Several E3 ubiquitin ligase mutations are known to drive human cancers (e.g., 91% of cases of clear cell renal cell carcinoma (ccRCC) show biallelic VHL inactivation, WWP1 mutation in prostate cancer, deletion in gene enoding parkin RBR E3 ubiquitin protein ligase [PARK2] in ovarian, bladder, and breast cancer) This section summarizes the roles of diverse E3 ligases in perturbing TGFβ signaling activity, ultimately leading to cancer progression. This evidence concerns the gene PRKN and breast carcinoma.