Ligand-dependent degradation of Smad3 by a ubiquitin ligase complex of ROC1 and associated proteins.

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.
Mesh Terms:
Active Transport, Cell Nucleus, Animals, Cell Line, Cysteine Endopeptidases, DNA-Binding Proteins, Genes, Reporter, Humans, Ligands, Ligases, Macromolecular Substances, Models, Biological, Multienzyme Complexes, Peptide Synthases, Precipitin Tests, Proteasome Endopeptidase Complex, Recombinant Fusion Proteins, SKP Cullin F-Box Protein Ligases, Signal Transduction, Smad3 Protein, Trans-Activators, Transfection, Transforming Growth Factor beta, Two-Hybrid System Techniques, Ubiquitin-Protein Ligase Complexes, Ubiquitin-Protein Ligases
Mol. Biol. Cell
Date: May. 01, 2001
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