TGF-beta signalling is regulated by Schnurri-2-dependent nuclear translocation of CLIC4 and consequent stabilization of phospho-Smad2 and 3.
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.
Shukla
Anjali
A
Laboratory of Cancer Biology and Genetics, 37 Convent Drive, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Malik
Mariam
M
Cataisson
Christophe
C
Ho
Yan
Y
Friesen
Travis
T
Suh
Kwang S
KS
Yuspa
Stuart H
SH
D021581:Active Transport, Cell Nucleus / Q000502:physiology*; D000818:Animals; D002478:Cells, Cultured; D018118:Chloride Channels / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D051899:Smad2 Protein / Q000235:genetics / Q000378:metabolism*; D051900:Smad3 Protein / Q000235:genetics / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D020798:Two-Hybrid System Techniques
C479423:CLIC protein, mouse; D018118:Chloride Channels; D004268:DNA-Binding Proteins; C490430:Hivep2 protein, mouse; D024101:Mitochondrial Proteins; D034741:RNA, Small Interfering; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D016212:Transforming Growth Factor beta