Fig. 7. Smads in ubiquitin pathways. Six documented examples of Smad-ubiquitin pathways are depicted: (1) Cytoplasmic R-Smad (e.g. Smad1) ubiquitination and proteasomal degradation mediated by Smurfs (Zhu et al., 1999). (2) Cytoplasmic activated R-Smads (e.g. Smad3) target HEF1 for degradation via unknown E3 (?) ligases (Liu et al., 2000). (3) Nuclear R-Smads (e.g. Smad3) target the co-repressor SnoN for degradation via Smurfs or the APC that act as E3 ligases (Bonni et al., 2001; Stroschein et al., 2001). (4) Nuclear R-Smads (e.g. Smad2) are degraded after Smurf-mediated ubiquitination (Lin et al., 2000; Lo and Massagué, 1999; Zhang et al., 2001). (5) Nuclear R-Smads (e.g. Smad3) are ubiquitinated by the action of the SCF^Fbw1a/Roc1 E3 ligase complex, exported to the cytoplasm and finally degraded there (Fukuchi et al., 2001). (6) The TGF-ß signal induces Smad7-Smurf association, export to the cytoplasm and targeting of the receptor kinases that become degraded (Ebisawa et al., 2001; Kavsak et al., 2000). R-Smads (S, with small black circles indicating C-terminal phosphorylation) and Smad7 (S7) are depicted as circles. The poly-ubiquitin chain is shown as a multi-circle attachment and an X indicates proteasomal degradation of the target protein.