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 VHL and cancer.