Transcriptional cofactors Ski and SnoN are major regulators of the TGF-β/Smad signaling pathway in health and disease

Abstract

The transforming growth factor-β (TGF-β) family plays major pleiotropic roles by regulating many physiological processes in development and tissue homeostasis. The TGF-β signaling pathway outcome relies on the control of the spatial and temporal expression of >500 genes, which depend on the functions of the Smad protein along with those of diverse modulators of this signaling pathway, such as transcriptional factors and cofactors. Ski (Sloan-Kettering Institute) and SnoN (Ski novel) are Smad-interacting proteins that negatively regulate the TGF-β signaling pathway by disrupting the formation of R-Smad/Smad4 complexes, as well as by inhibiting Smad association with the p300/CBP coactivators. The Ski and SnoN transcriptional cofactors recruit diverse corepressors and histone deacetylases to repress gene transcription. The TGF-β/Smad pathway and coregulators Ski and SnoN clearly regulate each other through several positive and negative feedback mechanisms. Thus, these cross-regulatory processes finely modify the TGF-β signaling outcome as they control the magnitude and duration of the TGF-β signals. As a result, any alteration in these regulatory mechanisms may lead to disease development. Therefore, the design of targeted therapies to exert tight control of the levels of negative modulators of the TGF-β pathway, such as Ski and SnoN, is critical to restore cell homeostasis under the specific pathological conditions in which these cofactors are deregulated, such as fibrosis and cancer.

Fig. 1

Regulation of the TGF-β/Smad signaling pathway by Ski and SnoN. In the absence of TGF-β, the Ski and SnoN proteins interact with Smad4 to inhibit the expression of TGF-β target genes, such as Smad7 and Skil, by recruiting other corepressors and HDACs to their promoters. Then, TGF-β induces the phosphorylation of Smad2/3 proteins to form the R-Smad/Smad4 complex, which associates with specific transcription factors and cofactors to modulate the expression of its target genes

Fig. 2

Regulation of Ski and SnoN expression by different mechanisms. Several signaling pathways and factors induce Ski and Skil gene expression; whereas, the TGF-β signaling pathway enhances or inhibits Skil gene expression via Smad2/4 or Smad3/4, respectively. Moreover, some miRNAs control the mRNA levels of these genes. The Ski and SnoN protein levels are also regulated by different signals

Fig. 3

Regulatory regions of human and mouse Skil genes. The Skil gene promoter includes two TGF-β-responsive elements (TRE) containing several Smad binding elements (SBEs and SIE). The human Skil gene superenhancer region contains binding sites for Oct4, Sox2, and Nanog proteins. The mouse Skil gene promoter includes the SBEs and SIE, as well as a binding site for STAT5 that is controlled by prolactin. The positions of response elements and transcription start site (TSS) are indicated with respect to the ATG (+1)

Fig. 4

Molecular structure, posttranslational modifications, and protein–protein interactions of the Ski and SnoN proteins. a, b The domains that define the Ski and SnoN proteins include: Dachshund homology domain (DHD), SAND-like domain, and coiled-coil domain (CC). Both the Ski and SnoN proteins are regulated by PTMs, as catalyzed by several enzymes at specific residues that are indicated. Known regions of interaction with some partners for Ski and SnoN are indicated. c Several proteins are also partners for Ski and/or SnoN but the interacting domains are not identified. Kinases are shown in green, transcriptional coregulators in blue, transcription factors in red, and other proteins in black

Fig. 5

Regulation of Ski and SnoN protein stability by the TGF-β/Smad signaling pathway. TGF-β induces Ski and SnoN protein degradation by the ubiquitin-proteasome system (UPS) after 15–30 min of treatment because activated R-Smads are adapters for ubiquitin E3-ligases APC, Smurf2, and Arkadia

Fig. 6

Ski and SnoN functions in health and disease. The specific or common biological functions of Ski and SnoN are linked to some physiological (black text) or pathological processes (white text)