K-Ras mediates cytokine-induced formation of E-cadherin-based adherens junctions during liver development

EMBO J. 2002 Mar 1;21(5):1021-30. doi: 10.1093/emboj/21.5.1021.

Abstract

The E-cadherin-based adherens junction (AJ) is essential for organogenesis of epithelial tissues including the liver, although the regulatory mechanism of AJ formation during development remains unknown. Using a primary culture system of fetal hepatocytes in which oncostatin M (OSM) induces differentiation, we show here that OSM induces AJ formation by altering the subcellular localization of AJ components including E-cadherin and catenins. By retroviral expression of dominant-negative forms of signaling molecules, Ras was shown to be required for the OSM-induced AJ formation. Fetal hepatocytes derived from K-Ras knockout (K-Ras-/-) mice failed to form AJs in response to OSM, whereas AJ formation was induced normally by OSM in mutant hepatocytes lacking both H-Ras and N-Ras. Moreover, the defective phenotype of K-Ras-/- hepatocytes was restored by expression of K-Ras, but not by H-Ras and N-Ras. Finally, pull-down assays using the Ras-binding domain of Raf1 demonstrated that OSM directly activates K-Ras in fetal hepatocytes. These results indicate that K-Ras specifically mediates cytokine signaling for formation of AJs during liver development.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adherens Junctions / drug effects
  • Adherens Junctions / metabolism*
  • Animals
  • Cadherins / metabolism*
  • Cell Differentiation / drug effects
  • Cells, Cultured / drug effects
  • Cytoskeletal Proteins / metabolism
  • Dexamethasone / pharmacology
  • Enzyme Activation
  • Fetal Proteins / physiology*
  • Genes, ras
  • Genetic Complementation Test
  • Hepatocytes / drug effects
  • Hepatocytes / ultrastructure*
  • Liver / embryology*
  • Membrane Proteins / analysis
  • Mice
  • Mice, Knockout
  • Oncostatin M
  • Peptides / pharmacology
  • Phenotype
  • Phosphoproteins / analysis
  • Protein Structure, Tertiary
  • Proto-Oncogene Proteins c-raf / chemistry
  • Proto-Oncogene Proteins c-raf / metabolism
  • Proto-Oncogene Proteins p21(ras) / physiology*
  • Recombinant Fusion Proteins / physiology
  • Signal Transduction
  • Trans-Activators*
  • Zonula Occludens-1 Protein
  • beta Catenin

Substances

  • CTNNB1 protein, mouse
  • Cadherins
  • Cytoskeletal Proteins
  • Fetal Proteins
  • Membrane Proteins
  • Osm protein, mouse
  • Peptides
  • Phosphoproteins
  • Recombinant Fusion Proteins
  • Tjp1 protein, mouse
  • Trans-Activators
  • Zonula Occludens-1 Protein
  • beta Catenin
  • Oncostatin M
  • Dexamethasone
  • Proto-Oncogene Proteins c-raf
  • Proto-Oncogene Proteins p21(ras)