TGF-beta induces assembly of a Smad2-Smurf2 ubiquitin ligase complex that targets SnoN for degradation

The receptor-regulated Smad proteins are essential intracellular mediators of signal transduction by the transforming growth factor-beta (TGF-beta) su perfamily of growth factors and are also important as regulators of gene tr anscription. Here we describe a new role for TGF-beta -regulated Smad2 and Smad3 as components of a ubiquitin ligase complex. We show that in the pres ence of TGF-beta signalling, Smad2 interacts through its proline-rich PPXY motif with the tryptophan-rich WW domains of Smurf2, a recently identified E3 ubiquitin ligases. TGF-beta also induces the association of Smurf2 with the transcriptional cc-repressor SnoN and we show that Smad2 can function t o mediate this interaction. This allows Smurf2 HECT domain to target SnoN f or ubiquitin-mediated degradation by the proteasome. Thus, stimulation by T GF-beta can induce the assembly of a Smad2-Smurf2 ubiquitin ligase complex that functions to target substrates for degradation.