Abstract
Smads are signal mediators for the members of the transforming growth factor-beta (TGF-beta) superfamily. Upon phosphorylation by the TGF-beta receptors, Smad3 translocates into the nucleus, recruits transcriptional coactivators and corepressors, and regulates transcription of target genes. Here, we show that Smad3 activated by TGF-beta is degraded by the ubiquitin-proteasome pathway. Smad3 interacts with a RING finger protein, ROC1, through its C-terminal MH2 domain in a ligand-dependent manner. An E3 ubiquitin ligase complex ROC1-SCF(Fbw1a) consisting of ROC1, Skp1, Cullin1, and Fbw1a (also termed betaTrCP1) induces ubiquitination of Smad3. Recruitment of a transcriptional coactivator, p300, to nuclear Smad3 facilitates the interaction with the E3 ligase complex and triggers the degradation process of Smad3. Smad3 bound to ROC1-SCF(Fbw1a) is then exported from the nucleus to the cytoplasm for proteasomal degradation. TGF-beta/Smad3 signaling is thus irreversibly terminated by the ubiquitin-proteasome pathway.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Active Transport, Cell Nucleus / physiology*
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Anaphase-Promoting Complex-Cyclosome
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Animals
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Cell Line
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Cysteine Endopeptidases / metabolism
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DNA-Binding Proteins / metabolism*
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Genes, Reporter / genetics
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Humans
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Ligands
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Ligases / metabolism*
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Macromolecular Substances
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Models, Biological
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Multienzyme Complexes / metabolism
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Peptide Synthases / metabolism*
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Precipitin Tests
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Proteasome Endopeptidase Complex
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Recombinant Fusion Proteins / genetics
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Recombinant Fusion Proteins / metabolism
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SKP Cullin F-Box Protein Ligases
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Signal Transduction / physiology
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Smad3 Protein
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Trans-Activators / metabolism*
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Transfection
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Transforming Growth Factor beta / metabolism*
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Two-Hybrid System Techniques
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Ubiquitin-Protein Ligase Complexes*
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Ubiquitin-Protein Ligases
Substances
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DNA-Binding Proteins
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Ligands
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Macromolecular Substances
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Multienzyme Complexes
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Recombinant Fusion Proteins
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SMAD3 protein, human
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Smad3 Protein
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Trans-Activators
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Transforming Growth Factor beta
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Ubiquitin-Protein Ligase Complexes
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Anaphase-Promoting Complex-Cyclosome
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SKP Cullin F-Box Protein Ligases
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Ubiquitin-Protein Ligases
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Cysteine Endopeptidases
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Proteasome Endopeptidase Complex
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Ligases
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Peptide Synthases