Interestingly, recent evidence on the role of the de-uibiquitinase USP2a that interacts with TβRI has pointed to the role of non-degradative ubiquitination of TβRI and TβRII for Smad2 and Smad3 recruitment to the receptors and phosphorylation in invasive cancer cells, thus linking even tighter the regulation of Smad with non-Smad pathways at the level of TGF-β receptors [58]. The gene discussed is SMAD3; the disease is cancer.