Point mutations and overexpression of Ron induce transformation, tumor formation, and metastasis

Oncogene. 2001 Sep 27;20(43):6142-51. doi: 10.1038/sj.onc.1204836.

Abstract

The receptor tyrosine kinase Ron is a member of the receptor family that includes the proto-oncogene Met and the avian oncogene Sea. The interaction of Ron with its ligand, known as hepatocyte growth factor-like protein (HGFL) or macrophage stimulating protein (MSP), induces crucial cellular responses including invasive growth, proliferation, cell scattering, and branching morphogenesis. Based on the homology and functional similarities between Met and Ron it was hypothesized that Ron may be important in tumor formation and metastasis. To test this hypothesis, wild-type mouse Ron and three mutant forms of Ron containing mutations similar to those found in the Met gene in human hereditary papillary renal carcinoma (HPRC), were expressed in NIH3T3 cells. A transformed phenotype was produced in cell lines expressing either wild-type Ron or the mutated Ron proteins. Further, these cell lines displayed oncogenic potential by exhibiting increased proliferation and constitutive phosphorylation of Ron. These cell lines were also tested for the ability to form solid tumors. Cells expressing wild-type Ron and the three proteins with single amino acid substitutions were highly tumorigenic in vivo. In a model of experimental metastasis, two of the cell lines with altered Ron protein formed highly aggressive tumors in the lungs. These results suggest that Ron may be an aggressive oncogene when either overexpressed or when activated by mutation.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 3T3 Cells
  • Amino Acid Sequence
  • Animals
  • Blotting, Western
  • Carcinoma / genetics
  • Cell Division
  • Cell Transformation, Neoplastic
  • DNA, Complementary / metabolism
  • Growth Substances / metabolism
  • Hepatocyte Growth Factor*
  • Humans
  • Kidney Neoplasms / genetics
  • Ligands
  • Lung Neoplasms / genetics
  • Lung Neoplasms / secondary
  • Mice
  • Molecular Sequence Data
  • Mutation
  • Neoplasm Metastasis
  • Neoplasms / genetics*
  • Phosphorylation
  • Point Mutation*
  • Protein Binding
  • Protein Structure, Tertiary
  • Proto-Oncogene Proteins*
  • RNA / metabolism
  • Receptor Protein-Tyrosine Kinases / genetics*
  • Receptor Protein-Tyrosine Kinases / metabolism*
  • Receptor Protein-Tyrosine Kinases / physiology
  • Receptors, Cell Surface / genetics*
  • Receptors, Cell Surface / metabolism*
  • Receptors, Cell Surface / physiology
  • Sequence Homology, Amino Acid
  • Transfection
  • Tumor Cells, Cultured

Substances

  • DNA, Complementary
  • Growth Substances
  • Ligands
  • Proto-Oncogene Proteins
  • Receptors, Cell Surface
  • macrophage stimulating protein
  • RNA
  • Hepatocyte Growth Factor
  • RON protein
  • Receptor Protein-Tyrosine Kinases