Regulation of Smad degradation and activity by Smurf2, an E3 ubiquitin ligase

Smad proteins are key intracellular signaling effecters for the transformin g growth factor-beta superfamily of peptide growth factors. Following recep tor-induced activation, Smads move into the nucleus to activate transcripti on of a select set of target genes. The activity of Smad proteins must be t ightly regulated to exert the biological effects of different ligands in a timely manner. Here, we report the identification of Smurf2, a new member o f the Hect family of E3 ubiquitin ligases. Smurf2 selectively interacts wit h receptor-regulated Smads and preferentially targets Smad1 for ubiquitinat ion and proteasome-mediated degradation. At higher expression levels, Smurf 2 also decreases the protein levels of Smad2, but not Smad3. In Xenopus emb ryos, ectopic Smurf2 expression specifically inhibits Smad1 responses and t hereby affects embryonic patterning by bone morphogenetic protein signals. These findings suggest that Smurf2 may regulate the competence of a cell to respond to transforming growth factor-beta /bone morphogenetic protein sig naling through a distinct degradation pathway that is similar to, yet indep endent of, Smurf1.