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Journal Article•DOI•

Role of YAP/TAZ in mechanotransduction

Sirio Dupont1, Leonardo Morsut1, Mariaceleste Aragona1, Elena Enzo1, Stefano Giulitti1, Michelangelo Cordenonsi1, Francesca Zanconato1, Jimmy Le Digabel2, Mattia Forcato3, Silvio Bicciato3, Nicola Elvassore1, Stefano Piccolo1 •
University of Padua1, Paris Diderot University2, University of Modena and Reggio Emilia3
09 Jun 2011-Nature (Nature Research)-Vol. 474, Iss: 7350, pp 179-183
TL;DR: YAP/TAZ are identified as sensors and mediators of mechanical cues instructed by the cellular microenvironment and are functionally required for differentiation of mesenchymal stem cells induced by ECM stiffness and for survival of endothelial cells regulated by cell geometry.
Abstract: Cells perceive their microenvironment not only through soluble signals but also through physical and mechanical cues, such as extracellular matrix (ECM) stiffness or confined adhesiveness. By mechanotransduction systems, cells translate these stimuli into biochemical signals controlling multiple aspects of cell behaviour, including growth, differentiation and cancer malignant progression, but how rigidity mechanosensing is ultimately linked to activity of nuclear transcription factors remains poorly understood. Here we report the identification of the Yorkie-homologues YAP (Yes-associated protein) and TAZ (transcriptional coactivator with PDZ-binding motif, also known as WWTR1) as nuclear relays of mechanical signals exerted by ECM rigidity and cell shape. This regulation requires Rho GTPase activity and tension of the actomyosin cytoskeleton, but is independent of the Hippo/LATS cascade. Crucially, YAP/TAZ are functionally required for differentiation of mesenchymal stem cells induced by ECM stiffness and for survival of endothelial cells regulated by cell geometry; conversely, expression of activated YAP overrules physical constraints in dictating cell behaviour. These findings identify YAP/TAZ as sensors and mediators of mechanical cues instructed by the cellular microenvironment.
Citations
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Journal Article•DOI•
Wound repair and regeneration: Mechanisms, signaling, and translation

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Sabine A. Eming1, Paul Martin2, Paul Martin3, Marjana Tomic-Canic4•
University of Cologne1, University of Bristol2, Cardiff University3, University of Miami4
03 Dec 2014-Science Translational Medicine
TL;DR: In this review, emerging concepts in tissue regeneration and repair are highlighted, and some perspectives on how to translate current knowledge into viable clinical approaches for treating patients with wound-healing pathologies are provided.
Abstract: The cellular and molecular mechanisms underpinning tissue repair and its failure to heal are still poorly understood, and current therapies are limited. Poor wound healing after trauma, surgery, acute illness, or chronic disease conditions affects millions of people worldwide each year and is the consequence of poorly regulated elements of the healthy tissue repair response, including inflammation, angiogenesis, matrix deposition, and cell recruitment. Failure of one or several of these cellular processes is generally linked to an underlying clinical condition, such as vascular disease, diabetes, or aging, which are all frequently associated with healing pathologies. The search for clinical strategies that might improve the body’s natural repair mechanisms will need to be based on a thorough understanding of the basic biology of repair and regeneration. In this review, we highlight emerging concepts in tissue regeneration and repair, and provide some perspectives on how to translate current knowledge into viable clinical approaches for treating patients with wound-healing pathologies.

1,947 citations

Journal Article•DOI•
Cancer Invasion and the Microenvironment: Plasticity and Reciprocity

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Peter Friedl1, Peter Friedl2, Peter Friedl3, Stephanie Alexander3, Stephanie Alexander1 •
University of Texas MD Anderson Cancer Center1, Radboud University Nijmegen Medical Centre2, University of Würzburg3
23 Nov 2011-Cell
TL;DR: The cell-matrix and cell-cell adhesion, protease, and cytokine systems that underlie tissue invasion by cancer cells are described and explained to explain how the reciprocal reprogramming of both the tumor cells and the surrounding tissue structures not only guides invasion, but also generates diverse modes of dissemination.

1,693 citations

Cites background from "Role of YAP/TAZ in mechanotransduct..."

  • ...As a central downstream signaling pathway that connectsmechanotransduction to gene expression, cell proliferation in response to substrate stiffness is regulated by Yap1, a transcription factor downstream of the hippo pathway (Dupont et al., 2011)....

