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...

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Bibliographic Details
Published in:Molecular biology of the cell 2001-05, Vol.12 (5), p.1431-1443
Main Authors: Fukuchi, M, Imamura, T, Chiba, T, Ebisawa, T, Kawabata, M, Tanaka, K, Miyazono, K
Format: Article
Language:English
Subjects:
Active Transport, Cell Nucleus - physiology
Anaphase-Promoting Complex-Cyclosome
Animals
Cell Line
Cysteine Endopeptidases - metabolism
DNA-Binding Proteins - metabolism
Genes, Reporter - genetics
Humans
Ligands
Ligases - metabolism
Macromolecular Substances
Models, Biological
Multienzyme Complexes - metabolism
Peptide Synthases - metabolism
Precipitin Tests
Proteasome Endopeptidase Complex
Recombinant Fusion Proteins - genetics
Recombinant Fusion Proteins - metabolism
Signal Transduction - physiology
SKP Cullin F-Box Protein Ligases
Smad3 Protein
Trans-Activators - metabolism
Transfection
Transforming Growth Factor beta - metabolism
Two-Hybrid System Techniques
Ubiquitin-Protein Ligase Complexes
Ubiquitin-Protein Ligases
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Summary: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.
ISSN:1059-1524
1939-4586
DOI:10.1091/mbc.12.5.1431