The role of sentrin-specific protease 2 substrate recognition in TGF-β-induced tumorigenesis

Smad4, a common-mediator of Smads, plays a central role in forming complexes with receptor-phosphorylated Smads, and then transduces transforming growth factor (TGF)-beta signals into the nuclei. Although many cellular factors are involved in TGF-beta induced epithelial-to-mesenchymal transition (EMT) and cell migration, very little is known with the mechanism of Smad4 regulation on pro-oncogenes response by TGF-beta. Herein, we demonstrate the interaction of Sentrin-specific protease 2 (SENP2) with Smad4 through SENP2 residue 363 similar to 400. The same segment is also important for desumoylation of Smad4, and able to relieve sumoylation-mediated TGF-beta repression. The SENP2363 similar to 400 segment is critical for TGF-beta-induced cell migration, which is correlated with SENP2363 similar to 400 deletion mutant failed to increase matrix metalloproteinase (MMP)-9 and EMT marker gene expression. Moreover, our results suggest that the interaction and desumoylation between SENP2 and Smad4 promote cell migration in triple-negative breast cancer cells. Altogether, our data show how SENP2 regulates its substrate for desumoylation, and also the role of SENP2 in TGF-beta induced cancer cell migration.