TGF-beta signalling is regulated by Schnurri-2-dependent nuclear translocation of CLIC4 and consequent stabilization of phospho-Smad2 and 3

Nat Cell Biol. 2009 Jun;11(6):777-84. doi: 10.1038/ncb1885. Epub 2009 May 17.


CLIC4 (chloride intracellular channel 4), a multifunctional protein that traffics between the cytoplasm and nucleus, interacts with Schnurri-2, a transcription factor in the bone morphogenetic protein (BMP) signalling pathway. Here we show that transforming growth factor beta (TGF-beta) promotes the expression of CLIC4 and Schnurri-2 as well as their association in the cytoplasm and their translocation to the nucleus. In the absence of CLIC4 or Schnurri-2, TGF-beta signalling is abrogated. Direct nuclear targeting of CLIC4 enhances TGF-beta signalling and removes the requirement for Schnurri-2. Nuclear CLIC4 associates with phospho (p)-Smad2 and p-Smad3, protecting them from dephosphorylation by nuclear phosphatases. An intact TGF-beta signalling pathway is essential for CLIC4-mediated growth-arrest. These results newly identify Schnurri-2 and CLIC4 as modifiers of TGF-beta signalling through their stabilization of p-Smad2 and 3 in the nucleus.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Active Transport, Cell Nucleus / physiology*
  • Animals
  • Cells, Cultured
  • Chloride Channels / genetics
  • Chloride Channels / metabolism*
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Gene Knockdown Techniques
  • Humans
  • Keratinocytes / cytology
  • Keratinocytes / metabolism
  • Mice
  • Mice, Inbred BALB C
  • Mice, Knockout
  • Mitochondrial Proteins / genetics
  • Mitochondrial Proteins / metabolism*
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Signal Transduction / physiology
  • Smad2 Protein / genetics
  • Smad2 Protein / metabolism*
  • Smad3 Protein / genetics
  • Smad3 Protein / metabolism*
  • Transforming Growth Factor beta / genetics
  • Transforming Growth Factor beta / metabolism*
  • Two-Hybrid System Techniques


  • CLIC protein, mouse
  • Chloride Channels
  • DNA-Binding Proteins
  • Hivep2 protein, mouse
  • Mitochondrial Proteins
  • RNA, Small Interfering
  • Smad2 Protein
  • Smad2 protein, mouse
  • Smad3 Protein
  • Smad3 protein, mouse
  • Transforming Growth Factor beta