Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

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

Nature volume 418, pages 641–646 (2002)Cite this article

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

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.

Similar content being viewed by others

References

  1. Massague, J. How cells read TGF-β signals. Nature Rev. Mol. Cell Biol. 1, 169–178 (2000)

    Article  CAS  Google Scholar 

  2. Whitman, M. Smads and early developmental signalling by the TGFβ superfamily. Genes Dev. 12, 2445–2462 (1998)

    Article  CAS  PubMed  Google Scholar 

  3. Näär, A. M. et al. Composite co-activator ARC mediates chromatin-directed transcriptional activation. Nature 398, 828–832 (1999)

    Article  ADS  PubMed  Google Scholar 

  4. Jiang, Y. W. et al. Mammalian mediator of transcriptional regulation and its possible role as an end-point of signal transduction pathways. Proc. Natl Acad. Sci. USA 95, 8538–8543 (1998)

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  5. Boyer, T. G., Martin, M. E. D., Lees, E., Ricciardi, R. P. & Berk, A. J. Mammalian Srb/Mediator complex is targeted by adenovirus E1A protein. Nature 399, 276–279 (1999)

    Article  ADS  CAS  PubMed  Google Scholar 

  6. Fondell, J. D., Ge, H. & Roeder, R. G. Ligand induction of a transcriptionally active thyroid hormone receptor coactivator complex. Proc. Natl Acad. Sci. USA 93, 8329–8333 (1996)

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  7. Rachez, C. et al. Ligand-dependent transcription activation by nuclear receptors requires the DRIP complex. Nature 398, 824–828 (1999)

    Article  ADS  CAS  PubMed  Google Scholar 

  8. Gu, W. et al. A novel human SRB/MED-containing cofactor complex, SMCC, involved in transcription regulation. Mol. Cell 3, 97–108 (1999)

    Article  CAS  PubMed  Google Scholar 

  9. Ryu, S., Zhou, S., Ladurner, A. G. & Tjian, R. The transcriptional cofactor complex CRSP is required for activity of the enhancer-binding protein Sp1. Nature 397, 446–450 (1999)

    Article  ADS  CAS  PubMed  Google Scholar 

  10. Malik, S., Gu, W., Wu, W., Qin, J. & Roeder, R. G. The USA-derived transcriptional coactivator PC2 is a submodule of TRAP/SMCC and acts synergistically with other PCs. Mol. Cell 5, 753–760 (2000)

    Article  CAS  PubMed  Google Scholar 

  11. Näär, A. M., Lemon, B. D. & Tjian, R. Transcriptional coactivator complexes. Annu. Rev. Biochem. 70, 475–501 (2001)

    Article  PubMed  Google Scholar 

  12. Rachez, C. & Freedman, L. P. Mediator complexes and transcription. Curr. Opin. Cell Biol. 13, 274–280 (2001)

    Article  CAS  PubMed  Google Scholar 

  13. Abraham, S. & Solomon, W. B. A novel glutamine-rich putative transcriptional adaptor protein (TIG-1) preferentially expressed in placental and bone-marrow tissues. Gene 255, 389–400 (2000)

    Article  CAS  PubMed  Google Scholar 

  14. Berti, L. et al. Isolation and characterization of a novel gene from the DiGeorge chromosomal region that encodes for a mediator subunit. Genomics 74, 320–332 (2001)

    Article  CAS  PubMed  Google Scholar 

  15. Harland, R. & Gerhart, J. Formation and function of Spemann's organizer. Annu. Rev. Cell Dev. Bio. 13, 611–667 (1997)

    Article  CAS  Google Scholar 

  16. Hemmati-Brivanlou, A. & Melton, D. A. A truncated activin receptor inhibits mesoderm induction and formation of axial structures in Xenopus embryos. Nature 359, 609–614 (1992)

    Article  ADS  CAS  PubMed  Google Scholar 

  17. Candia, A. F. et al. Cellular interpretation of multiple TGF-β signals: intracellular antagonism between activin/BVg1 and BMP-2/4 signalling mediated by Smads. Development 124, 4467–4480 (1997)

