Hyaluronidase 2 negatively regulates RON receptor tyrosine kinase and mediates transformation of epithelial cells by jaagsiekte sheep retrovirus.
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.
Danilkovitch-Miagkova
Alla
A
Laboratory of Immunobiology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA. alla.danikovitch@richmond.ppdi.com
Duh
Fuh-Mei
FM
Kuzmin
Igor
I
Angeloni
Debora
D
Liu
Shan-Lu
SL
Miller
A Dusty
AD
Lerman
Michael I
MI
D000818:Animals; D015815:Cell Adhesion Molecules / Q000235:genetics* / Q000378:metabolism*; D002460:Cell Line; D002472:Cell Transformation, Viral; D004285:Dogs; D015536:Down-Regulation; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D058851:GPI-Linked Proteins; D015686:Gene Products, env / Q000378:metabolism; D016147:Genes, Tumor Suppressor; D015752:Genes, env; D006801:Humans; D006821:Hyaluronoglucosaminidase / Q000235:genetics* / Q000378:metabolism*; D022141:Jaagsiekte sheep retrovirus / Q000235:genetics / Q000378:metabolism / Q000472:pathogenicity*; D008954:Models, Biological; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000378:metabolism*; D012756:Sheep; D015398:Signal Transduction; D014162:Transfection
D015815:Cell Adhesion Molecules; D058851:GPI-Linked Proteins; D015686:Gene Products, env; D011956:Receptors, Cell Surface; C080835:RON protein; D020794:Receptor Protein-Tyrosine Kinases; C473096:Hyal2 protein, human; D006821:Hyaluronoglucosaminidase