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Journal Article•DOI•
Hippo Pathway in Organ Size Control, Tissue Homeostasis, and Cancer.

[...]

Fa-Xing Yu1, Bin Zhao2, Kun-Liang Guan3•
Fudan University1, Life Sciences Institute2, University of California, San Diego3
05 Nov 2015-Cell
TL;DR: The Hippo pathway regulates cell proliferation, apoptosis, and stemness in response to a wide range of extracellular and intracellular signals, including cell-cell contact, cell polarity, mechanical cues, ligands of G-protein-coupled receptors, and cellular energy status.

1,571 citations

Cites background or methods from "Role of YAP/TAZ in mechanotransduct..."

  • ...TEAD1–4 or Sd can bind to a consensus motif similar to the GTIIC sequence (TGGAATGT or ACATTCCA), and transcription reporters under control of GTIIC concatemers are now widely used to measure Hippo pathway activity (Dupont et al., 2011; Mohseni et al., 2014; Ota and Sasaki, 2008)....

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  • ...In general, RhoGTPase activity and F-actin appear to activate YAP/TAZ, whereas destabilization of F-actin inhibits YAP/TAZ (Dupont et al., 2011; Miller et al., 2012; Wada et al., 2011; Yu et al., 2012; Zhao et al., 2012)....

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  • ...Manipulation of the actin cytoskeleton, such as overexpressionofRhoGTPasesor inhibition ofRhobyC3 toxin, dramatically modulates YAP/TAZ activity (Dupont et al., 2011; Yu et al., 2012; Zhao et al., 2012)....

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  • ...Mechanical cues, such as ECM stiffness and cell geometry, are also potent regulators of YAP/TAZ (Dupont et al., 2011) (Figure 3)....

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  • ...Inhibition of tension-related enzymes, such as nonmuscle myosin (by Blebbistatin), Rho kinases (ROCK, by Y27632), and myosin light-chain kinase (by ML-7), results in YAP/TAZ inhibition (Dupont et al., 2011;Wada et al., 2011)....

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Journal Article•DOI•
Nuclear lamin-A Scales With Tissue Stiffness and Enhances Matrix-Directed Differentiation

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Joe Swift1, Irena L. Ivanovska1, Amnon Buxboim1, Takamasa Harada1, P.C. Dave P. Dingal1, Joel Pinter1, J. David Pajerowski1, Kyle R. Spinler1, Jae-Won Shin1, Manorama Tewari1, Florian Rehfeldt1, David W. Speicher2, Dennis E. Discher2, Dennis E. Discher1 •
University of Pennsylvania1, Wistar Institute2
30 Aug 2013-Science
TL;DR: In this article, proteomics analyses revealed that levels of the nucleoskeletal protein lamin-A scaled with tissue elasticity, as did levels of collagens in the extracellular matrix that determine E.
Abstract: Tissues can be soft like fat, which bears little stress, or stiff like bone, which sustains high stress, but whether there is a systematic relationship between tissue mechanics and differentiation is unknown. Here, proteomics analyses revealed that levels of the nucleoskeletal protein lamin-A scaled with tissue elasticity, E, as did levels of collagens in the extracellular matrix that determine E. Stem cell differentiation into fat on soft matrix was enhanced by low lamin-A levels, whereas differentiation into bone on stiff matrix was enhanced by high lamin-A levels. Matrix stiffness directly influenced lamin-A protein levels, and, although lamin-A transcription was regulated by the vitamin A/retinoic acid (RA) pathway with broad roles in development, nuclear entry of RA receptors was modulated by lamin-A protein. Tissue stiffness and stress thus increase lamin-A levels, which stabilize the nucleus while also contributing to lineage determination.

1,563 citations

Cites background from "Role of YAP/TAZ in mechanotransduct..."

  • ...A complex interplay between YAP1 and/or lamin-A might reconcile past observations that YAP1 promotes osteogenesis (11) but also inhibits RUNX2 (72); switching betweenYAP1 and TAZ (WWTR1) activities is also possible, because TAZ can promote osteoblast differentiation of MSCs by enhancing RUNX2-dependent transcriptional...

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  • ...LMNA protein also influences location of YAP1 (through a possible intermediary, Y) to drive cell fate (11), and LMNA regulates SRF through interaction with nuclear actin (49)....

