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PMID:12676986

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Citation

Danilkovitch-Miagkova, A, Duh, FM, Kuzmin, I, Angeloni, D, Liu, SL, Miller, AD and Lerman, MI (2003) Hyaluronidase 2 negatively regulates RON receptor tyrosine kinase and mediates transformation of epithelial cells by jaagsiekte sheep retrovirus. Proc. Natl. Acad. Sci. U.S.A. 100:4580-5

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.

Links

PubMed PMC153598 Online version:10.1073/pnas.0837136100

Keywords

Animals; Cell Adhesion Molecules/genetics; Cell Adhesion Molecules/metabolism; Cell Line; Cell Transformation, Viral; Dogs; Down-Regulation; Epithelial Cells/cytology; Epithelial Cells/metabolism; GPI-Linked Proteins; Gene Products, env/metabolism; Genes, Tumor Suppressor; Genes, env; Humans; Hyaluronoglucosaminidase/genetics; Hyaluronoglucosaminidase/metabolism; Jaagsiekte sheep retrovirus/genetics; Jaagsiekte sheep retrovirus/metabolism; Jaagsiekte sheep retrovirus/pathogenicity; Models, Biological; Receptor Protein-Tyrosine Kinases/metabolism; Receptors, Cell Surface/metabolism; Sheep; Signal Transduction; Transfection

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HV1JR:ENV

involved_in

GO:0030307: positive regulation of cell growth

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

JSRV:ENV

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q12891

F

Seeded From UniProt

complete

HUMAN:RON

enables

GO:0019899: enzyme binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q12891

F

Seeded From UniProt

complete

HUMAN:RON

involved_in

GO:0009615: response to virus

ECO:0000314: direct assay evidence used in manual assertion

P

  • occurs_in:(CL:0002328)

Seeded From UniProt

complete

HUMAN:RON

involved_in

GO:0051897: positive regulation of protein kinase B signaling

ECO:0000314: direct assay evidence used in manual assertion

P

  • occurs_in:(CL:0002328)

Seeded From UniProt

complete

HUMAN:RON

involved_in

GO:0043406: positive regulation of MAP kinase activity

ECO:0000314: direct assay evidence used in manual assertion

P

  • occurs_in:(CL:0002328)

Seeded From UniProt

complete

HUMAN:HYAL2

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P31621

F

Seeded From UniProt

complete

HUMAN:HYAL2

enables

GO:0005540: hyaluronic acid binding

ECO:0000314: direct assay evidence used in manual assertion

F

  • occurs_in:(CL:0002328)

Seeded From UniProt

complete

HUMAN:HYAL2

involved_in

GO:0009615: response to virus

ECO:0000314: direct assay evidence used in manual assertion

P

  • occurs_in:(CL:0002328)

Seeded From UniProt

complete

HUMAN:HYAL2

enables

GO:0030294: receptor signaling protein tyrosine kinase inhibitor activity

ECO:0000314: direct assay evidence used in manual assertion

F

  • occurs_in:(CL:0002328)

Seeded From UniProt

complete

HUMAN:HYAL2

enables

GO:0030971: receptor tyrosine kinase binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q04912

F

Seeded From UniProt

complete

HUMAN:HYAL2

involved_in

GO:0051898: negative regulation of protein kinase B signaling

ECO:0000314: direct assay evidence used in manual assertion

P

  • occurs_in:(CL:0002328)

Seeded From UniProt

complete

HUMAN:HYAL2

involved_in

GO:0061099: negative regulation of protein tyrosine kinase activity

ECO:0000314: direct assay evidence used in manual assertion

P

  • occurs_in:(CL:0002328)

Seeded From UniProt

complete

HUMAN:HYAL2

involved_in

GO:0043407: negative regulation of MAP kinase activity

ECO:0000314: direct assay evidence used in manual assertion

P

  • occurs_in:(CL:0002328)

Seeded From UniProt

complete


See also

References

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