The regulation of TGF-β/SMAD signaling by protein deubiquitination

Transforming growth factor-beta (TGF-beta) members are key cytokines that control embryogenesis and tissue homeostasis via transmembrane TGF-beta type II (T beta R II) and type I (T beta RI) and serine/threonine kinases receptors. Aberrant activation of TGF-beta signaling leads to diseases, including cancer. In advanced cancer, the TGF-beta/SMAD pathway can act as an oncogenic factor driving tumor cell invasion and metastasis, and thus is considered to be a therapeutic target. The activity of TGF-beta/SMAD pathway is known to be regulated by ubiquitination at multiple levels. As ubiquitination is reversible, emerging studies have uncovered key roles for ubiquitin-removals on TGF-beta signaling components by deubiquitinating enzymes (DUBs). In this paper, we summarize the latest findings on the DUBs that control the activity of the TGF-beta signaling pathway. The regulatory roles of these DUBs as a driving force for cancer progression as well as their underlying working mechanisms are also discussed.