Smurf1 and Smurf2 (SMAD ubiquitination regulatory factor-1 and 2) are members of the Hect family of proteins, which also includes the ubiquitin (Ub) E3-type ligases Nedd3 and E6-AP. E3 ligases are involved in the enzymatic reactions of the Ub conjugating pathway, which targets proteins for degradation by the 26S proteasome. Within the Ub pathway, the E3 ligases specifically catalyze the transfer of Ub from the Ub-conjugating enzymes to the individual protein substrate. As an E3 ligase, Smurf1 selectively interacts with receptor-regulated SMADs specific to the BMP pathway in order to trigger their ubiquitination and degradation. Smurf2 interacts with receptor-activated Smads (R-Smads), including Smad1, Smad2, and Smad3, but not Smad4. Although Smurf2 localizes to the nucleus, binding to Smad7 induces its export and its recruitment to the activated TGFβ receptor, where it causes degradation of Smad7.