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.