Regulation of TGF‐β family signaling by E3 ubiquitin ligases

Abstract

Members of the transforming growth factor‐β (TGF‐β) family, including TGF‐β, activin and bone morphogenetic proteins (BMPs), are multifunctional proteins that regulate a wide variety of cellular responses, such as proliferation, differentiation, migration and apoptosis. Alterations in their downstream signaling pathways are associated with a range of human diseases like cancer. TGF‐β family members transduce signals through membrane serine/threonine kinase receptors and intracellular Smad proteins. The ubiquitin–proteasome pathway, an evolutionarily conserved cascade, tightly regulates TGF‐β family signaling. In this pathway, E3 ubiquitin ligases play a crucial role in the recognition and degradation of target proteins by the 26S proteasomes. Smad degradation regulates TGF‐β family signaling; HECT (homologous to the E6‐accessory protein C‐terminus)‐type E3 ubiquitin ligases, Smad ubiquitin regulatory factor 1 (Smurf1), Smurf2, and a RING‐type E3 ubiquitin ligase, ROC1‐SCF^Fbw1a have been implicated in Smad degradation. Smurf1 and Smurf2 bind to TGF‐β family receptors via the inhibitory Smads, Smad6 and Smad7, to induce their ubiquitin‐dependent degradation. Arkadia, a RING‐type E3 ubiquitin ligase, induces the ubiquitination and degradation of Smad7 and corepressors, c‐Ski and SnoN, to enhance TGF‐β family signaling. Abnormalities in E3 ubiquitin ligases that control components of TGF‐β family signaling may lead to the development and progression of various cancers. (Cancer Sci 2008; 99: 2107–2112)