Organisation und Methode

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. © 2008 Japanese Cancer Association.