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G-protein-coupled receptor of Kaposi's sarcoma-associated herpesvirus is a viral oncogene and angiogenesis activator

Nature volume 391, pages 86–89 (1998)Cite this article

Abstract

The Kaposi's sarcoma-associated herpesvirus (KSHV/HHV8) is a γ-2 herpesvirus1,2,3,4,5 that is implicated in the pathogenesis of Kaposi's sarcoma1,5 and of primary effusion B-cell lymphomas (PELs)6. KSHV infects malignant and progenitor cells of Kaposi's sarcoma7 and PEL2,6,8, it encodes putative oncogenes4,5,9 and genes that may cause Kaposi's sarcoma pathogenesis by stimulating angiogenesis4,5,9,10. The G-protein-coupled receptor encoded by an open reading frame (ORF 74) of KSHV9 is expressed in Kaposi's sarcoma lesions and in PEL9,11 and stimulates signalling pathways linked to cell proliferation12 in a constitutive (agonist-independent) way12. Here we show that signalling by this KSHV G-protein-coupled receptor leads to cell transformation and tumorigenicity, and induces a switch to an angiogenic phenotype13 mediated by vascular endothelial growth factor14, an angiogenesis13,14 and Kaposi's-spindle-cell growth factor15,16,17. We find that this receptor can activate two protein kinases, JNK/SAPK and p38MAPK, by triggering signalling cascades like those induced by inflammatory cytokines18 that are angiogenesis activators19 and mitogens for Kaposi's sarcoma cells10 and B cells. We conclude that the KSHV G-protein-coupled receptor is a viral oncogene that can exploit cell signalling pathways to induce transformation and angiogenesis in KSHV-mediated oncogenesis.

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Figure 1: Inhibition of KSHV-GPCR-induced focus formation by GRK-5.
Figure 2: Tumorigenicity of KSHV-GPCR-transformed NIH3T3 cells in nude mice.
Figure 3: Angiogenic response in vitro induced by NIH3T3 cells transfected with KSHV-GPCR.
Figure 4: The angiogenic response induced by KSHV-GPCR is mediated by VEGF.
Figure 5: KSHV-GPCR can activate members of the MAPK superfamily.

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Acknowledgements

We thank G. Lam for HUVECs, R. Nador and O. Flore for sharing data and for comments, and A. Chadburn for help with histopathological characterization. Plasmids encoding GRK-2 and GRK-5 were a gift from R. J. Lefkowitz. This work was supported by NIH grants from NIAID to E.A.M., from NCI to E.C., and from NIDDK to M.C.G.

Author information

Author notes

  1. Leandros Arvanitakis

    Present address: Molecular Virology Laboratory, Hellenic Pasteur Institute, Athens, GR-115 21, Greece

  2. Omar Coso

    Present address: Laboratorio de Fisiologia y Biologia Molecular, Dept de Cs. Biologicas, F.C.E. y N. Universidad de Buenos Aires, Buenos Aires, Argentina

Authors and Affiliations

  1. Laboratory of Viral Oncogenesis, Cornell University Medical College, New York, 10021, New York , USA

    Carlos Bais, Bianca Santomasso & Enrique A. Mesri

  2. Division of HematologyOncology, Cornell University Medical College, New York, 10021, New York, USA

    Carlos Bais, Bianca Santomasso, Adam S. Asch & Enrique A. Mesri

  3. Division of Molecular Medicine, Department of Medicine, Cornell University Medical College, New York, 10021, New York, USA

    Elizabeth Geras Raaka & Marvin C. Gerhengorn

  4. Department of Pathology, Cornell University Medical College, New York, 10021, New York, USA

    Leandros Arvanitakis & Ethel Cesarman

  5. Molecular Signaling Unit, Laboratory of Cellular Development and Oncology, NIDR, NIH, Bethesda, 20892, Maryland, USA

    Omar Coso & J. Silvio Gutkind

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Correspondence to Enrique A. Mesri.

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Bais, C., Santomasso, B., Coso, O. et al. G-protein-coupled receptor of Kaposi's sarcoma-associated herpesvirus is a viral oncogene and angiogenesis activator. Nature 391, 86–89 (1998). https://doi.org/10.1038/34193

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