To Ub or not to Ub: a regulatory question in TGF-β signaling

The TGF-β signaling pathway consists of two types of cell-surface receptors (TβRI and TβRII) that activate the intracellular Smad pathway. Activated R-Smads (i.e., Smad2 and Smad3) and Co-Smad (Smad4) form a complex that eventually controls ligand-induced context-dependent transcriptional responses. I-Smads are transcriptionally induced by TGF-β ligands and serve as negative feedback products in TGF-β signaling. The activities of TGF-β receptors and Smads are tightly regulated by post-translational modifications such as reversible ubiquitination and ubiquitin-like modifications. Ubiquitin ligase (E3) enzymes and deubiqutinating enzymes (DUBs) may play crucial roles in tumor development through regulating TGF-β signaling. Targeting E3s and DUBs may offer potential cancer therapies. The transforming growth factor β (TGF-β) superfamily controls a wide spectrum of biological processes in metazoans, including cell proliferation, apoptosis, differentiation, cell-fate determination, and embryonic development. Deregulation of TGF-β–Smad signaling contributes to developmental anomalies and a variety of disorders and diseases such as tumorigenesis, fibrotic disorders, and immune diseases. In cancer, TGF-β has dual effects through its antiproliferative and prometastatic actions. At the cellular level, TGF-β functions mainly through the canonical Smad-dependent pathway in a cell type-specific and context-dependent manner. Accumulating evidence has demonstrated that ubiquitination plays a vital role in regulating TGF-β–Smad signaling. We summarize current progress on ubiquitination (Ub) and the ubiquitin ligases that regulate TGF-β–Smad signaling. The transforming growth factor β (TGF-β) superfamily controls a wide spectrum of biological processes in metazoans, including cell proliferation, apoptosis, differentiation, cell-fate determination, and embryonic development. Deregulation of TGF-β–Smad signaling contributes to developmental anomalies and a variety of disorders and diseases such as tumorigenesis, fibrotic disorders, and immune diseases. In cancer, TGF-β has dual effects through its antiproliferative and prometastatic actions. At the cellular level, TGF-β functions mainly through the canonical Smad-dependent pathway in a cell type-specific and context-dependent manner. Accumulating evidence has demonstrated that ubiquitination plays a vital role in regulating TGF-β–Smad signaling. We summarize current progress on ubiquitination (Ub) and the ubiquitin ligases that regulate TGF-β–Smad signaling. a post-translational modification in which the ubiquitin-like protein NEDD8 is attached to a substrate via an isopeptide bond. a group of structurally related signal transducers and transcription factors that are immediately downstream of the TGF-β receptor superfamily. Smad ubiquitin regulatory factors 1 and 2 (Smurf1/2) are members of the NEDD4 subfamily of HECT domain-containing E3 ubiquitin ligases. They promote proteasome-mediated degradation of components of the TGF-β/BMP signaling. a post-translational modification in which one or more small ubiquitin-like modifier (SUMO) molecules are added to a substrate via isopeptide bonds. a multifunctional growth factor secreted by most cell types. It can exert its functions in autocrine and paracrine manners. a polypeptide of 76 amino acids that can be attached to other proteins via isopeptide bonds. a post-translational modification in which one or more ubiquitin moieties are conjugated to a substrate, thereby regulating the localization, activity, or stability of the substrate.