Acetylation of Smad2 by the co-activator p300 regulates activin and transforming growth factor beta response.
Transforming growth factor beta (TGFbeta) signals primarily through the Smad proteins to regulate cell growth, differentiation, and extracellular matrix production. Post-translational modifications, such as phosphorylation, play an important role in the regulation of the Smad proteins. TGFbeta signaling results in the phosphorylation of Smad2 and Smad3 that then oligomerize with Smad4 and translocate into the nucleus to initiate transcription of TGFbeta target genes. The initiation of transcription is significantly enhanced by the direct interaction of the Smad complex with p300/CBP (CREB-binding protein), a co-activator with intrinsic acetyltransferase activity. However, how p300/CBP enhances transcription through this interaction is not entirely understood. In this report, we show that Smad2, but not the highly homologous Smad3, can be acetylated by p300/CBP in a ligand-dependent manner. At least three lysine residues, Lys(19), Lys(20), and Lys(39), are required for efficient acetylation of Smad2, as mutations altering these lysines abolished Smad2 acetylation in vivo. This acetylation event is required for the ability of Smad2 to mediate activin and TGFbeta signaling. Mutation of the three key lysine residues did not alter the stability of Smad2 or the ability of Smad2 to form a complex with Smad4 on promoter DNA, but it prevented nuclear accumulation of Smad2 and subsequent TGFbeta and activin responses. Thus, our studies reveal a novel mechanism of modulating Smad2 activity and localization through protein acetylation.
Tu
Andrea W
AW
Department of Molecular and Cell Biology, University of California, and Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA.
Luo
Kunxin
K
D028341:Activins / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D041681:NIH 3T3 Cells; D010766:Phosphorylation; D015398:Signal Transduction; D051899:Smad2 Protein / Q000378:metabolism / Q000502:physiology*; D051900:Smad3 Protein / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D050880:p300-CBP Transcription Factors / Q000378:metabolism
D051899:Smad2 Protein; D051900:Smad3 Protein; D016212:Transforming Growth Factor beta; D028341:Activins; D050880:p300-CBP Transcription Factors