1887

Journal of General Virology header logo

Volume 88, Issue 3

encodes a functionally distinct VEGF that binds both VEGFR-1 and VEGFR-2 Free

Abstract

(BPSV), a member of the genus , causes proliferative dermatitis in cattle and humans. Other species of the genus cause similar lesions, the nature of which has been attributed, at least in part, to a viral-encoded vascular endothelial growth factor (VEGF) that induces vascularization and dermal oedema through VEGF receptor-2 (VEGFR-2). The results of this study showed that BPSV strain V660 encodes a novel VEGF and that the predicted BPSV protein showed only 33–52 % amino acid identity to VEGFs encoded by the other species of the genus. BPSV VEGF showed higher identity to mammalian VEGF-A (51 %) than the other parapoxviral VEGFs (31–46 %). Assays of the purified BPSV VEGF (BPSVVEGF) demonstrated that it was also functionally more similar to VEGF-A, as it showed significant binding to VEGFR-1 and induced monocyte migration. Like VEGF-A and the other viral VEGFs, BPSVVEGF bound VEGFR-2 with high affinity. Sequence analysis and structural modelling of BPSVVEGF revealed specific residues, outside the known receptor-binding face, that are predicted either to influence VEGF structure or to mediate binding directly to the VEGFRs. These results indicate that BPSVVEGF is a biologically active member of the VEGF family and that, via its interaction with VEGFR-2, it is likely to contribute to the proliferative and highly vascularized nature of BPSV lesions. This is also the first example of a viral VEGF acting via VEGFR-1 and influencing haematopoietic cell function. These data suggest that BPSVVEGF is an evolutionary and functional intermediate between VEGF-A and the other parapoxviral VEGFs.

  • Received:
  • Accepted:
  • Published Online:
SGM
Loading

Article metrics loading...

/content/journal/jgv/10.1099/vir.0.82582-0
2007-03-01
2024-05-10
Loading full text...

Full text loading...

/deliver/fulltext/jgv/88/3/781.html?itemId=/content/journal/jgv/10.1099/vir.0.82582-0&mimeType=html&fmt=ahah