    CAS  PubMed  Google Scholar 

  18. Chen, X. et al. Smad4 and FAST-1 in the assembly of activin-responsive factor. Nature 389, 85–89 (1997)

    Article  ADS  CAS  PubMed  Google Scholar 

  19. Yeo, C-Y., Chen, X. & Whitman, M. The role of FAST-1 and Smads in transcriptional regulation by activin during early Xenopus embryogenesis. J. Biol. Chem. 274, 26584–26590 (1999)

    Article  CAS  PubMed  Google Scholar 

  20. Stroschein, S. L., Wang, W., Zhou, S., Zhou, Q. & Luo, K. Negative feedback regulation of TGF-β signalling by the SnoN oncoprotein. Science 286, 771–774 (1999)

    Article  CAS  PubMed  Google Scholar 

  21. Singh, N. & Han, M. sur-2, a novel gene, functions late in the let-60 ras-mediated signalling pathway during Caenorhabditis elegans vulval induction. Genes Dev. 9, 2251–2265 (1995)

    Article  CAS  PubMed  Google Scholar 

  22. Zhang, H. & Emmons, S. W. A C. elegans mediator protein confers regulatory selectivity on lineage-specific expression of a transcription factor gene. Genes Dev. 14, 2161–2172 (2000)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Boube, M., Faucher, C., Joulia, L., Cribbs, D. L. & Bourbon, H. M. Drosophila homologs of transcriptional mediator complex subunits are required for adult cell and segment identity specification. Genes Dev. 14, 2906–2917 (2000)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Treisman, J. E. Drosophila homologue of the transcriptional coactivation complex subunits TRAP240 and TRAP230 are required for identical processes in eye-antennal disc development. Development 128, 603–615 (2001)

    CAS  PubMed  Google Scholar 

  25. Shimizu, K., Bourillot, P.-V., Nielsen, S. J., Zorn, A. M. & Gurdon, J. B. Swift is a novel BRCT domain coactivator of Smad2 in transforming growth factor β signalling. Mol. Cell Biol. 21, 3901–3912 (2001)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Bai, R.-Y. et al. SMIF, a Smad4-interacting protein that functions as a co-activator in TGFβ signalling. Nature Cell Biol. 4, 181–190 (2002)

    Article  CAS  PubMed  Google Scholar 

  27. Hsu, D. R. et al. The Xenopus dorsalizing factor Gremlin identifies a novel family of secreted proteins that antagonize BMP activities. Mol. Cell 1, 673–683 (1998)

    Article  CAS  PubMed  Google Scholar 

  28. Kato, Y., Shi, Y. & He, X. Neuralization of the Xenopus embryo by inhibition of p300/CREB-binding protein function. J. Neurosci. 19, 9364–9373 (1999)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Elbashir, S. M. et al. Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells. Nature 411, 494–498 (2001)

    Article  ADS  CAS  PubMed  Google Scholar 

  30. Sachs, L. M. & Shi, Y-B. Target chromatin binding and histone acetylation in vivo by thyroid hormone receptor during amphibian development. Proc. Natl Acad. Sci. USA 24, 13138–13143 (2000)

    Article  ADS  Google Scholar 

Download references

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.

Author information

Author notes

  1. Raymond Habas

    Present address: Laboratory of Molecular Genetics, The National Institute of Child Health and Human Development, NIH, Bethesda, Maryland, 20892, USA

  2. Yu Katsuyama

    Present address: Department of Developmental and Cell Biology, University of California, Irvine, California, 92697, USA

Authors and Affiliations

  1. Division of Neuroscience, Children's Hospital, Department of Neurology, Harvard Medical School, Boston, Massachusetts, 02115, USA

    Yoichi Kato, Raymond Habas, Yu Katsuyama & Xi He

  2. Department of Cell Biology, Harvard Medical School, Massachusetts General Hospital Cancer Center, Charlestown, Massachusetts, 02129, USA

    Anders M. Näär

Authors
  1. Yoichi Kato
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Raymond Habas
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yu Katsuyama
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Anders M. Näär
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Xi He
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Xi He.

Ethics declarations

Competing interests

The authors declare that they have no competing financial interests.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature00969

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing