Hyaluronidase 2 negatively regulates RON receptor tyrosine kinase and mediates transformation of epithelial cells by jaagsiekte sheep retrovirus

Abstract

The candidate tumor-suppressor gene hyaluronidase 2 (HYAL2) encodes a glycosylphosphatidylinositol-anchored cell-surface protein that serves as an entry receptor for jaagsiekte sheep retrovirus, a virus that causes contagious lung cancer in sheep that is morphologically similar to human bronchioloalveolar carcinoma. The viral envelope (Env) protein alone can transform cultured cells, and we hypothesized that Env could bind and sequester the HYAL2 receptor and thus liberate a potential oncogenic factor bound and negatively controlled by HYAL2. Here we show that the HYAL2 receptor protein is associated with the RON receptor tyrosine kinase (also called MST1R or Stk in the mouse), rendering it functionally silent. In human cells expressing a jaagsiekte sheep retrovirus Env transgene, the Env protein physically associates with HYAL2. RON liberated from the association with HYAL2 becomes functionally active and consequently activates the Akt and mitogen-activated protein kinase pathways leading to oncogenic transformation of immortalized human bronchial epithelial cells. We find activated RON in a subset of human bronchioloalveolar carcinoma tumors, suggesting RON involvement in this type of human lung cancer.

Human RON receptor tyrosine kinase induces complete epithelial-to-mesenchymal transition but causes cellular senescence

“…This is also reflected in the RON-expressing RE7 cell line that shows no apparent morphological transformation [12]. Here, we established a series of MDCK clones, namely RON c1, c5, c6 and c8, which express various levels of human RON by transfection of MDCK cells with a retroviral vector [13] encoding the same human RON protein (Fig. 1A).…”

Evaluation of the 3p21.3 tumour-suppressor gene cluster

“…Therefore, the binding of JSRV to its receptor (HYAL2) may allow MST1R to activate downstream pathways resulting in transformation. Interestingly, hyperactivated MST1R was also found in some human bronchioalveolar carcinomas (Danilkovitch-Miagkova et al, 2003).…”

“…The ability of the JSRV Env to transform the bronchial epithelial cell line BEAS-2B depends on the activation of MST1R (a cell surface receptor tyrosine kinase also known as receptor tyrosine kinase (RON) that is located at 3p21.31). HYAL2 can bind to and suppress the activity of MST1R (Danilkovitch-Miagkova et al, 2003) and JSRV Env complexed with HYAL2 induces HYAL2 degradation. Therefore, the binding of JSRV to its receptor (HYAL2) may allow MST1R to activate downstream pathways resulting in transformation.…”

Interplay between scatter factor receptors and B plexins controls invasive growth

“…Moreover, the role of Met in neoplastic cell spreading has been clearly demonstrated (Giordano et al, 1997;Vande Woude et al, 1997;Di Renzo et al, 2000;Pennacchietti et al, 2003). An oncogenic role of Ron was also established in colorectal, breast, gastric and lung carcinomas (Maggiora et al, 1998;Willett et al, 1998;Danilkovitch-Miagkova et al, 2003;Zhou et al, 2003), as well as in experimental models in vivo .…”

“…The interaction between Met and Fas prevents Fas selfaggregation and binding of Fas ligand to its receptor and thus regulates cell survival . The recently described association between Ron and hyaluronidase-2 negatively regulates Ron that becomes functionally active only when it is liberated from the Scatter factor receptors and B plexins control invasive growth P Conrotto et al association with this enzyme (Danilkovitch-Miagkova et al, 2003). The role of Met/Ron interaction with Plexins could be the fine-tuning of the invasive growth program.…”