TGF-β/Smad Signaling

The TGF-β/Smad signaling pathway regulates many cellular processes including differentiation, growth, apoptosis and the death of cells. TGF-β, which is a ligand of the TGF-β receptors, not only inhibits proliferation, but also promotes cell migration. ^[1]The TGF-β superfamily includes nearly 30 proteins in mammals, e.g. TGF-βs, activins and inhibins, nodal, myostatin, BMPs, GDFs and AMH.^[2] After the production of bioactive TGF-β superfamily members, their activity can be modulated by several extracellular proteins including decorin, biglycan, noggin and xnr3. TGF-β receptor consists of two types of receptors: type I TGF-β receptor and type II TGF-β receptor. When TGF-β binds to a TGF-β receptor on the surface of the cell, the Smad protein is activated. Signals are transduced from the extracellular to the intracellular compartment of the cell. Smads are intracellular proteins that transduce extracellular signals to the nucleus, and activating downstream molecules. Smads exist ubiquitously throughout development in all adult tissues and are degraded by proteasomes.^[3] They consist of two groups of proteins: receptor-regulated Smads and a common-mediator Smad (also called R-Smads and co-Smad, respectively). R-Smads include Smad1, Smad2, Smad3, Smad5 and Smad8/9 while co-Smad includes only Smad4. TGF-β/Smad signaling maintains tissue homeostasis, but its disregulation leads to disease. The TGF-β/Smad signaling pathway is a crucial target for treating diseases. For example, various inhibitors, such as Ponatinib, Y-27632 and SB 431542, have been developed for the treatment of cancer.

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