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TAZ controls Smad nucleocytoplasmic shuttling and regulates human embryonic stem-cell self-renewal

Nature Cell Biology volume 10, pages 837–848 (2008)Cite this article

Abstract

Transforming growth fazctor-β (TGFβ) family members regulate many developmental and pathological events through Smad transcriptional modulators. How nuclear accumulation of Smad is coupled to the transcriptional machinery is poorly understood. Here we demonstrate that in response to TGFβ stimulation the transcriptional regulator TAZ binds heteromeric Smad2/3–4 complexes and is recruited to TGFβ response elements. In human embryonic stem cells TAZ is required to maintain self-renewal markers and loss of TAZ leads to inhibition of TGFβ signalling and differentiation into a neuroectoderm lineage. In the absence of TAZ, Smad2/3–4 complexes fail to accumulate in the nucleus and activate transcription. Furthermore, TAZ, which itself engages in shuttling, dominantly controls Smad nucleocytoplasmic localization and can be retained in the nucleus by transcriptional co-factors such as ARC105, a component of the Mediator complex. TAZ thus defines a hierarchical system regulating Smad nuclear accumulation and coupling to the transcriptional machinery.

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Figure 1: TAZ interacts with Smad2/3–Smad4 heteromeric complexes.
Figure 2: TAZ is required for TGFβ-mediated transcription.
Figure 3: TAZ is required to maintain hESC pluripotency.
Figure 4: TAZ is required for TGFβ-dependent Smad nuclear accumulation.
Figure 5: The TAZ coiled-coil domain mediates Smad binding.
Figure 6: TAZ functions dominantly to control Smad activity.
Figure 7: TAZ and ARC105 form a complex to mediate the TGFβ-dependent nuclear localization of Smads.
Figure 8: A model for the function of TAZ in Smad signalling.

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Acknowledgements

We would like to thank L. Attisano and R. Bremner for critical review and helpful discussions, A. Nagy for the CA1 hES cells and M. Barrios-Rodiles for expertise with LUMIER. This work was supported by funds from Genome Canada through the Ontario Genomics Institute and the Canadian Institutes of Health Research (J.W.L., CIHR Grant number MT 12860; P.W.Z., CIHR Grant number MOP-57885) and the National Cancer Institute of Canada with funds from the Canadian Cancer Society. X.V. is supported by a National Cancer Institute of Canada fellowship. J.L.W. is a CRC Chair and an International Scholar of the Howard Hughes Medical Institute.

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Author notes

  1. Joanna Dembowy & Michael B. Yaffe

    Present address: Departments of Biology and Biological Engineering, Center for Cancer Research, Massachusetts Institute of Technology, 77 Massachusetts Avenue, E18-580, Cambridge, 02139, Massachusetts, USA

  2. Balaji M. Rao

    Present address: Current address: Department of Chemical and Biomolecular Engineering, North Carolina State University, 911 Partners Way, Engineering Building 1, Raleigh, NC 27695-7905, USA.,

Authors and Affiliations

  1. Program in Molecular Biology and Cancer, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, M5G 1X5, Ontario, Canada

    Xaralabos Varelas, Rui Sakuma & Jeffrey L. Wrana

  2. Department of Molecular Genetics and Microbiology, University of Toronto, Toronto, M5S 1A8, Ontario, Canada

    Payman Samavarchi-Tehrani, Joanna Dembowy & Jeffrey L. Wrana

  3. Institute of Biomaterials and Biomedical Engineering, University of Toronto, 160 College Street, 11th Floor, Toronto, M5S 3E1, Ontario, Canada

    Raheem Peerani, Balaji M. Rao & Peter W. Zandstra

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Contributions

X.V. and J.L.W. designed and wrote the paper; X.V carried out most of the experiments; R.S. performed the mESC experiments; R.P. and B.M.R. performed the hESC knockdown experiments and cellomics analysis in P.W.Z.'s lab; P.S.T. carried out the knockdown experiments in NIH3T3 cells and helped with other experiments; J.D. carried out the initial follow-up to the LUMIER screen; M.B.Y. and P.W.Z. contributed reagents and discussion.

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Correspondence to Jeffrey L. Wrana.

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Supplementary Figures S1, S2, S3, S4, S5, S6 and Supplementary Table 1 (PDF 2301 kb)

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Varelas, X., Sakuma, R., Samavarchi-Tehrani, P. et al. TAZ controls Smad nucleocytoplasmic shuttling and regulates human embryonic stem-cell self-renewal. Nat Cell Biol 10, 837–848 (2008). https://doi.org/10.1038/ncb1748

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