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 facto r-beta (TGF-beta) superfamily. Upon phosphorylation by the TGF-beta recepto rs, Smad3 translocates into the nucleus, recruits transcriptional coactivat ors and corepressors, and regulates transcription of target genes. Here, we show that Smad3 activated by TGF-beta is degraded by the ubiquitin-proteas ome pathway. Smad3 interacts with a RING finger protein, ROC1, through its C-terminal MH2 domain in a ligand-dependent manner. Am E3 ubiquitin ligase complex ROC1-SCFFbw1a consisting of ROC1, Skp1, Cullin1, and Fbw1a (also te rmed beta TrCP1) induces ubiquitination of Smad3. Recruitment of a transcri ptional coactivator, p300, to nuclear Smad3 facilitates the interaction wit h the E3 ligase complex and triggers the degradation process of Smad3. Smad 3 bound to ROC1-SCFFbw1a is then exported from the nucleus to the cytoplasm for proteasomal degradation. TGF-beta /Smad3 signaling is thus irreversibl y terminated by the ubiquitin-proteasome pathway.