The oncoprotein Ski acts as an antagonist of transforming growth factor-beta signaling by suppressing Smad2 phosphorylation

J Biol Chem. 2003 Jul 11;278(28):26249-57. doi: 10.1074/jbc.M304459200. Epub 2003 May 5.


The phosphorylation of Smad2 and Smad3 by the transforming growth factor (TGF)-beta-activated receptor kinases and their subsequent heterodimerization with Smad4 and translocation to the nucleus form the basis for a model how Smad proteins work to transmit TGF-beta signals. The transcriptional activity of Smad2-Smad4 or Smad3-Smad4 complexes can be limited by the corepressor Ski, which is believed to interact with Smad complexes on TGF-beta-responsive promoters and represses their ability to activate TGF-beta target genes by assembling on DNA a repressor complex containing histone deacetylase. Here we show that Ski can block TGF-beta signaling by interfering with the phosphorylation of Smad2 and Smad3 by the activated TGF-beta type I receptor. Furthermore, we demonstrate that overexpression of Ski induces the assembly of Smad2-Smad4 and Smad3-Smad4 complexes independent of TGF-beta signaling. The ability of Ski to engage Smad proteins in nonproductive complexes provides new insights into the molecular mechanism used by Ski for disabling TGF-beta signaling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Active Transport, Cell Nucleus
  • Animals
  • COS Cells
  • Cytoplasm / metabolism
  • DNA / metabolism
  • DNA-Binding Proteins / metabolism*
  • DNA-Binding Proteins / physiology*
  • Dimerization
  • Immunoblotting
  • Ligands
  • Microscopy, Fluorescence
  • Phosphorylation
  • Plasmids / metabolism
  • Precipitin Tests
  • Protein Transport
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins / physiology*
  • Signal Transduction*
  • Smad2 Protein
  • Smad3 Protein
  • Trans-Activators / metabolism*
  • Transfection
  • Transforming Growth Factor beta / metabolism*


  • DNA-Binding Proteins
  • Ligands
  • Proto-Oncogene Proteins
  • Smad2 Protein
  • Smad3 Protein
  • Trans-Activators
  • Transforming Growth Factor beta
  • DNA