Post-translational modifications such as ubiquitination, phosphorylation, and acetylation play important roles in the regulation of Smad-mediated functions. Here, we demonstrate that Smad4 is covalently modified by SUMO-1, which was characterized recently as a key modulator of many transcription factors. Sumoylation of Smad4 mainly occurs at lysine 159, located in the linker region, and facilitates Smad-dependent transcriptional activation. Furthermore, we show that the PIAS family proteins, PIAS1 and PIASx beta, function as E3 ligase factors for Smad4. Intriguingly, sumoylation of Smad4 was strongly enhanced by TGF-beta-induced activation of the p38 MAP kinase pathway but not the Smad pathway. Activation of p38 not only stabilized PIASx beta protein but also enhanced PIASx beta gene expression, suggesting that PIAS-mediated sumoylation of Smad4 is regulated by the p38 MAP kinase pathway. These findings illustrate a novel regulatory mechanism by which Smad-dependent transcriptional activation cooperatively modulates Smad proteins through receptor-mediated phosphorylation and sumoylation.
SciCrunch is a data sharing and display platform. Anyone can create a custom portal where they can select searchable subsets of hundreds of data sources, brand their web pages and create their community. SciCrunch will push data updates automatically to all portals on a weekly basis. User communities can also add their own data to scicrunch, however this is not currently a free service.