Interaction with Smad4 is indispensable for suppression of BMP signaling by c-Ski

Mol Biol Cell. 2004 Mar;15(3):963-72. doi: 10.1091/mbc.e03-07-0478. Epub 2003 Dec 29.


c-Ski is a transcriptional corepressor that interacts strongly with Smad2, Smad3, and Smad4 but only weakly with Smad1 and Smad5. Through binding to Smad proteins, c-Ski suppresses signaling of transforming growth factor-beta (TGF-beta) as well as bone morphogenetic proteins (BMPs). In the present study, we found that a mutant of c-Ski, termed c-Ski (ARPG) inhibited TGF-beta/activin signaling but not BMP signaling. Selectivity was confirmed in luciferase reporter assays and by determination of cellular responses in mammalian cells (BMP-induced osteoblastic differentiation of C2C12 cells and TGF-beta-induced epithelial-to-mesenchymal transdifferentiation of NMuMG cells) and Xenopus embryos. The ARPG mutant recruited histone deacetylases 1 (HDAC1) to the Smad3-Smad4 complex but not to the Smad1/5-Smad4 complex. c-Ski (ARPG) was unable to interact with Smad4, and the selective loss of suppression of BMP signaling by c-Ski (ARPG) was attributed to the lack of Smad4 binding. We also found that c-Ski interacted with Smad3 or Smad4 without disrupting Smad3-Smad4 heteromer formation. c-Ski (ARPG) would be useful for selectively suppressing TGF-beta/activin signaling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bone Morphogenetic Proteins / metabolism*
  • COS Cells
  • Cell Differentiation / physiology*
  • Cells, Cultured
  • Chlorocebus aethiops
  • DNA-Binding Proteins / metabolism*
  • Embryo, Nonmammalian / metabolism
  • Histone Deacetylases / metabolism
  • Humans
  • Mutation / genetics
  • Nerve Growth Factors
  • Osteoblasts / cytology
  • Osteoblasts / metabolism
  • Protein Binding
  • Proto-Oncogene Proteins / metabolism*
  • Signal Transduction / physiology
  • Smad Proteins
  • Smad1 Protein
  • Smad4 Protein
  • Trans-Activators / metabolism*
  • Transforming Growth Factor beta / metabolism*
  • Xenopus / embryology
  • Xenopus / metabolism
  • Xenopus Proteins*


  • Bone Morphogenetic Proteins
  • DNA-Binding Proteins
  • MXD1 protein, Xenopus
  • Nerve Growth Factors
  • Proto-Oncogene Proteins
  • SMAD1 protein, human
  • SMAD4 protein, human
  • Smad Proteins
  • Smad1 Protein
  • Smad4 Protein
  • Trans-Activators
  • Transforming Growth Factor beta
  • Xenopus Proteins
  • smad4.1 protein, Xenopus
  • smad4.2 protein, Xenopus
  • SKI protein, human
  • Histone Deacetylases