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

  1. Author:
    Danilkovitch-Miagkova, A.
    Duh, F. M.
    Kuzmin, I.
    Angeloni, D.
    Liu, S. L.
    Miller, A. D.
    Lerman, M. I.

  2. Author Address

    PPD Dev, Dept Immunochem, 2244 Dabney Rd, Richmond, VA 23230 USA NCI, Immunobiol Lab, Ctr Canc Res, Frederick, MD 21702 USA NCI, Basic Res Program, Sci Applicat Int Corp SAIC Frederick Inc, Frederick, MD 21702 USA Fred Hutchinson Canc Res Ctr, Seattle, WA 98109 USA Danilkovitch-Miagkova A PPD Dev, Dept Immunochem, 2244 Dabney Rd, Richmond, VA 23230 USA
    1. Year: 2003
  2. Journal: Proceedings of the National Academy of Sciences of the United States of America
    1. 100
    2. 8
    3. Pages: 4580-4585
  4. Type of Article: Article
  1. Abstract:

    The candidate tumor-suppressor gene hyaluroniclase 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.

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