Candidate tumor suppressor HYAL2 is a glycosylphosphatidylinositol (GPI)-anchored cell-surface receptor for jaagsiekte sheep retrovirus, the envelopeprotein of which mediates oncogenic transformation

Jaagsiekte sheep retrovirus (JSRV) can induce rapid, multifocal lung cancer , but JSRV is a simple retrovirus having no known oncogenes. Here we show t hat the envelope (env) gene of JSRV has the unusual property that it can in duce transformation in rat fibroblasts, and thus is likely to be responsibl e for oncogenesis in animals. Retrovirus entry into cells is mediated by En v interaction with particular cell-surface receptors, and we have used phen otypic screening of radiation hybrid cell lines to identify the candidate l ung cancer tumor suppressor HYAL2/LUCA2 as the receptor for JSRV. HYAL2 was previously described as a lysosomal hyaluronidase, but we show that HYAL2 is actually a glycosylphosphatidylinositol (CPI)-anchored cell-surface prot ein. Furthermore, we could not detect hyaluronidase activity associated wit h or secreted by cells expressing HYAL2, whereas we could easily detect suc h activity from cells expressing the related serum hyaluronidase HYAL1. Alt hough the function of HYAL2 is currently unknown, other GPI-anchored protei ns are involved in signal transduction, and some mediate mitogenic response s, suggesting a potential role of HYAL2 in JSRV Env-mediated oncogenesis. L ung cancer induced by JSRV closely resembles human bronchiolo-alveolar carc inoma, a disease that is increasing in frequency and now accounts for appro ximate to 25% of all lung cancer. The finding that JSRV env is oncogenic an d the identification of HYAL2 as the JSRV receptor provide tools for furthe r investigation of the mechanism of JSRV oncogenesis and its relationship t o human bronchiolo-alveolar carcinoma.