Cross-talk between the receptor tyrosine kinases Ron and epidermal growth factor receptor

Exp Cell Res. 2003 Oct 1;289(2):317-25. doi: 10.1016/s0014-4827(03)00280-5.


Heterogeneous receptor-receptor interactions may play a role in intracellular signaling. Accordingly, the interaction of two dissimilar tyrosine kinase receptors, Ron and epidermal growth factor receptor (EGFR) was investigated. The functional interaction of Ron and EGFR in cell scatter and oncogenic transformation was investigated in vivo. Transfection of a dominant negative form of EGFR into human embryonic kidney cells stably expressing Ron (293-Ron) dramatically reduced the scatter response induced by the Ron ligand hepatocyte growth factor-like protein/macrophage stimulating protein (HGFL). The scatter response of the 293-Ron cells was also attenuated by treatment of the cells with the specific EGFR inhibitor AG 1478. Co-transfection of Ron and dominant-negative EGFR, or co-transfection of EGFR and a dominant-negative form of Ron reduced focus formation in NIH/3T3 cells. Western analysis of NIH/3T3 cells overexpressing murine Ron and expressing endogenous levels of EGFR was used to demonstrate that Ron and EGFR co-immunoprecipitate. Stimulation of the cells in vitro with the Ron ligand HGFL or with the EGFR ligand epidermal growth factor (EGF) appeared to induce phosphorylation of both receptors. Co-immunoprecipitation and phosphorylation of phosphatidyl inositol 3-kinase (PI3-K) was also observed. This novel finding of a functional and biochemical interaction between Ron and EGFR suggests that heterologous tyrosine kinase receptor interactions may play a role in cellular processes such as scatter and transformation.

Publication types

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

MeSH terms

  • 3T3 Cells
  • Animals
  • Cell Communication / drug effects
  • Cell Communication / physiology*
  • Enzyme Inhibitors / pharmacology
  • Epidermal Growth Factor / pharmacology
  • ErbB Receptors / drug effects
  • ErbB Receptors / genetics
  • ErbB Receptors / metabolism*
  • Fibroblasts / metabolism
  • Hepatocyte Growth Factor / metabolism
  • Hepatocyte Growth Factor / pharmacology
  • Humans
  • Kidney / cytology
  • Kidney / metabolism
  • Mice
  • Mutation / genetics
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphorylation / drug effects
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins / pharmacology
  • Quinazolines
  • Receptor Cross-Talk / physiology*
  • Receptor Protein-Tyrosine Kinases / drug effects
  • Receptor Protein-Tyrosine Kinases / genetics
  • Receptor Protein-Tyrosine Kinases / metabolism*
  • Signal Transduction / drug effects
  • Signal Transduction / physiology*
  • Transfection
  • Tyrphostins / pharmacology


  • Enzyme Inhibitors
  • Proto-Oncogene Proteins
  • Quinazolines
  • Tyrphostins
  • macrophage stimulating protein
  • RTKI cpd
  • Epidermal Growth Factor
  • Hepatocyte Growth Factor
  • Phosphatidylinositol 3-Kinases
  • ErbB Receptors
  • RON protein
  • Receptor Protein-Tyrosine Kinases