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PMID:18568018

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Citation

Varelas, X, Sakuma, R, Samavarchi-Tehrani, P, Peerani, R, Rao, BM, Dembowy, J, Yaffe, MB, Zandstra, PW and Wrana, JL (2008) TAZ controls Smad nucleocytoplasmic shuttling and regulates human embryonic stem-cell self-renewal. Nat. Cell Biol. 10:837-48

Abstract

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

Links

PubMed Online version:10.1038/ncb1748

Keywords

Active Transport, Cell Nucleus/physiology; Animals; Cell Line; Cell Nucleus/metabolism; Embryonic Stem Cells/cytology; Embryonic Stem Cells/physiology; Genes, Reporter; Humans; Mediator Complex; RNA, Small Interfering/genetics; RNA, Small Interfering/metabolism; Signal Transduction/physiology; Smad2 Protein/genetics; Smad2 Protein/metabolism; Smad3 Protein/genetics; Smad3 Protein/metabolism; Smad4 Protein/genetics; Smad4 Protein/metabolism; Transcription Factors/genetics; Transcription Factors/metabolism; Transcription, Genetic; Transforming Growth Factor beta/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:SMAD3

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q9GZV5

F

Seeded From UniProt

complete

HUMAN:SMAD4

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q9GZV5

F

Seeded From UniProt

complete

HUMAN:SMAD2

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q9GZV5

F

Seeded From UniProt

complete

HUMAN:MED15

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q9GZV5

F

Seeded From UniProt

complete

HUMAN:WWTR1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q96RN5

F

Seeded From UniProt

complete

HUMAN:WWTR1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q13485

F

Seeded From UniProt

complete

HUMAN:WWTR1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P84022

F

Seeded From UniProt

complete

HUMAN:WWTR1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q15796

F

Seeded From UniProt

complete

HUMAN:WWTR1

involved_in

GO:0017145: stem cell division

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:WWTR1

located_in

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:WWTR1

involved_in

GO:0060390: regulation of SMAD protein signal transduction

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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