstein D. J., Schlegel R. The human T-cell leukemia/lymphotropic virus type I p12I protein cooperates with the E5 oncoprotein of bovine papillomavirus in cell transformation and binds the 16-kilodalton subunit of the vacuolar H+ ATPase. J Virol. 1993 Dec;67(12):7701–7704. doi: 10.1128/jvi.67.12.7701-7704.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Goldstein D. J., Andresson T., Sparkowski J. J., Schlegel R. The BPV-1 E5 protein, the 16 kDa membrane pore-forming protein and the PDGF receptor exist in a complex that is dependent on hydrophobic transmembrane interactions. EMBO J. 1992 Dec;11(13):4851–4859. doi: 10.1002/j.1460-2075.1992.tb05591.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Goldstein D. J., Finbow M. E., Andresson T., McLean P., Smith K., Bubb V., Schlegel R. Bovine papillomavirus E5 oncoprotein binds to the 16K component of vacuolar H(+)-ATPases. Nature. 1991 Jul 25;352(6333):347–349. doi: 10.1038/352347a0. [DOI] [PubMed] [Google Scholar]
  15. Goldstein D. J., Kulke R., Dimaio D., Schlegel R. A glutamine residue in the membrane-associating domain of the bovine papillomavirus type 1 E5 oncoprotein mediates its binding to a transmembrane component of the vacuolar H(+)-ATPase. J Virol. 1992 Jan;66(1):405–413. doi: 10.1128/jvi.66.1.405-413.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Goldstein D. J., Schlegel R. The E5 oncoprotein of bovine papillomavirus binds to a 16 kd cellular protein. EMBO J. 1990 Jan;9(1):137–145. doi: 10.1002/j.1460-2075.1990.tb08089.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Green M., Loewenstein P. M. Demonstration that a chemically synthesized BPV1 oncoprotein and its C-terminal domain function to induce cellular DNA synthesis. Cell. 1987 Dec 4;51(5):795–802. doi: 10.1016/0092-8674(87)90102-4. [DOI] [PubMed] [Google Scholar]
  18. Horwitz B. H., Burkhardt A. L., Schlegel R., DiMaio D. 44-amino-acid E5 transforming protein of bovine papillomavirus requires a hydrophobic core and specific carboxyl-terminal amino acids. Mol Cell Biol. 1988 Oct;8(10):4071–4078. doi: 10.1128/mcb.8.10.4071. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Horwitz B. H., Weinstat D. L., DiMaio D. Transforming activity of a 16-amino-acid segment of the bovine papillomavirus E5 protein linked to random sequences of hydrophobic amino acids. J Virol. 1989 Nov;63(11):4515–4519. doi: 10.1128/jvi.63.11.4515-4519.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Jaskulski D., Kaczmarek L., DiMaio D. Stimulation of cellular DNA synthesis by wild type and mutant bovine papillomavirus DNA. Biochem Biophys Res Commun. 1987 Oct 14;148(1):86–91. doi: 10.1016/0006-291x(87)91079-5. [DOI] [PubMed] [Google Scholar]
  21. Kacinski B. M., Scata K. A., Carter D., Yee L. D., Sapi E., King B. L., Chambers S. K., Jones M. A., Pirro M. H., Stanley E. R. FMS (CSF-1 receptor) and CSF-1 transcripts and protein are expressed by human breast carcinomas in vivo and in vitro. Oncogene. 1991 Jun;6(6):941–952. [PubMed] [Google Scholar]
  22. Kulke R., Horwitz B. H., Zibello T., DiMaio D. The central hydrophobic domain of the bovine papillomavirus E5 transforming protein can be functionally replaced by many hydrophobic amino acid sequences containing a glutamine. J Virol. 1992 Jan;66(1):505–511. doi: 10.1128/jvi.66.1.505-511.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Kypta R. M., Goldberg Y., Ulug E. T., Courtneidge S. A. Association between the PDGF receptor and members of the src family of tyrosine kinases. Cell. 1990 Aug 10;62(3):481–492. doi: 10.1016/0092-8674(90)90013-5. [DOI] [PubMed] [Google Scholar]
  24. Leechanachai P., Banks L., Moreau F., Matlashewski G. The E5 gene from human papillomavirus type 16 is an oncogene which enhances growth factor-mediated signal transduction to the nucleus. Oncogene. 1992 Jan;7(1):19–25. [PubMed] [Google Scholar]
  25. Leptak C., Ramon y Cajal S., Kulke R., Horwitz B. H., Riese D. J., 2nd, Dotto G. P., DiMaio D. Tumorigenic transformation of murine keratinocytes by the E5 genes of bovine papillomavirus type 1 and human papillomavirus type 16. J Virol. 1991 Dec;65(12):7078–7083. doi: 10.1128/jvi.65.12.7078-7083.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Marquardt T., Helenius A. Misfolding and aggregation of newly synthesized proteins in the endoplasmic reticulum. J Cell Biol. 1992 May;117(3):505–513. doi: 10.1083/jcb.117.3.505. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Martin P., Vass W. C., Schiller J. T., Lowy D. R., Velu T. J. The bovine papillomavirus E5 transforming protein can stimulate the transforming activity of EGF and CSF-1 receptors. Cell. 1989 Oct 6;59(1):21–32. doi: 10.1016/0092-8674(89)90866-0. [DOI] [PubMed] [Google Scholar]