References

  1. Achen M. G., Jeltsch M., Kukk E., Makinen T., Vitali A., Wilks A. F., Alitalo K., Stacker S. A. 1998; Vascular endothelial growth factor D (VEGF-D) is a ligand for the tyrosine kinases VEGF receptor 2 (Flk1) and VEGF receptor 3 (Flt4). Proc Natl Acad Sci U S A 95:548–553 [CrossRef]
     [Google Scholar]
  2. Autiero M., Luttun A., Tjwa M., Carmeliet P. 2003; Placental growth factor and its receptor, vascular endothelial growth factor receptor-1: novel targets for stimulation of ischemic tissue revascularization and inhibition of angiogenic and inflammatory disorders. J Thromb Haemost 1:1356–1370 [CrossRef]
     [Google Scholar]
  3. Bendtsen J. D., Nielsen H., von Heijne G., Brunak S. 2004; Improved prediction of signal peptides: SignalP 3.0. J Mol Biol 340:783–795 [CrossRef]
     [Google Scholar]
  4. Bowman K. F., Barbery R. T., Swango L. J., Schnurremberger P. R. 1981; Cutaneous form of bovine papular stomatitis virus in man. JAMA 246:2813–2818 [CrossRef]
     [Google Scholar]
  5. Buller R. M., Arif B. M., Black D. N., Dumbell K. R., Esposito J. J., Lefkowitz E. J., McFadden G., Moss B., Mercer A. A. other authors 2005; Family Poxviridae . In Virus Taxonomy, Classification and Nomenclature of Viruse. Eighth Report of the International Committee on Taxonomy of Viruses pp  117–133 Edited by Fauquet C. M., Mayo M. A., Maniloff J., Desselberger U., Ball L. A. London: Elsevier/Academic Press;
     [Google Scholar]
  6. Carmeliet P. 2005; VEGF as a key mediator of angiogenesis in cancer. Oncology 69 (Suppl. 3):4–10 [CrossRef]
     [Google Scholar]
  7. Carson C. A., Kerr K. M. 1967; Bovine papular stomatitis with apparent transmission to man. J Am Vet Med Assoc 151:183–187
     [Google Scholar]
  8. Clauss M., Weich H., Breier G., Knies U., Rockl W., Waltenberger J., Risau W. 1996; The vascular endothelial growth factor receptor Flt-1 mediates biological activities. Implications for a functional role of placenta growth factor in monocyte activation and chemotaxis. J Biol Chem 271:17629–17634 [CrossRef]
     [Google Scholar]
  9. Delhon G., Tulman E. R., Afonso C. L., Lu Z., de la Concha-Bermejillo A., Lehmkuhl H. D., Piccone M. E., Kutish G. F., Rock D. L. 2004; Genomes of the parapoxvirus orf virus and bovine papular stomatis virus. J Virol 78:168–177 [CrossRef]
     [Google Scholar]
  10. Evans M. J., Hartman S. L., Wolff D. W., Rollins S. A., Squinto S. P. 1995; Rapid expression of an anti-human C5 chimeric Fab utilizing a vector that replicates in COS and 293 cells. J Immunol Methods 184:123–138 [CrossRef]
     [Google Scholar]
  11. Ferrara N. 2004; Vascular endothelial growth factor: basic science and clinical progress. Endocr Rev 25:581–611 [CrossRef]
     [Google Scholar]
  12. Fleming S. B., Lyttle D. J., Sullivan J. T., Mercer A. A., Robinson A. J. 1995; Genomic analysis of a transposition-deletion variant of orf virus reveals a 3.3 kbp region of non-essential DNA. J Gen Virol 76:2969–2978 [CrossRef]
     [Google Scholar]
  13. Fleming S. B., Haig D. M., Nettleton P., Reid H. W., McCaughan C. A., Wise L. M., Mercer A. 2000; Sequence and functional analysis of a homolog of interleukin-10 encoded by the parapoxvirus orf virus. Virus Genes 21:85–95 [CrossRef]
     [Google Scholar]
  14. Fuh G., Garcia K. C., de Vos A. M. 2000; The interaction of neuropilin-1 with vascular endothelial growth factor and its receptor Flt-1. J Biol Chem 275:26690–26695
     [Google Scholar]
  15. Gabrilovich D., Ishida T., Oyama T., Ran S., Kravtsov V., Nadaf S., Carbone D. P. 1998; Vascular endothelial growth factor inhibits the development of dendritic cells and dramatically affects the differentiation of multiple hematopoietic lineages in vivo. Blood 92:4150–4166
     [Google Scholar]
  16. Gassmann U., Wyler R., Wittek R. 1985; Analysis of parapoxvirus genomes. Arch Virol 83:17–31 [CrossRef]
