Smad ubiquitin regulatory factor 2 (Smurf2) is a HECT domain E3 ubiquitin ligase. It was initially identified as an inhibitor of TGF-?/BMP signaling by targeting R-Smads and TGF type I receptor for ubiquitination and degradation. Subsequent studies have revealed its role in neuronal and planar cell polarity, as well as in the senescence response and suppression of tumorigenesis. Smurf2 has a broad range of substrates including RUNX2, AMSH, Rap1B, and RNF11. Smurf2 is widely expressed in various tissues. The C2 domain of Smurf2 inhibits its catalytic activity by interacting with the HECT domain. Research studies have shown that Smurf2 functions as a tumor suppressor by maintaining genomic stability through targeting RNF20.