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. 2001 Apr 10;98(8):4443-8.
doi: 10.1073/pnas.071572898.

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

S K Rai  1 , F M Duh, V Vigdorovich, A Danilkovitch-Miagkova, M I Lerman, A D Miller
Affiliations

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

S K Rai et al. Proc Natl Acad Sci U S A. .

Abstract

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 a potential role of HYAL2 in JSRV Env-mediated oncogenesis. Lung cancer induced by JSRV closely resembles human bronchiolo-alveolar carcinoma, a disease that is increasing in frequency and now accounts for approximately 25% of all lung cancer. The finding that JSRV env is oncogenic and the identification of HYAL2 as the JSRV receptor provide tools for further investigation of the mechanism of JSRV oncogenesis and its relationship to human bronchiolo-alveolar carcinoma.

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Figures

Figure 1
Figure 1
JSRV receptor localization to the human chromosome 3p21.3 lung cancer cosmid and phage contig. The human genome is depicted as a bold line with overlapping cosmid and phage clones indicated above. Luca cosmid numbers are indicated, and the asterisk indicates the cosmid that contains the JSRV receptor. The positions of Stanford Human Genome Center (SHGC) markers are shown by vertical lines, and the degree of linkage to the JSRV receptor is indicated by LOD (logarithm of odds) scores that were calculated by the radiation hybrid web server at the SHGC.
Figure 2
Figure 2
Dendrogram (clustal w) of relationships between hyaluronidase family members. Scale bar indicates 10% amino acid sequence difference.
Figure 3
Figure 3
HYAL2 posttranslational processing signals.
Figure 4
Figure 4
HYAL2 localizes to the cell surface and can be removed by PI-PLC treatment. Human embryonic kidney 293 cells were transfected with plasmids that express the Flag-tagged HYAL2 protein with (SS-Flag-M2HYAL2) or without (Flag-M2HYAL2) an endoplasmic reticulum signal sequence and were analyzed 2 days later. (A) Immunofluorescence analysis of Flag-tagged protein. (B) Western analysis of Flag-tagged protein in cell lysates and in the incubation medium after incubation of cells with PI-PLC at the indicated concentrations (units/ml).
Figure 5
Figure 5
Electrophoretic analysis of hyaluronidase activity in cell lysates. Fifty-microgram samples of human umbilical cord hyaluronic acid were incubated with 500 ng of hyaluronidase (Spam1) from bovine testes at pH 3.8 for the indicated times (A) or with cell lysates (prepared in 0.5% Triton X-100, ≈2 × 104 cells per reaction) at pH 3.8 for 12 h (B), and the digestion products were analyzed by agarose gel electrophoresis, followed by detection with the Stains-All. HindIII-digested λ-phage DNA size markers and their sizes are shown.
Figure 6
Figure 6
Focus formation in 208F rat cells after transfection with JSRV env (pSX2.Jenv), fos (pFBJ/R), or a plasmid containing alkaline phosphatase and neo genes (pLAPSN).
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