     [Google Scholar]
  17. Griesemer R. A., Cole C. R. 1960; Bovine papular stomatitis. I. Recognition in the United States. J Am Vet Med Assoc 137:404–410
     [Google Scholar]
  18. Groves R. W., Wilson-Jones E., MacDonald D. M. 1991; Human orf and milkers' nodule: a clinicopathologic study. J Am Acad Dermatol 25:706–711 [CrossRef]
     [Google Scholar]
  19. Guex N., Peitsch M. C. 1997; swiss-model and the Swiss-PdbViewer: an environment for comparative protein modeling. Electrophoresis 18:2714–2723 [CrossRef]
     [Google Scholar]
  20. Haig D. M., Mercer A. A. 1998; Ovine diseases. Orf. Vet Res 29:311–326
     [Google Scholar]
  21. Haig D. M., Thomson J., McInnes C., McCaughan C., Imlach W., Mercer A., Fleming S. 2002; Orf virus immuno-modulation and the host immune response. Vet Immunol Immunopathol 87:395–399 [CrossRef]
     [Google Scholar]
  22. Horner G. W., Robinson A. J., Hunter R., Cox B. T., Smith R. 1987; Parapoxvirus infections in New Zealand farmed red deer ( Cervus elaphus ). N Z Vet J 35:41–45 [CrossRef]
     [Google Scholar]
  23. Imlach W., McCaughan C. A., Mercer A. A., Haig D., Fleming S. B. 2002; Orf virus-encoded interleukin-10 stimulates the proliferation of murine mast cells and inhibits cytokine synthesis in murine peritoneal macrophages. J Gen Virol 83:1049–1058
     [Google Scholar]
  24. Jolly R. D., Daniel R. C. 1966; Papular stomatitis of cattle. N Z Vet J 14:168–170 [CrossRef]
     [Google Scholar]
  25. Julenius K., Molgaard A., Gupta R., Brunak S. 2005; Prediction, conservation analysis, and structural characterization of mammalian mucin-type O -glycosylation sites. Glycobiology 15:153–164
     [Google Scholar]
  26. Keyt B. A., Nguyen H. V., Berleau L. T., Duarte C. M., Park J., Chen H., Ferrara N. 1996; Identification of vascular endothelial growth factor determinants for binding KDR and FLT-1 receptors. Generation of receptor-selective VEGF variants by site-directed mutagenesis. J Biol Chem 271:5638–5646 [CrossRef]
     [Google Scholar]
  27. Li B., Fuh G., Meng G., Xin X., Gerritsen M. E., Cunningham B., de Vos A. M. 2000; Receptor-selective variants of human vascular endothelial growth factor. Generation and characterization. J Biol Chem 275:29823–29828 [CrossRef]
     [Google Scholar]
  28. Lyttle D. J., Fraser K. M., Fleming S. B., Mercer A. A., Robinson A. J. 1994; Homologs of vascular endothelial growth factor are encoded by the poxvirus orf virus. J Virol 68:84–92
     [Google Scholar]
  29. Makinen T., Veikkola T., Mustjoki S., Karpanen T., Catimel B., Nice E. C., Wise L., Mercer A., Kowalski H. other authors 2001; Isolated lymphatic endothelial cells transduce growth, survival and migratory signals via the VEGF-C/D receptor VEGFR-3. EMBO J 20:4762–4773 [CrossRef]
     [Google Scholar]
  30. McColl B. K., Stacker S. A., Achen M. G. 2004; Molecular regulation of the VEGF family – inducers of angiogenesis and lymphangiogenesis. APMIS 112:463–480 [CrossRef]
     [Google Scholar]
  31. Mercer A., Haig D. 1999; Parapoxviruses (Poxviridae. In Encyclopedia of Virology , 2nd edn. pp  1140–1146 Edited by Granoff A., Webster R. G. Oxford: Elsevier;
     [Google Scholar]
  32. Mercer A. A., Fraser K., Barns G., Robinson A. J. 1987; The structure and cloning of orf virus DNA. Virology 157:1–12 [CrossRef]
     [Google Scholar]
  33. Mercer A. A., Fraser K. M., Stockwell P. A., Robinson A. J. 1989; A homologue of retroviral pseudoproteases in the parapoxvirus, orf virus. Virology 172:665–668 [CrossRef]
     [Google Scholar]
  34. Mercer A. A., Wise L. M., Scagliarini A., McInnes C. J., Buttner M., Rziha H. J., McCaughan C. A., Fleming S. B., Ueda N., Nettleton P. F. 2002; Vascular endothelial growth factors encoded by Orf virus show surprising sequence variation but have a conserved, functionally relevant structure. J Gen Virol 83:2845–2855
     [Google Scholar]
