Regulation of TGF-beta signaling by Smad7

Abstract

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.

Fig. 1

The Transforming growth factor (TGF)-β signaling pathway  Once activated, TGF-β brings together two types of serine/threonine kinase receptors and propagates the signal through R-Smads phosphorylation, R-Smads/Co-Smad complex formation, and nuclear translocation, thus regulating the transcription of target genes, among which Smad7 is. Besides the canonical Smad pathway, TGF-β can also activate MAPK signaling, in which Smad7 may act as a scaffold protein. In addition, TGF-β may also activate PI3K, PP2A, Par6 as well as Rho GTPases independent of Smad signaling.

Fig. 2

I-Smads mediate the crosstalk of the TGF-β signaling pathway with other pathways  I-Smads could be transcriptionally induced by TGF-β/BMPs signaling and inhibit their signaling by negative feedback loops. Besides, they could also be induced by many other cytokines or stimuli, such as TNF-α/IL1, INF-γ, EGF, laminar shear stress, UV, TPA, etc. Smad7 has been reported to enhance the transcription of IκB, which is a key inhibitor of NF-κB signaling pathway. It may also disrupt the TRAF–TAK1–TAB2/3 complex, thus inhibiting NF-κB signaling. In addition, Smad7 was reported to down-regulate the protein level of β-catenin by recruitment of E3 ligase Smurf1. Smad7 itself could be degraded both in the nucleus and in the cytoplasm in proteasomal pathway.