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

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.

A role for the transducer of the Hippo pathway, TAZ, in the development of aggressive types of endometrial cancer

“…For instance, it has been demonstrated that TAZ is implicated in promoting migration and invasion in breast cancer cell models, 15 and it has also been shown that TAZ knockdown provokes defects in the maintenance of pluripotency in embryonic stem cells. 34 Hence, it would appear that TAZ is a potent activator of cell transformation and tumorigenesis. 35,36 On the basis of this evidence, and given the importance of epithelial to mesenchymal transition and stemness in the carcinogenesis of certain subtypes of endometrial tumors, 3,4 we analyzed TAZ expression in a series of 143 endometrial carcinoma samples.…”

The Hippo pathway regulates stem cell proliferation, self-renewal, and differentiation

“…Chromatin immunoprecipitation (ChIP) experiments demonstrated that YAP-TEAD bind to promoters of many stemnesspromoting genes such as Oct4 (Lian et al, 2010;Tamm et al, 2011). Intriguingly, knockdown of TAZ in human ESCs also led to differentiation and loss of pluripotency, although YAP was intact (Varelas et al, 2008). Such a difference in TAZ and YAP requirement by human and mouse ESCs might be explained by the differential requirement of TGFbeta or bone morphogenetic protein (BMP) signaling by human and mouse ESCs respectively.…”

“…Such a difference in TAZ and YAP requirement by human and mouse ESCs might be explained by the differential requirement of TGFbeta or bone morphogenetic protein (BMP) signaling by human and mouse ESCs respectively. TAZ was shown to promote Smad2/3 nuclear localization in response to TGFbeta signaling and YAP was demonstrated to support Smad1-dependent transcription under BMP signaling (Varelas et al, 2008;Alarcón et al, 2009). However, the mechanism responsible for specificity of YAP and TAZ in BMP and TGFbeta signaling is not known.…”

Hippo Pathway Effectors Control Cardiac Progenitor Cell Fate by Acting as Dynamic Sensors of Substrate Mechanics and Nanostructure

“…3,4 YAP/TAZ axis has also emerged as a central regulator of human embryonic stem cell self-renewal through the control of SMAD complex shuttling to the nucleus, with TAZ knock-down resulting in the loss of cell pluripotency. 5 The same cofactors control intestinal 6 and neural progenitor cell number and differentiation 7 by targeting We identify a novel activity of YAP and TAZ in the regulation of tubulogenesis in 3D environments and highlight a role for YAP/TAZ in cardiac progenitor proliferation and differentiation. Furthermore, we show that YAP/TAZ expression is triggered in the heart cells located at the infarct border zone.…”

“…3,4 YAP/TAZ axis has also emerged as a central regulator of human embryonic stem cell self-renewal through the control of SMAD complex shuttling to the nucleus, with TAZ knock-down resulting in the loss of cell pluripotency. 5 The same cofactors control intestinal 6 and neural progenitor cell number and differentiation 7 by targeting B the Notch signaling. YAP activity has also been proven fundamental in controlling epidermal stem cell homeostasis.…”