A component of the ARC/mediator complex required for TGFβ/Nodal signalling

The transforming growth factor beta (TGFbeta) family of cytokines, including Nodal, Activin and bone morphogenetic protein (BMP), have essential roles in development and tumorigenesis(1,2). TGFbeta molecules activate the Smad family of signal transducers, which form complexes with specific DNA-binding proteins to regulate gene expression(1,2). Two discrete Smad-dependent signalling pathways have been identified: TGFbeta, Activin and Nodal signal via the Smad2 (or Smad3)-Smad4 complex, whereas BMP signals via the Smad1-Smad4 complex(1,2). How distinct Smad complexes regulate specific gene expression is not fully understood. Here we show that ARC105, a component of the activator-recruited co-factor (ARC)(3) complex or the metazoan Mediator complex, is essential for TGFbeta/Activin/Nodal/Smad2/3 signal transduction. Expression of ARC105 stimulates Activin/Nodal/Smad2 signalling in Xenopus laevis embryos, inducing axis duplication and mesendoderm differentiation, and enhances TGFbeta response in human cells. Depletion of ARC105 inhibits TGFbeta/Activin/Nodal/Smad2/3 signalling and Xenopus axis formation, but not BMP/Smad1 signalling. ARC105 protein binds to Smad2/3-Smad4 in response to TGFbeta and is recruited to Activin/Nodal-responsive promoters in chromatin in a Smad2-dependent fashion. Thus ARC105 is a specific and key ARC/Mediator component linking TGFbeta/Activin/Nodal/Smad2/3 signalling to transcriptional activation.