Journal of Biological Chemistry
Volume 281, Issue 52, 29 December 2006, Pages 39870-39880
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Genes: Structure and Regulation
The DNA Binding Activities of Smad2 and Smad3 Are Regulated by Coactivator-mediated Acetylation*

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Phosphorylation-dependent activation of the transcription factors Smad2 and Smad3 plays an important role in TGFβ-dependent signal transduction. Following phosphorylation of Smad2 and Smad3, these molecules are translocated to the nucleus where they interact with coactivators and/or corepressors, including p300, CBP, and P/CAF, and regulate the expression of TGFβ target genes. In the current study, we demonstrate that both Smad2 and Smad3 are acetylated by the coactivators p300 and CBP in a TGFβ-dependent manner. Smad2 is also acetylated by P/CAF. The acetylation of Smad2 was significantly higher than that of Smad3. Lys19 in the MH1 domain was identified as the major acetylated residue in both the long and short isoform of Smad2. Mutation of Lys19 also reduced the p300-mediated acetylation of Smad3. By generating acetyl-Lys19-specific antibodies, we demonstrate that endogenous Smad2 is acetylated on this residue in response to TGFβ signaling. Acetylation of the short isoform of Smad2 improves its DNA binding activity in vitro and enhances its association with target promoters in vivo, thereby augmenting its transcriptional activity. Acetylation of Lys19 also enhanced the DNA binding activity of Smad3. Our data indicate that acetylation of Lys19 induces a conformational change in the MH1 domain of the short isoform of Smad2, thereby making its DNA binding domain accessible for interactions with DNA. Thus, coactivator-mediated acetylation of receptor-activated Smad molecules could represent a novel way to regulate TGFβ signaling.

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*

This work was supported in part by grants from the Swedish Research Council, the Swedish Cancer Foundation, and the Ludwig Institute for Cancer Research (to J. E.), and the Swedish Cancer Foundation (to E. G.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement”in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1–S3.

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These authors contributed equally to this work and should be considered jointly as first author.