Control of Smad7 stability by competition between acetylation and ubiquitination

• Smad proteins regulate gene expression in response to TGFbeta signaling. Here we present evidence that Smad7 interacts with the transcriptional coactivator p300, resulting in acetylation of Smad7 on two lysine residues in its N terminus. Acetylation or mutation of these lysine residues stabilizes Smad7 and protects it from TGFbeta-induced degradation. Furthermore, we demonstrate that the acetylated residues in Smad7 also are targeted by ubiquitination and that acetylation of these lysine residues prevents subsequent ubiquitination. Specifically, acetylation of Smad7 protects it against ubiquitination and degradation mediated by the ubiquitin ligase Smurf1. Thus, our data suggest that competition between ubiquitination and acetylation of overlapping lysine residues constitutes a novel mechanism to regulate protein stability.

Keyword

Acetylation

Activin Receptors; Type I/genetics/metabolism

Amino Acid Sequence

Animals

Cell Line

DNA-Binding Proteins/genetics/*metabolism

Humans

Ligases/metabolism

Lysine/*metabolism

Molecular Sequence Data

Mutation

Nuclear Proteins/genetics/*metabolism

Protein Binding

Proto-Oncogene Proteins c-myc/genetics/metabolism

Receptors; Transforming Growth Factor beta/genetics/metabolism

Recombinant Fusion Proteins/genetics/metabolism

Signal Transduction/physiology

Smad7 Protein

Trans-Activators/genetics/*metabolism

Transforming Growth Factor beta/*metabolism

Ubiquitin/*metabolism

Ubiquitin-Protein Ligases

Publication and Content Type

ref (subject category)

art (subject category)