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

Yoichi Kato, Raymond Habas, Yu Katsuyama, Anders M. Näär and Xi He ()
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Yoichi Kato: Children's Hospital, Department of Neurology, Harvard Medical School
Raymond Habas: Children's Hospital, Department of Neurology, Harvard Medical School
Yu Katsuyama: Children's Hospital, Department of Neurology, Harvard Medical School
Anders M. Näär: Harvard Medical School, Massachusetts General Hospital Cancer Center
Xi He: Children's Hospital, Department of Neurology, Harvard Medical School

Nature, 2002, vol. 418, issue 6898, 641-646

Abstract: Abstract The transforming growth factor β (TGFβ) family of cytokines, including Nodal, Activin and bone morphogenetic protein (BMP), have essential roles in development and tumorigenesis1,2. TGFβ molecules activate the Smad family of signal transducers, which form complexes with specific DNA-binding proteins to regulate gene expression1,2. Two discrete Smad-dependent signalling pathways have been identified: TGFβ, Activin and Nodal signal via the Smad2 (or Smad3)–Smad4 complex, whereas BMP signals via the Smad1–Smad4 complex1,2. 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 TGFβ/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 TGFβ response in human cells. Depletion of ARC105 inhibits TGFβ/Activin/Nodal/Smad2/3 signalling and Xenopus axis formation, but not BMP/Smad1 signalling. ARC105 protein binds to Smad2/3–Smad4 in response to TGFβ 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 TGFβ/Activin/Nodal/Smad2/3 signalling to transcriptional activation.

Date: 2002
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DOI: 10.1038/nature00969

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