Mishra and coworkers have shown that the adapter protein β2 spectrin is required for SMAD3-mediated cytostatic TGF-β signaling in hepatocytes, and that its downregulation, e.g., by induced expression of the E3 ligase PRAJA and subsequent β2 spectrin ubiquitinylation and proteasomal degradation facilitates cancer stem cell development and HCC formation55–57. Here, SMAD3 is linked to hepatocellular carcinoma.