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  • ...Matrix elasticity–directed lineage specification of MSCs is based in part on myosin-II– generated cell tension and the accompanying cell spreading (5, 11), which roughly paralleled nuclear shape changes (Figs....

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  • ...Widely expressed transcriptional regulators that include YAP1 of the Hippo pathway, which promotes growth and regeneration (17), as well as components of the serum response factor (SRF) pathway, which promote cytoskeletal gene expression in differentiation (18), exhibit low nuclear activity in cells on substrates designed to limit cell spreading and cytoskeleton tensions (11, 19)....

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  • ...YAP1 has been reported to be excluded from the nucleus in a functionally important manner during adipogenesis of MSCs and also functionally localized to the nucleus during osteogenesis of MSCs (11), but neither YAP1 transcript levels nor its binding partners or target genes changed with lamin-A knockdown (Fig....

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Journal Article•DOI•
Hydrogels with tunable stress relaxation regulate stem cell fate and activity

[...]

Ovijit Chaudhuri1, Ovijit Chaudhuri2, Ovijit Chaudhuri3, Luo Gu1, Luo Gu2, Darinka D. Klumpers1, Darinka D. Klumpers4, Darinka D. Klumpers2, Max Darnell2, Max Darnell1, Sidi A. Bencherif1, Sidi A. Bencherif2, James C. Weaver1, Nathaniel Huebsch2, Hong-pyo Lee3, Evi Lippens5, Evi Lippens1, Georg N. Duda5, David J. Mooney1, David J. Mooney2 •
Wyss Institute for Biologically Inspired Engineering1, Harvard University2, Stanford University3, VU University Medical Center4, Charité5
01 Mar 2016-Nature Materials
TL;DR: It is found that cell spreading, proliferation, and osteogenic differentiation of mesenchymal stem cells (MSCs) are all enhanced in cells cultured in gels with faster relaxation, highlighting stress relaxation as a key characteristic of cell-ECM interactions and as an important design parameter of biomaterials for cell culture.
Abstract: Natural extracellular matrices (ECMs) are viscoelastic and exhibit stress relaxation. However, hydrogels used as synthetic ECMs for three-dimensional (3D) culture are typically elastic. Here, we report a materials approach to tune the rate of stress relaxation of hydrogels for 3D culture, independently of the hydrogel's initial elastic modulus, degradation, and cell-adhesion-ligand density. We find that cell spreading, proliferation, and osteogenic differentiation of mesenchymal stem cells (MSCs) are all enhanced in cells cultured in gels with faster relaxation. Strikingly, MSCs form a mineralized, collagen-1-rich matrix similar to bone in rapidly relaxing hydrogels with an initial elastic modulus of 17 kPa. We also show that the effects of stress relaxation are mediated by adhesion-ligand binding, actomyosin contractility and mechanical clustering of adhesion ligands. Our findings highlight stress relaxation as a key characteristic of cell-ECM interactions and as an important design parameter of biomaterials for cell culture.

1,528 citations

References
More filters
Journal Article•DOI•
Matrix elasticity directs stem cell lineage specification.

[...]

Adam J. Engler1, Shamik Sen1, H. Lee Sweeney1, Dennis E. Discher•
University of Pennsylvania1
25 Aug 2006-Cell
TL;DR: Naive mesenchymal stem cells are shown here to specify lineage and commit to phenotypes with extreme sensitivity to tissue-level elasticity, consistent with the elasticity-insensitive commitment of differentiated cell types.

12,204 citations

Journal Article•DOI•
Geometric control of cell life and death.

[...]

Christopher S. Chen1, Milan Mrksich1, Sui Huang1, George M. Whitesides1, Donald E. Ingber1 •
Harvard University1
30 May 1997-Science
TL;DR: Human and bovine capillary endothelial cells were switched from growth to apoptosis by using micropatterned substrates that contained extracellular matrix-coated adhesive islands of decreasing size to progressively restrict cell extension.
Abstract: Human and bovine capillary endothelial cells were switched from growth to apoptosis by using micropatterned substrates that contained extracellular matrix-coated adhesive islands of decreasing size to progressively restrict cell extension. Cell spreading also was varied while maintaining the total cell-matrix contact area constant by changing the spacing between multiple focal adhesion-sized islands. Cell shape was found to govern whether individual cells grow or die, regardless of the type of matrix protein or antibody to integrin used to mediate adhesion. Local geometric control of cell growth and viability may therefore represent a fundamental mechanism for developmental regulation within the tissue microenvironment.

