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.
Highlights
The transforming growth factor-beta (TGF-β) superfamily comprises a large group of related growth factors, such as transforming growth factor-β (TGF-β), activins, inhibins, bone morphogenetic proteins (BMPs), myostatin, nodal, lefty, anti-Müllerian hormone/Müllerian inhibiting substance (AMH/MIS), and growth and differentiation factors (GDFs).[1]
Receptor-regulated Smads (R-Smad) have an SSXS motif in their C-terminal region that is phosphorylated by type I receptors; R-Smad phosphorylation (p-R-Smad) allows their association with Smad4.11–18 After translocation of the p-R-Smad/ Smad[4] heterotrimeric complex into the nucleus, Smads associate with other transcriptional factors and coregulators to regulate the expression of specific target genes
The Ski protein has been localized in multivesicular with Ski and SnoN and endosomes (MVE); recently, we reported that cytoplasmic Ski is catalyzes their polyubiquitination in a manner dependent on the recruitment of activated Smad2/Smad3.144–146,148 Recently, it was present in lipid raft-rich endosomes of normal hepatocytes and co-localizes with markers of multivesicular bodies, such as shown that Smurf[2] induces Smad[4] monoubiquitination to inhibit CD63 and Alix
Summary
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. The TGF-β/Smad pathway and coregulators Ski and SnoN clearly regulate each other through several positive and negative feedback mechanisms. These cross-regulatory processes finely modify the TGF-β signaling outcome as they control the magnitude and duration of the TGF-β signals. 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.
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