  35. Mercer A. A., Ueda N., Friederichs S. M., Hofmann K., Fraser K. M., Bateman T., Fleming S. B. 2006; Comparative analysis of genome sequences of three isolates of Orf virus reveals unexpected sequence variation. Virus Res 116:146–158 [CrossRef]
     [Google Scholar]
  36. Meyer M., Clauss M., Lepple-Wienhues A., Waltenberger J., Augustin H. G., Ziche M., Lanz C., Buttner M., Rziha H. J., Dehio C. 1999; A novel vascular endothelial growth factor encoded by Orf virus, VEGF-E, mediates angiogenesis via signalling through VEGFR-2 (KDR) but not VEGFR-1 (Flt-1) receptor tyrosine kinases. EMBO J 18:363–374 [CrossRef]
     [Google Scholar]
  37. Muller Y. A., Christinger H. W., Keyt B. A., de Vos A. M. 1997a; The crystal structure of vascular endothelial growth factor (VEGF) refined to 1.93 A resolution: multiple copy flexibility and receptor binding. Structure 5:1325–1338 [CrossRef]
     [Google Scholar]
  38. Muller Y. A., Li B., Christinger H. W., Wells J. A., Cunningham B. C., de Vos A. M. 1997b; Vascular endothelial growth factor: crystal structure and functional mapping of the kinase domain receptor binding site. Proc Natl Acad Sci U S A 94:7192–7197 [CrossRef]
     [Google Scholar]
  39. Nagington J., Lauder I. M., Smith J. S. 1967; Bovine papular stomatitis, pseudocowpox and milker's nodules. Vet Rec 81:306–313 [CrossRef]
     [Google Scholar]
  40. Novak N., Allam J. P., Betten H., Haberstok J., Bieber T. 2004; The role of antigen presenting cells at distinct anatomic sites: they accelerate and they slow down allergies. Allergy 59:5–14
     [Google Scholar]
  41. Ogawa S., Oku A., Sawano A., Yamaguchi S., Yazaki Y., Shibuya M. 1998; A novel type of vascular endothelial growth factor, VEGF-E (NZ-7 VEGF), preferentially utilizes KDR/Flk-1 receptor and carries a potent mitotic activity without heparin-binding domain. J Biol Chem 273:31273–31282 [CrossRef]
     [Google Scholar]
  42. Page R. D. 1996; TreeView: an application to display phylogenetic trees on personal computers. Comput Appl Biosci 12:357–358
     [Google Scholar]
  43. Pieren M., Prota A., Ruch C., Kostrewa D., Wagner A., Biedermann K., Winkler F., Ballmer-Hofer K. 2006; Crystal structure of the Orf virus NZ2 variant of VEGF-E: implications for receptor specificity. J Biol Chem 281:19578–19587 [CrossRef]
     [Google Scholar]
  44. Robinson A. J., Ellis G., Balassu T. 1982; The genome of orf virus: restriction endonuclease analysis of viral DNA isolated from lesions of orf in sheep. Arch Virol 71:43–55 [CrossRef]
     [Google Scholar]
  45. Savory L. J., Stacker S. A., Fleming S. B., Niven B. E., Mercer A. A. 2000; Viral vascular endothelial growth factor plays a critical role in orf virus infection. J Virol 74:10699–10707 [CrossRef]
     [Google Scholar]
  46. Seet B. T., McCaughan C. A., Handel T. M., Mercer A., Brunetti C., McFadden G., Fleming S. B. 2003; Analysis of an orf virus chemokine-binding protein: shifting ligand specificities among a family of poxvirus viroceptors. Proc Natl Acad Sci U S A 100:15137–15142 [CrossRef]
     [Google Scholar]
  47. Selvaraj S. K., Giri R. K., Perelman N., Johnson C., Malik P., Kalra V. K. 2003; Mechanism of monocyte activation and expression of proinflammatory cytochemokines by placenta growth factor. Blood 102:1515–1524 [CrossRef]
     [Google Scholar]
  48. Senger D. R., Galli S. J., Dvorak A. M., Perruzzi C. A., Harvey V. S., Dvorak H. F. 1983; Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science 219:983–985 [CrossRef]
     [Google Scholar]
  49. Shibuya M. 2001; Structure and dual function of vascular endothelial growth factor receptor-1 (Flt-1). Int J Biochem Cell Biol 33:409–420 [CrossRef]
     [Google Scholar]
  50. Shibuya M. 2003; Vascular endothelial growth factor receptor-2: its unique signaling and specific ligand, VEGF-E. Cancer Sci 94:751–756 [CrossRef]
     [Google Scholar]
