Abstract
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
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Research Support, N.I.H., Intramural
MeSH terms
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Active Transport, Cell Nucleus / physiology*
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Animals
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Cells, Cultured
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Chloride Channels / genetics
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Chloride Channels / metabolism*
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism*
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Gene Knockdown Techniques
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Humans
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Keratinocytes / cytology
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Keratinocytes / metabolism
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Mice
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Mice, Inbred BALB C
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Mice, Knockout
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Mitochondrial Proteins / genetics
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Mitochondrial Proteins / metabolism*
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RNA, Small Interfering / genetics
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RNA, Small Interfering / metabolism
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Signal Transduction / physiology
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Smad2 Protein / genetics
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Smad2 Protein / metabolism*
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Smad3 Protein / genetics
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Smad3 Protein / metabolism*
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Transforming Growth Factor beta / genetics
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Transforming Growth Factor beta / metabolism*
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Two-Hybrid System Techniques
Substances
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CLIC protein, mouse
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Chloride Channels
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DNA-Binding Proteins
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Hivep2 protein, mouse
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Mitochondrial Proteins
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RNA, Small Interfering
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Smad2 Protein
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Smad2 protein, mouse
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Smad3 Protein
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Smad3 protein, mouse
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Transforming Growth Factor beta