Mutations in the tumor suppressors Smad2 and Smad4 inactivate transforming growth factor β signaling by targeting Smads to the ubiquitin-proteasome pathway

摘要

Biological signals for transforming growth factor β(TGF-β) are transduced through transmembrane serine/threonine kinase re- ceptors that signal to a family of intracellular mediators known as Smads. Smad2 and Smad4 are important for transcriptional and antiproliferative responses to TGF-β, and their inactivation in human cancers indicates that they are tumor suppressors. A mis- sense mutation at a conserved arginine residue in the amino- terminal MH1 domain of both Smad2 and Smad4 has been iden- tified in tumors from patients with colorectal and pancreatic cancers, respectively. However, the mechanism whereby this mu- tation interferes with Smad activity is uncertain. Here we show that these mutations do not disrupt activation of Smads, including receptor-mediated phosphorylation of Smad2, Smad2/Smad4 het- eromeric complex formation, and Smad nuclear translocation. In contrast, we demonstrate that the mutant Smads are degraded rapidly in comparison with their wild-type counterparts. We show that this decrease in Smad protein stability occurs through induc- tion of Smad ubiquitination by pathways involving the UbcH5 family of ubiquitin ligases. These studies thus reveal a mechanism for tumorigenesis whereby genetic defects in Smads induce their degradation through the ubiquitin-mediated pathway.