SMAD3 and neoplasm: In tumor cells, ubiquitination of Smurfs mediated by regulatory proteins (e.g., Smurf2, CKIP-1, TRAF4, TRB3) aggravates the degradation of Smurfs through the proteasome pathway, leading to elevated protein levels of their substrates (e.g., RhoA, p53, Smad3) and subsequent tumor biological functions, such as cell growth, migration, and invasion, are regulated (Figure 3).