Protein Acetylation – A Multifunctional Regulator of TGF-? Signaling

Abstract: Transforming growth factor ? (TGF-?) is a member of a large family of cytokines that regulate many crucial events in cells, including proliferation, differentiation, migration and apoptosis. Deregulated TGF-? signaling is associated with various forms of cancers and developmental disorders. TGF-? binds to a receptor complex at the surface of cells and activates a signaling cascade involving specific intracellular signaling proteins, known as Smads. Following receptor activation, the Smads are activated by phosphorylation and translocate to the nucleus, where they activate or repress the expression of specific genes.Posttranslational modifications regulate the function of proteins in a number of ways, including their activity, stability, localization, and/or interactions with other proteins. These modifications are important to modulate the strength and specificity of cellular signal transduction. Smad7, an important negative modulator of TGF-? signaling, has been shown to be acetylated by the acetyltransferase p300. My aim was to further explore the involvement of protein acetylation in TGF-?-dependent signaling.We could show that the acetylation of Smad7 is a reversible process. Interestingly, earlier work had shown that the acetylation of Smad7 prevented its degradation. In agreement with this observation, we found that the ubiquitylation and degradation of Smad7 was increased following cotransfection with HDAC1, a protein deacetylase. Based on our observations, we propose a model in which the stability of Smad7 is controlled by the balance between its acetylation, deacetylation and ubiquitylation. In a separate study, we found that also Smad2 and Smad3 are acetylated by p300/CBP and P/CAF upon TGF-? stimulation. Moreover, we found that the acetylation of the short isoform of Smad2 promoted its DNA binding activity, resulting in an increased transcriptional activity. Our results suggest that the increased DNA binding in response to acetylation is due to a conformational change in Smad2.