  28. Nilson L. A., DiMaio D. Platelet-derived growth factor receptor can mediate tumorigenic transformation by the bovine papillomavirus E5 protein. Mol Cell Biol. 1993 Jul;13(7):4137–4145. doi: 10.1128/mcb.13.7.4137. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Petti L., DiMaio D. Stable association between the bovine papillomavirus E5 transforming protein and activated platelet-derived growth factor receptor in transformed mouse cells. Proc Natl Acad Sci U S A. 1992 Aug 1;89(15):6736–6740. doi: 10.1073/pnas.89.15.6736. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Petti L., Nilson L. A., DiMaio D. Activation of the platelet-derived growth factor receptor by the bovine papillomavirus E5 transforming protein. EMBO J. 1991 Apr;10(4):845–855. doi: 10.1002/j.1460-2075.1991.tb08017.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Pim D., Collins M., Banks L. Human papillomavirus type 16 E5 gene stimulates the transforming activity of the epidermal growth factor receptor. Oncogene. 1992 Jan;7(1):27–32. [PubMed] [Google Scholar]
  32. Rawls J. A., Loewenstein P. M., Green M. Mutational analysis of bovine papillomavirus type 1 E5 peptide domains involved in induction of cellular DNA synthesis. J Virol. 1989 Nov;63(11):4962–4964. doi: 10.1128/jvi.63.11.4962-4964.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Rose J. K., Bergmann J. E. Altered cytoplasmic domains affect intracellular transport of the vesicular stomatitis virus glycoprotein. Cell. 1983 Sep;34(2):513–524. doi: 10.1016/0092-8674(83)90384-7. [DOI] [PubMed] [Google Scholar]
  34. Roussel M. F., Dull T. J., Rettenmier C. W., Ralph P., Ullrich A., Sherr C. J. Transforming potential of the c-fms proto-oncogene (CSF-1 receptor). Nature. 1987 Feb 5;325(6104):549–552. doi: 10.1038/325549a0. [DOI] [PubMed] [Google Scholar]
  35. Sarver N., Byrne J. C., Howley P. M. Transformation and replication in mouse cells of a bovine papillomavirus--pML2 plasmid vector that can be rescued in bacteria. Proc Natl Acad Sci U S A. 1982 Dec;79(23):7147–7151. doi: 10.1073/pnas.79.23.7147. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Schiller J. T., Vass W. C., Vousden K. H., Lowy D. R. E5 open reading frame of bovine papillomavirus type 1 encodes a transforming gene. J Virol. 1986 Jan;57(1):1–6. doi: 10.1128/jvi.57.1.1-6.1986. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Schlegel R., Wade-Glass M., Rabson M. S., Yang Y. C. The E5 transforming gene of bovine papillomavirus encodes a small, hydrophobic polypeptide. Science. 1986 Jul 25;233(4762):464–467. doi: 10.1126/science.3014660. [DOI] [PubMed] [Google Scholar]
  38. Settleman J., DiMaio D. Efficient transactivation and morphologic transformation by bovine papillomavirus genes expressed from a bovine papillomavirus/simian virus 40 recombinant virus. Proc Natl Acad Sci U S A. 1988 Dec;85(23):9007–9011. doi: 10.1073/pnas.85.23.9007. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Settleman J., Fazeli A., Malicki J., Horwitz B. H., DiMaio D. Genetic evidence that acute morphologic transformation, induction of cellular DNA synthesis, and focus formation are mediated by a single activity of the bovine papillomavirus E5 protein. Mol Cell Biol. 1989 Dec;9(12):5563–5572. doi: 10.1128/mcb.9.12.5563. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Straight S. W., Hinkle P. M., Jewers R. J., McCance D. J. The E5 oncoprotein of human papillomavirus type 16 transforms fibroblasts and effects the downregulation of the epidermal growth factor receptor in keratinocytes. J Virol. 1993 Aug;67(8):4521–4532. doi: 10.1128/jvi.67.8.4521-4532.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Takebe Y., Seiki M., Fujisawa J., Hoy P., Yokota K., Arai K., Yoshida M., Arai N. SR alpha promoter: an efficient and versatile mammalian cDNA expression system composed of the simian virus 40 early promoter and the R-U5 segment of human T-cell leukemia virus type 1 long terminal repeat. Mol Cell Biol. 1988 Jan;8(1):466–472. doi: 10.1128/mcb.8.1.466. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Velu T. J., Beguinot L., Vass W. C., Zhang K., Pastan I., Lowy D. R. Retroviruses expressing different levels of the normal epidermal growth factor receptor: biological properties and new bioassay. J Cell Biochem. 1989 Feb;39(2):153–166. doi: 10.1002/jcb.240390207. [DOI] [PubMed] [Google Scholar]
  43. Waters C. M., Overholser K. A., Sorkin A., Carpenter G. Analysis of the influences of the E5 transforming protein on kinetic parameters of epidermal growth factor binding and metabolism. J Cell Physiol. 1992 Aug;152(2):253–263. doi: 10.1002/jcp.1041520206. [DOI] [PubMed] [Google Scholar]
  44. Willumsen B. M., Vass W. C., Velu T. J., Papageorge A. G., Schiller J. T., Lowy D. R. The bovine papillomavirus E5 oncogene can cooperate with ras: identification of p21 amino acids critical for transformation by c-rasH but not v-rasH. Mol Cell Biol. 1991 Dec;11(12):6026–6033. doi: 10.1128/mcb.11.12.6026. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Yarden Y., Escobedo J. A., Kuang W. J., Yang-Feng T. L., Daniel T. O., Tremble P. M., Chen E. Y., Ando M. E., Harkins R. N., Francke U. Structure of the receptor for platelet-derived growth factor helps define a family of closely related growth factor receptors. Nature. 1986 Sep 18;323(6085):226–232. doi: 10.1038/323226a0. [DOI] [PubMed] [Google Scholar]

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

RESOURCES