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

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.

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Figure 1: XARC105 induces axis duplication, morphogenetic elongation and mesendoderm formation.
Figure 2: XARC105 is required for Nodal/Activin/Smad2 signalling.
Figure 3: ARC105 is required for TGFβ/Activin but not BMP signalling in 293T cells.
Figure 4: ARC105 protein associates with Smad2/3 and Smad4 in response to TGFβ in 293T cells (western blots).
Figure 5: Association between endogenous ARC/Mediator and Smad2/3-Smad4 complex and recruitment of ARC105 to chromatin via Smad2.

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Acknowledgements

We apologize for our inability to cite many original papers owing to space constraints. We thank Z. Chang, K. Cho, E. DeRobertis, R. Harland, A. Hata, A. Hemmati-Brivanlou, D. Kessler, K. Luo, J. Massague, J.-P. Saint-Jeannet, Y. Shi, W. Solomon, G. Thomson, T. Wang, M. Whitman, Y. Zhang and Y. Etoh for reagents; P. Dikkes for help; Y. Sun and M. Greenberg for comments; and K. Luo, Y. Shi, T. Wang, X. Wang and members of the He lab for discussion. This work is supported by postdoctoral fellowships from the Uehara Memorial Foundation (Japan) and Charles A. King Trust and the Medical Foundation to Y.K., from US Department of Defense (DOD) to R.H. A.M.N. is supported by the Bertucci Foundation. X.H. is supported by grants from the Rockefeller Brothers Fund, DOD and NIH, and is a Pew Scholar, Klingenstein Fellow, and Keck Foundation Distinguished Young Scholar.

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Kato, Y., Habas, R., Katsuyama, Y. et al. A component of the ARC/Mediator complex required for TGFβ/Nodal signalling. Nature 418, 641–646 (2002). https://doi.org/10.1038/nature00969

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