Abstract

Transforming growth fazctor- (TGF) 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 TGF stimulation the transcriptional regulator TAZ binds heteromeric Smad2/3–4 complexes and is recruited to TGF response elements. In human embryonic stem cells TAZ is required to maintain self-renewal markers and loss of TAZ leads to inhibition of TGF 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.

1. Program in Molecular Biology and Cancer, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, M5G 1X5, Canada.
2. Department of Molecular Genetics and Microbiology, University of Toronto, Toronto, Ontario, M5S 1A8, Canada.
3. Current address: Department of Medical Biophysics, University of Toronto, Toronto, Ontario, M5S 2M9, Canada.
4. Institute of Biomaterials and Biomedical Engineering, University of Toronto, 160 College Street, 11th Floor, Toronto, Ontario, M5S 3E1, Canada.
5. Center for Cancer Research, Departments of Biology and Biological Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, E18-580, Cambridge, Massachusetts, 02139, USA.
6. Current address: Department of Chemical and Biomolecular Engineering, North Carolina State University, 911 Partners Way, Engineering Building 1, Raleigh, NC 27695-7905, USA.

Correspondence to: Jeffrey L. Wrana^1,2 e-mail: wrana@mshri.on.ca

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