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.
Grönroos
Eva
E
Ludwig Institute for Cancer Research, Box 595, Husargatan 3, S-751 24 Uppsala, Sweden.
Hellman
Ulf
U
Heldin
Carl-Henrik
CH
Ericsson
Johan
J
D000107:Acetylation; D030201:Activin Receptors, Type I / Q000235:genetics / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008025:Ligases / Q000378:metabolism; D008239:Lysine / Q000378:metabolism*; D008969:Molecular Sequence Data; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D051906:Smad7 Protein; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases
D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D016271:Proto-Oncogene Proteins c-myc; D018125:Receptors, Transforming Growth Factor beta; D011993:Recombinant Fusion Proteins; C497806:SMAD7 protein, human; D051906:Smad7 Protein; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D025801:Ubiquitin; C471641:SMURF2 protein, human; D044767:Ubiquitin-Protein Ligases; D017346:Protein Serine-Threonine Kinases; D030201:Activin Receptors, Type I; D000077293:Receptor, Transforming Growth Factor-beta Type I; D008025:Ligases; D008239:Lysine