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.
Fukuchi
M
M
Department of Biochemistry, the Cancer Institute of Japanese Foundation for Cancer Research, and Research for the Future Program, the Japan Society for the Promotion of Science, 1-37-1 Kami-ikebukuro, Toshima-ku, Tokyo 170-8455, Japan.
Imamura
T
T
Chiba
T
T
Ebisawa
T
T
Kawabata
M
M
Tanaka
K
K
Miyazono
K
K
D021581:Active Transport, Cell Nucleus / Q000502:physiology*; D064173:Anaphase-Promoting Complex-Cyclosome; D000818:Animals; D002460:Cell Line; D003546:Cysteine Endopeptidases / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D017930:Genes, Reporter / Q000235:genetics; D006801:Humans; D008024:Ligands; D008025:Ligases / Q000378:metabolism*; D046911:Macromolecular Substances; D008954:Models, Biological; D009097:Multienzyme Complexes / Q000378:metabolism; D010453:Peptide Synthases / Q000378:metabolism*; D011233:Precipitin Tests; D046988:Proteasome Endopeptidase Complex; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D044843:SKP Cullin F-Box Protein Ligases; D015398:Signal Transduction / Q000502:physiology; D051900:Smad3 Protein; D015534:Trans-Activators / Q000378:metabolism*; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D020798:Two-Hybrid System Techniques; D043743:Ubiquitin-Protein Ligase Complexes; D044767:Ubiquitin-Protein Ligases
D004268:DNA-Binding Proteins; D008024:Ligands; D046911:Macromolecular Substances; D009097:Multienzyme Complexes; D011993:Recombinant Fusion Proteins; C497790:SMAD3 protein, human; D051900:Smad3 Protein; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D043743:Ubiquitin-Protein Ligase Complexes; D064173:Anaphase-Promoting Complex-Cyclosome; D044843:SKP Cullin F-Box Protein Ligases; D044767:Ubiquitin-Protein Ligases; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; D008025:Ligases; D010453:Peptide Synthases