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

The Kaposi's sarcoma-associated herpesvirus (KSHV/HHV8) is a gamma-2 herpesvirus(1-5) that is implicated in the pathogenesis of Kaposi's sarcoma(1,5) and of primary effusion B-cell lymphomas (PELs)(6). KSHV infects malignant and progenitor cells of Kaposi's sarcoma(7) and PEL2,6,8, it encodes putative oncogenes(4,5,9) and genes that may cause Kaposi's sarcoma pathogenesis by stimulating angiogenesis(4,5,9,10). 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 proliferation(12) in a constitutive (agonist-independent) way(12). 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 phenotype(13) mediated by vascular endothelial growth factor(14), an angiogenesis(13,14) and Kaposi's-spindle-cell growth factor(15-17). We find that this receptor can activate two protein kinases, JNK/SAPK and p38MAPK, by triggering signalling cascades like those induced by inflammatory cytokines(18) that are angiogenesis activators(19) and mitogens for Kaposi's sarcoma cells(10) 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.