Transcriptional induction of Smurf2 ubiquitin ligase by TGF-β

Smad ubiquitination regulatory factor 2 (Smurf2), a ubiquitin ligase for Smads, plays critical roles in the regulation of transforming growth factor-β (TGF-β)-Smad signaling via ubiquitin-dependent degradation of Smad2 and Smad7. We found that TGF-β stimulates Smurf2 expression. TGF-β activated the Smurf2 promoter in a TGF-β responsive cell lines, whereas IL-1α, PDGF and epidermal growth factor did not. TGF-β-mediated Smurf2 promoter activation was inhibited by Smad7 or an activin receptor-like kinase 5 inhibitor but not by dominant negative Smad or disruption of Smad-binding elements in the promoter. Moreover, inhibition of the phosphatidil inositol 3 kinase (PI3K)/Akt pathway suppressed TGF-β-mediated Smurf2 induction. These results suggest that TGF-β stimulates Smurf2 expression by Smad-independent pathway such as PI3K/Akt pathway via TGF-β receptor.