Klin Onkol 2005; 18(6): 199-206.
Summary: The signaling responses to the transforming growth factor-β (TGF-β) and other members of this cytokine family are mediated by a heteromeric complex of two types of transmembrane serine/threonine kinase receptors at the cell surface and their intracellular substrates, the Smad proteins. The specificity, diversity, intensity, and timing of TGF-β signaling are tightly controlled by activation and inactivation of signal transduction components. These key transducer proteins (TGF-β receptors and Smad proteins) undergo ubiquitin-proteasome-mediated degradation. The inhibitor of TGF-β signaling proto-oncoprotein SnoN (Ski-related novel gene product) is also a substrate for proteasome degradation. It was found that SnoN is amplified in stomach, thyroid and lung carcinoma and lymphoma. The disruption of proper degradation of Smads has been observed in human cancers. Missense mutations of Smad2 and Smad4 at a conserved arginine residue in colorectal and pancreatic cancers increased the turnover rate of Smad proteins via the proteasome pathway. The dysregulated proteasomal degradation is a novel pathway how tumor cells silence TGF-β signaling and thus these cells are resistant to the anti-proliferative activity of TGF-β.
