A component of the ARC/Mediator complex required for TGF beta/Nodal signalling.
The transforming growth factor beta (TGF beta) family of cytokines, including Nodal, Activin and bone morphogenetic protein (BMP), have essential roles in development and tumorigenesis. TGF beta molecules activate the Smad family of signal transducers, which form complexes with specific DNA-binding proteins to regulate gene expression. Two discrete Smad-dependent signalling pathways have been identified: TGF beta, Activin and Nodal signal via the Smad2 (or Smad3)-Smad4 complex, whereas BMP signals via the Smad1-Smad4 complex. 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) complex or the metazoan Mediator complex, is essential for TGF beta/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 TGF beta response in human cells. Depletion of ARC105 inhibits TGF beta/Activin/Nodal/Smad2/3 signalling and Xenopus axis formation, but not BMP/Smad1 signalling. ARC105 protein binds to Smad2/3-Smad4 in response to TGF beta 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 TGF beta/Activin/Nodal/Smad2/3 signalling to transcriptional activation.
Kato
Yoichi
Y
Division of Neuroscience, Children's Hospital, Department of Neurology, Harvard Medical School, Boston, Massachusetts 02115, USA.
Habas
Raymond
R
Katsuyama
Yu
Y
Näär
Anders M
AM
He
Xi
X
D028341:Activins / Q000378:metabolism; D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D046911:Macromolecular Substances; D008648:Mesoderm / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009414:Nerve Growth Factors; D055457:Nodal Protein; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D051785:Smad Proteins; D051899:Smad2 Protein; D051900:Smad3 Protein; D051901:Smad4 Protein; D015534:Trans-Activators / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism* / Q000494:pharmacology*; D029867:Xenopus Proteins / Q000737:chemistry* / Q000378:metabolism*; D014982:Xenopus laevis / Q000196:embryology* / Q000235:genetics / Q000378:metabolism*
D019485:Bone Morphogenetic Proteins; D004268:DNA-Binding Proteins; C464923:MED15 protein, Xenopus; D046911:Macromolecular Substances; C526007:NODAL protein, human; D009414:Nerve Growth Factors; D055457:Nodal Protein; D012333:RNA, Messenger; C497782:SMAD2 protein, human; C497790:SMAD3 protein, human; C497796:SMAD4 protein, human; D051785:Smad Proteins; D051899:Smad2 Protein; C497785:Smad2 protein, Xenopus; D051900:Smad3 Protein; D051901:Smad4 Protein; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D029867:Xenopus Proteins; C497789:madh3 protein, Xenopus; C490808:smad4.1 protein, Xenopus; C117263:smad4.2 protein, Xenopus; D028341:Activins