Candidate tumor suppressor HYAL2 is a glycosylphosphatidylinositol (GPI)-anchored cell-surface receptor forjaagsiekte sheep retrovirus the envelope protein of which mediates oncogenic transformation

摘要

Jaagsiekte sheep retrovirus (JSRV) can induce rapid, multifocal lung cancer, but JSRV is a simple retrovirus having no known oncogenes. Here we show that the envelope (env) gene of JSRV has the unusual property that it can induce transformation in rat fibroblasts, and thus is likely to be responsible for oncogenesis in animals. Retrovirus entry into cells is mediated by Env interaction with particular cell-surface receptors, and we have used phenotypic screening of radiation hybrid cell lines to identify the candidate lung 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 (GPI)-anchored cell-surface protein. Furthermore, we could not detect hyaluronidase activity associated with or secreted by cells expressing HYAL2, whereas we could easily detect such activity from cells expressing the related serum hyaluronidase HYAL1. Although the function of HYAL2 is currently unknown, other GPI-anchored proteins are involved in signal transduction, and some mediate mitogenic responses, suggesting apotential role of HYAL2 in JSRV Env-mediated oncogenesis. Lung cancerinduced by JSRV closely resembles human bronchiolo-alveolar carcinoma,a disease that is increasing in frequency and now accounts for ≈25%of all lung cancer. The finding that JSRV env isoncogenic and the identification of HYAL2 as the JSRV receptor providetools for further investigation of the mechanism of JSRV oncogenesisand its relationship to human bronchiolo-alveolar carcinoma.