Transforming growth factor (TGF)-beta is a pleiotropic cytokine regulating a 
variety of cellular processes such as cell growth, differentiation, apoptosis, 
migration, cell adhesion, and immune response. In the well-understood classical 
TGF-beta signaling pathway, TGF-beta activates Smad signalling via its two cell 
surface receptors such as TbetaRII and ALK5/TbetaRI, leading to Smad-mediated 
transcriptional regulation. In addition, TGF-beta may also activate other 
signaling pathways like mitogen-activated protein kinase, PI3K, etc. The 
signaling of TGF-beta is finely regulated at different levels. Inhibitory Smads, 
including Smad6 and Smad7, are key regulators of TGF-beta/bone morphogenetic 
protein (BMP) signaling by negative feedback loops. They can form stable 
complexes with activated type I receptors and thereby blocking the 
phosphorylation of R-Smads, or recruit ubiquitin E3 ligases, such as Smurf1/2, 
resulting in the ubiquitination and degradation of the activated type I 
receptors. Besides, these inhibitory Smad proteins also inhibit TGF-beta/BMP 
signaling in the nucleus by interacting with transcriptional repressors, such as 
histone deacetylases, Hoxc-8, and CtBP, or disrupting the formation of the 
TGF-beta-induced functional Smad-DNA complexes. Smad7 is in turn regulated by 
different stimuli, including TGF-beta, IFN-gamma, TNF-alpha as well as 
ultraviolet and TPA, and mediates the crosstalk between TGF-beta and other 
signaling pathways. Deregulation of Smad7 expression has been associated with 
various human diseases, such as tissue fibrosis, inflammatory disease as well as 
carcinogenesis. Overexpression of Smad7 has been shown to antagonize 
TGF-beta-mediated fibrosis, carcinogenesis, and inflammation, suggesting a 
therapeutic potential of Smad7 to treat these diseases.