Smad ubiquitin regulatory factor 2 (Smurf2) is an E3 ubiquitin ligase that regulates transforming growth factor β (TGF-β)/Smad signaling and is implicated in a wide range of cellular responses. However， the exact mechanism whereby Smurf2 controls TGF-β-induced signaling pathways remains unknown. Here， we identified the relationship between the alternate TGF-β signaling pathways: TGF-β/PI3K/Akt/β-catenin and TGF-β/Smad2/3/FoxO1/PUMA and Smurf2. The results showed that TGF-β promoted proliferation， invasion， and migration of human pancreatic carcinoma (PANC-1) cells through the PI3K/Akt/β-catenin pathway. Inhibiting the PI3K/Akt signal transformed the TGF-β-induced cell response from promoting proliferation to Smad2/3/FoxO1/PUMA-mediated apoptosis. The activation of Akt inhibited the phosphorylation/activation of Smad3 and promoted the phosphorylation/inactivation of FoxO1， inhibiting the nuclear translocation of both Smad3 and FoxO1 and inhibiting the expression of PUMA， a key apoptotic mediator. However， downregulation of Smurf2 in PANC-1 cells removed Akt-mediated suppression of Smad3 and FoxO1， allowing TGF-β-induced phosphorylation/activation of Smad2/3， dephosphorylation/activation of FoxO1， nuclear translocation of both factors， and activation of PUMA-mediated apoptosis. Downregulation of Smurf2 also decreased invasion and migration in TGF-β-induced PANC-1 cells. The in vivo experiments also revealed that downregulation of Smurf2 delayed the growth of xenograft tumors originating from PANC-1 cells especially when treated with TGF-β. Taken together， these results indicate that expression of Smurf2 plays a central role in the determination and activation/inhibition of particular cellular pathways and the ultimate fate of cells induced by TGF-β. An increased understanding of the intricacies of the TGF-β signaling pathway may provide a new anti-cancer therapeutic target.