4,641 citations

Journal Article•DOI•
Cell shape, cytoskeletal tension, and rhoa regulate stem cell lineage commitment

[...]

Rowena McBeath1, Dana M. Pirone1, Celeste M. Nelson1, Kiran Bhadriraju1, Christopher S. Chen1 •
Johns Hopkins University School of Medicine1
01 Apr 2004-Developmental Cell
TL;DR: It is demonstrated that cell shape regulates commitment of human mesenchymal stem cells to adipocyte or osteoblast fate and mechanical cues experienced in developmental and adult contexts, embodied by cell shape, cytoskeletal tension, and RhoA signaling, are integral to the commitment of stem cell fate.

3,995 citations

Journal Article•DOI•
Inactivation of YAP oncoprotein by the Hippo pathway is involved in cell contact inhibition and tissue growth control

[...]

Bin Zhao1, Xiaomu Wei2, Weiquan Li1, Ryan S. Udan3, Ryan S. Udan4, Qian Yang1, Joungmok Kim1, Joungmok Kim5, Joe Xie1, Tsuneo Ikenoue1, Jindan Yu1, Li Li1, Li Li5, Pan Zheng1, Keqiang Ye6, Arul M. Chinnaiyan1, Georg Halder3, Georg Halder4, Zhi Chun Lai2, Kun-Liang Guan1, Kun-Liang Guan5 •
University of Michigan1, Pennsylvania State University2, University of Texas MD Anderson Cancer Center3, Baylor College of Medicine4, University of California, San Diego5, Emory University6
01 Nov 2007-Genes & Development
TL;DR: It is demonstrated that in mammalian cells, the transcription coactivator YAP (Yes-associated protein), is inhibited by cell density via the Hippo pathway, and YAP overexpression regulates gene expression in a manner opposite to cell density, and is able to overcome cell contact inhibition.
Abstract: The Hippo pathway plays a key role in organ size control by regulating cell proliferation and apoptosis in Drosophila. Although recent genetic studies have shown that the Hippo pathway is regulated by the NF2 and Fat tumor suppressors, the physiological regulations of this pathway are unknown. Here we show that in mammalian cells, the transcription coactivator YAP (Yes-associated protein), is inhibited by cell density via the Hippo pathway. Phosphorylation by the Lats tumor suppressor kinase leads to cytoplasmic translocation and inactivation of the YAP oncoprotein. Furthermore, attenuation of this phosphorylation of YAP or Yorkie (Yki), the Drosophila homolog of YAP, potentiates their growth-promoting function in vivo. Moreover, YAP overexpression regulates gene expression in a manner opposite to cell density, and is able to overcome cell contact inhibition. Inhibition of YAP function restores contact inhibition in a human cancer cell line bearing deletion of Salvador (Sav), a Hippo pathway component. Interestingly, we observed that YAP protein is elevated and nuclear localized in some human liver and prostate cancers. Our observations demonstrate that YAP plays a key role in the Hippo pathway to control cell proliferation in response to cell contact.

2,547 citations

Journal Article•DOI•
Local force and geometry sensing regulate cell functions.

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Viola Vogel1, Michael P. Sheetz2•
École Polytechnique Fédérale de Lausanne1, Columbia University2
01 Apr 2006-Nature Reviews Molecular Cell Biology
TL;DR: Tissue scaffolds that have been engineered at the micro- and nanoscale level now enable better dissection of the mechanosensing, transduction and response mechanisms of eukaryotic cells.
Abstract: The shapes of eukaryotic cells and ultimately the organisms that they form are defined by cycles of mechanosensing, mechanotransduction and mechanoresponse Local sensing of force or geometry is transduced into biochemical signals that result in cell responses even for complex mechanical parameters such as substrate rigidity and cell-level form These responses regulate cell growth, differentiation, shape changes and cell death Recent tissue scaffolds that have been engineered at the micro- and nanoscale level now enable better dissection of the mechanosensing, transduction and response mechanisms

2,147 citations

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Trending Questions (1)
How does tumor microenvironment lead to yap taz translocation to nucleus?

The provided paper does not specifically mention how the tumor microenvironment leads to YAP/TAZ translocation to the nucleus.

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