G-PROTEIN-COUPLED RECEPTOR OF KAPOSIS SARCOMA-ASSOCIATED HERPESVIRUS IS A VIRAL ONCOGENE AND ANGIOGENESIS ACTIVATOR

The Kaposi's sarcoma-associated herpesvirus (KSHV/HHV8) is a gamma-2 h erpesvirus(1-5) that is implicated in the pathogenesis of Kaposi's sar coma(1,5) and of primary effusion B-cell lymphomas (PELs)(6). KSHV inf ects 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 Kapos i'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 stim ulates signalling pathways linked to cell proliferation(12) in a const itutive (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) m ediated 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 tr iggering signalling cascades like those induced by inflammatory cytoki nes(18) that are angiogenesis activators(19) and mitogens for Kaposi's sarcoma cells(10) and B cells. We conclude that the KSHV G-protein-co upled receptor is a viral oncogene that can exploit cell signalling pa thways to induce transformation and angiogenesis in KSHV-mediated onco genesis.