Collaborative activities of macrophage-stimulating protein and transforming growth factor-beta1 in induction of epithelial to mesenchymal transition: roles of the RON receptor tyrosine kinase

Oncogene. 2004 Mar 4;23(9):1668-80. doi: 10.1038/sj.onc.1207282.

Abstract

Epithelial to mesenchymal transition (EMT) is a process occurring during embryonic development and cancer progression. Using recepteur d'origine nantais (RON)-expressing epithelial cells as a model, we showed that RON activation causes spindle-shaped morphology with increased cell motilities. These activities resemble those observed in EMT induced by transforming growth factor (TGF)-beta1 or by Ras-Raf signaling. By immunofluorescent and Western blot analyses, we found that constitutive RON expression results in diminished expression of E-cadherin, redistribution of beta-catenin, reorganization of actin cytoskeleton, and increased expression of vimentin, a mesenchymal filament. RON expression is also essential for TGF-beta1-induced expression of alpha-smooth muscle actin (alpha-SMA), a specialized mesenchymal marker. In the study of signaling pathways responsible for RON-mediated EMT, it was found that PD98059, a MAP kinase inhibitor, blocks the collaborative activities of RON and TGF-beta1 in induction of alpha-SMA expression and restores epithelial cells to their original morphology. Moreover, we showed that RON expression increases Smad2 gene promoter activities and protein expression, which significantly lowers TGF-beta1 threshold for EMT induction. These results suggest that persistent RON expression and activation cause the loss of epithelial phenotypes. These changes, collaborating with TGF-beta1 signaling, could play a critical role in epithelial transdifferentiation towards invasiveness and metastasis of certain cancers.

Publication types

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

MeSH terms

  • Actins / metabolism
  • Animals
  • Biomarkers / analysis
  • Cadherins / metabolism
  • Cell Differentiation / drug effects*
  • Cell Line
  • Cell Nucleus / drug effects
  • Cell Nucleus / metabolism
  • Cell Size / drug effects
  • Cytoskeletal Proteins / metabolism
  • Cytoskeleton / drug effects
  • Cytoskeleton / metabolism
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Dogs
  • Epithelial Cells / cytology
  • Epithelial Cells / drug effects*
  • Flavonoids / pharmacology
  • Gene Expression Regulation / drug effects
  • Hepatocyte Growth Factor / pharmacology*
  • Humans
  • Mesoderm / cytology*
  • Mesoderm / drug effects*
  • Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • Mitogen-Activated Protein Kinases / metabolism
  • Phosphorylation / drug effects
  • Protein Transport / drug effects
  • Proto-Oncogene Proteins / pharmacology*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Receptor Protein-Tyrosine Kinases / genetics
  • Receptor Protein-Tyrosine Kinases / metabolism*
  • Smad2 Protein
  • Trans-Activators / genetics
  • Trans-Activators / metabolism
  • Transforming Growth Factor beta / pharmacology*
  • Transforming Growth Factor beta1
  • beta Catenin

Substances

  • Actins
  • Biomarkers
  • CTNNB1 protein, human
  • Cadherins
  • Cytoskeletal Proteins
  • DNA-Binding Proteins
  • Flavonoids
  • Proto-Oncogene Proteins
  • RNA, Messenger
  • SMAD2 protein, human
  • Smad2 Protein
  • TGFB1 protein, human
  • Trans-Activators
  • Transforming Growth Factor beta
  • Transforming Growth Factor beta1
  • beta Catenin
  • macrophage stimulating protein
  • Hepatocyte Growth Factor
  • RON protein
  • Receptor Protein-Tyrosine Kinases
  • Mitogen-Activated Protein Kinases
  • 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one