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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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.
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