Inhibitory effect of c-Met mutants on the formation of branching tubules by a porcine aortic endothelial cell line

Cancer Sci. 2006 Dec;97(12):1343-50. doi: 10.1111/j.1349-7006.2006.00335.x. Epub 2006 Oct 9.


The association of hepatocyte growth factor (HGF) with its high-affinity receptor (c-Met) has been shown to induce mitogenesis, motogenesis and morphogenesis in a variety of cell types. Various point mutations in c-Met have been identified in hereditary and sporadic papillary renal carcinomas as well as in other carcinomas. In the present study, we examined the effects of c-Met point mutations on the morphology of a porcine aortic endothelial (PAE) cell line. When cultured in three-dimensional collagen gel, PAE cells formed branching tubule structures, and HGF treatment caused breakdown of the structures and induced a scattered morphology. The exogenous expression of c-Met point mutants inhibited the formation of tubules. HGF treatment induced the formation of tubules by PAE cells expressing some c-Met mutants, but it induced the scattering of PAE cells expressing other c-Met mutants. The presence of a low concentration of a mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK) inhibitor cancelled the inhibitory effect of the c-Met point mutations on the formation of tubules. These results suggest that c-Met point mutations affect the extracellular signal-regulated kinase (ERK) signaling required for the formation of tubules by PAE cells, and HGF binding changes the conformation of c-Met mutants, leading to the different signals required for formation of tubules and cell scattering.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aorta / drug effects
  • Aorta / growth & development*
  • Cells, Cultured / drug effects
  • Cells, Cultured / metabolism
  • Endothelium, Vascular / cytology*
  • Endothelium, Vascular / drug effects
  • Endothelium, Vascular / metabolism
  • Hepatocyte Growth Factor / pharmacology
  • MAP Kinase Kinase Kinases / metabolism
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • Phenotype
  • Phosphatidylinositol 3-Kinases / metabolism
  • Proto-Oncogene Proteins c-met / genetics
  • Proto-Oncogene Proteins c-met / pharmacology*
  • Signal Transduction
  • Swine


  • Hepatocyte Growth Factor
  • Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-met
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • MAP Kinase Kinase Kinases