  51. Shibuya M., Claesson-Welsh L. 2006; Signal transduction by VEGF receptors in regulation of angiogenesis and lymphangiogenesis. Exp Cell Res 312:549–560 [CrossRef]
     [Google Scholar]
  52. Snider T. G. III, McConnell S., Pierce K. R. 1982; Increased incidence of bovine papular stomatitis in neonatal calves. Arch Virol 71:251–258 [CrossRef]
     [Google Scholar]
  53. Stacker S. A., Achen M. G. 1999; The vascular endothelial growth factor family: signalling for vascular development. Growth Factors 17:1–11 [CrossRef]
     [Google Scholar]
  54. Stacker S. A., Vitali A., Caesar C., Domagala T., Groenen L. C., Nice E., Achen M. G., Wilks A. F. 1999; A mutant form of vascular endothelial growth factor (VEGF) that lacks VEGF receptor-2 activation retains the ability to induce vascular permeability. J Biol Chem 274:34884–34892 [CrossRef]
     [Google Scholar]
  55. Szpaderska A. M., Zuckerman J. D., DiPietro L. A. 2003; Differential injury responses in oral mucosal and cutaneous wounds. J Dent Res 82:621–626 [CrossRef]
     [Google Scholar]
  56. Tlaskalova-Hogenova H., Stepankova R., Hudcovic T., Tuckova L., Cukrowska B., Lodinova-Zadnikova R., Kozakova H., Rossmann P., Bartova J. other authors 2004; Commensal bacteria (normal microflora), mucosal immunity and chronic inflammatory and autoimmune diseases. Immunol Lett 93:97–108 [CrossRef]
     [Google Scholar]
  57. Tokunaga Y., Yamazaki Y., Morita T. 2006; Localization of heparin- and neuropilin-1-recognition sites of viral VEGFs. Biochem Biophys Res Commun 348:957–962 [CrossRef]
     [Google Scholar]
  58. Ueda N., Wise L. M., Stacker S. A., Fleming S. B., Mercer A. A. 2003; Pseudocowpox virus encodes a homolog of vascular endothelial growth factor. Virology 305:298–309 [CrossRef]
     [Google Scholar]
  59. von Wronski M. A., Raju N., Pillai R., Bogdan N. J., Marinelli E. R., Nanjappan P., Ramalingam K., Arunachalam T., Eaton S. other authors 2006; Tuftsin binds neuropilin-1 through a sequence similar to that encoded by exon 8 of vascular endothelial growth factor. J Biol Chem 281:5702–5710
     [Google Scholar]
  60. Wiesmann C., Fuh G., Christinger H. W., Eigenbrot C., Wells J. A., de Vos A. M. 1997; Crystal structure at 1.7 A resolution of VEGF in complex with domain 2 of the Flt-1 receptor. Cell 91:695–704 [CrossRef]
     [Google Scholar]
  61. Wilgus T. A., Matthies A. M., Radek K. A., Dovi J. V., Burns A. L., Shankar R., DiPietro L. A. 2005; Novel function for vascular endothelial growth factor receptor-1 on epidermal keratinocytes. Am J Pathol 167:1257–1266 [CrossRef]
     [Google Scholar]
  62. Wise L. M., Veikkola T., Mercer A. A., Savory L. J., Fleming S. B., Caesar C., Vitali A., Makinen T., Alitalo K., Stacker S. A. 1999; Vascular endothelial growth factor (VEGF)-like protein from orf virus NZ2 binds to VEGFR2 and neuropilin-1. Proc Natl Acad Sci U S A 96:3071–3076 [CrossRef]
     [Google Scholar]
  63. Wise L. M., Ueda N., Dryden N. H., Fleming S. B., Caesar C., Roufail S., Achen M. G., Stacker S. A., Mercer A. A. 2003; Viral vascular endothelial growth factors vary extensively in amino acid sequence, receptor-binding specificities, and the ability to induce vascular permeability yet are uniformly active mitogens. J Biol Chem 278:38004–38024 [CrossRef]
     [Google Scholar]
  64. Zachary I. 2003; VEGF signalling: integration and multi-tasking in endothelial cell biology. Biochem Soc Trans 31:1171–1177 [CrossRef]
     [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/vir.0.82582-0
Loading
Bovine papular stomatitis virus encodes a functionally distinct VEGF that binds both VEGFR-1 and VEGFR-2
J. Gen. Virol. 88, 781 (2007); https://doi.org/10.1099/vir.0.82582-0
/content/journal/jgv/10.1099/vir.0.82582-0
/content/journal/jgv/10.1099/vir.0.82582-0
Loading

Data & Media loading...

Most cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error