Abstract
The TGFβ receptors signal through phosphorylation and nuclear translocation of SMAD2/3. SMAD7, a transcriptional target of TGFβ signals, negatively regulates the TGFβ pathway by recruiting E3 ubiquitin ligases and targeting TGFβ receptors for ubiquitin-mediated degradation. In this report, we identify a deubiquitylating enzyme USP11 as an interactor of SMAD7. USP11 enhances TGFβ signalling and can override the negative effects of SMAD7. USP11 interacts with and deubiquitylates the type I TGFβ receptor (ALK5), resulting in enhanced TGFβ-induced gene transcription. The deubiquitylase activity of USP11 is required to enhance TGFβ-induced gene transcription. RNAi-mediated depletion of USP11 results in inhibition of TGFβ-induced SMAD2/3 phosphorylation and TGFβ-mediated transcriptional responses. Central to TGFβ pathway signalling in early embryogenesis and carcinogenesis is TGFβ-induced epithelial to mesenchymal transition. USP11 depletion results in inhibition of TGFβ-induced epithelial to mesenchymal transition.
Keywords:
ALK5; TGFβ; USP11; USP15; cancer; ubiquitin.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Epithelial-Mesenchymal Transition / physiology*
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HEK293 Cells
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Humans
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Mice
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Phosphorylation / physiology
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism*
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RNA Interference
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Receptor, Transforming Growth Factor-beta Type I
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Receptors, Transforming Growth Factor beta / genetics
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Receptors, Transforming Growth Factor beta / metabolism*
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Signal Transduction / physiology*
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Smad Proteins / genetics
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Smad Proteins / metabolism
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Thiolester Hydrolases / genetics
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Thiolester Hydrolases / metabolism*
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Transcription, Genetic / physiology
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Transforming Growth Factor beta / genetics
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Transforming Growth Factor beta / metabolism*
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Ubiquitin-Protein Ligases / genetics
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Ubiquitin-Protein Ligases / metabolism
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Ubiquitination / physiology*
Substances
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Receptors, Transforming Growth Factor beta
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Smad Proteins
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Transforming Growth Factor beta
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USP11 protein, human
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Ubiquitin-Protein Ligases
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Protein Serine-Threonine Kinases
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Receptor, Transforming Growth Factor-beta Type I
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TGFBR1 protein, human
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Tgfbr1 protein, mouse
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Thiolester Hydrolases