Novel Regulation of the Stability of Transcriptional Cofactors Ski and SnoN by GPCR Signals and Actin‐Cytoskeleton Dynamics

Abstract

TGF‐β signaling controls several cellular processes from growth arrest to apoptosis in epithelial cells. The transcriptional cofactors Ski and SnoN are main regulators of TGF‐β signaling by sequestering SMAD proteins or recruiting transcriptional repressor complexes at TGF‐β/SMADs target genes. TGF‐β signaling regulates the stability of Ski and SnoN proteins through the ubiquitin‐proteasome system. Even though the important role that Ski and SnoN proteins play in early development and homeostasis, cell cycle was the unique signal besides TGF‐β pathway that regulated their stability. Nevertheless, the mechanisms that regulate Ski and SnoN protein stability in diverse cellular processes remain unknown. In this study, we found out that the actin cytoskeleton dynamics is a novel regulator of Ski and SnoN protein stability in hepatocytes. Inhibitors of actin cytoskeleton dynamics and cell confluence status regulate Ski and SnoN protein levels. Actin polymerization is a signal for Ski protein degradation via proteasome. We also demonstrated that G protein‐coupled receptors (GPCR) signaling control Ski and SnoN protein levels through promoting and decreasing its stability by cAMP or Rho signals, respectively. In conclusion, we identified a new regulation for Ski and SnoN protein stability by changes in actin cytoskeleton rearrangements. These findings suggest that changes in Ski and SnoN protein stability could be controlled by this novel regulation in physiological and pathological events as a result of changes in actin cytoskeleton dynamics induced by cell contact, extracellular matrix remodeling and soluble ligands; thus, it will be important to evaluate TGF‐β/SMADs signaling in all these cellular contexts.Support or Funding InformationThis work is supported by grants from DGAPA/PAPIIT/UNAM (IN208115) and CONACYT (No. 240224).