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Role of YAP/TAZ in mechanotransduction.
Nature. 2011 Jun 9; 474(7350):179-83
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14 Jun 2011
Ken Irvine
F1000 Developmental Biology
Rutgers, The State University of New Jersey,
Piscataway, NJ, USA.
F1000 Developmental Biology
Rutgers, The State University of New Jersey,
Piscataway, NJ, USA.
New Finding
DOI: 10.3410/f.11206957.12191055
This manuscript establishes a link between cytoskeletal tension and regulation of the Hippo pathway transcription factors Yap and Taz. It has long been appreciated that cells respond to both chemical and mechanical signals, but our understanding of mechanical signaling processes has lagged behind our...Continue reading
This manuscript establishes a link between cytoskeletal tension and regulation of the Hippo pathway transcription factors Yap and Taz. It has long been appreciated that cells respond to both chemical and mechanical signals, but our understanding of mechanical signaling processes has lagged behind our understanding of chemical signaling. Here, the authors show that culturing cells on soft versus stiff matrices modulates the activity of a pair of related transcriptional co-activator proteins, Yap and Taz.
Yap and Taz are best known as the transcriptional effectors of the Hippo signaling pathway, which plays an important role in controlling organ growth. The author’s experiments imply that the influence of substrate tension on Yap and Taz is not mediated through the canonical Hippo signaling pathway, but rather through some other, as yet unidentified, mechanism. Nonetheless, their studies identify Yap and Taz as critical effectors of the influence of mechanical tension on cell behavior, and a foundation for further investigations into how mechanical forces influence cellular differentiation and proliferation.
Yap and Taz are best known as the transcriptional effectors of the Hippo signaling pathway, which plays an important role in controlling organ growth. The author’s experiments imply that the influence of substrate tension on Yap and Taz is not mediated through the canonical Hippo signaling pathway, but rather through some other, as yet unidentified, mechanism. Nonetheless, their studies identify Yap and Taz as critical effectors of the influence of mechanical tension on cell behavior, and a foundation for further investigations into how mechanical forces influence cellular differentiation and proliferation.
Disclosures
None declared
Add Comment
Irvine K: F1000Prime Recommendation of [Dupont S et al., Nature 2011, 474(7350):179-83]. In F1000Prime, 14 Jun 2011; DOI: 10.3410/f.11206957.12191055. F1000Prime.com/11206957#eval12191055
27 Jun 2011
Kenneth Yamada
F1000 Cell Biology
National Institute of Dental and Craniofacial Research, National Institutes of Health,
Bethesda, MD, USA.
F1000 Cell Biology
National Institute of Dental and Craniofacial Research, National Institutes of Health,
Bethesda, MD, USA.
New Finding
DOI: 10.3410/f.11206957.12614054
This paper reports the discovery of a long-sought transcriptional mediator of mechanotransduction, which appears to be used by a variety of cell types. Dupont et al. provide intriguing evidence that YAP/TAZ (Yes-associated protein/transcriptional co-activator with PDZ-binding motif) regulation serves...Continue reading
This paper reports the discovery of a long-sought transcriptional mediator of mechanotransduction, which appears to be used by a variety of cell types. Dupont et al. provide intriguing evidence that YAP/TAZ (Yes-associated protein/transcriptional co-activator with PDZ-binding motif) regulation serves as a central mediator of mechanosensing from Rho and the actin cytoskeleton to the nucleus.
Dupont, Morsut, Piccolo, and co-workers searched for a novel mechanotransduction pathway by screening signaling pathway signatures of gene expression that were activated in mouse mammary epithelial cells by a stiff substrate, e.g. possible activation of signatures for TGF-beta (transforming growth factor-beta), Ras, or other pathways. Quite surprisingly, they found that only YAP/TAZ target genes were upregulated. The activation of YAP/TAZ by substrate stiffness was characterized by nuclear retention of these proteins during mechanosensing, apparently modifying a process of continual cytoplasm-nucleus shuttling of the proteins to provide a novel, important link between mechanotransduction and transcriptional control. The authors provide evidence for the generality of this new form of regulation for at least four different cell types on two types of soft versus stiff substrate. In addition, they provide knockdown and overexpression data showing its powerful capacity to mediate the regulatory effects of substrate stiffness on mesenchymal stem cell differentiation.
What input information regulates this mechanotransduction process? The authors report that activation of YAP/TAZ is strongly correlated with cell spread area, a cellular feature that increases with increasing substrate stiffness. The authors provide evidence to confirm YAP/TAZ as a transducer of mechanotransduction by linking its regulation to known cellular mechanical responses: Rho activity, the presence of stress fibers, and cytoskeletal tension dependent on Rho kinase and myosin II contractility, but not protein synthesis, were all involved in YAP/TAZ activation.
Overall, the phenomena described by the authors point to YAP/TAZ as a central transcriptional mediator or transducer of mechanotransduction. These potentially exciting findings will need verification and further analysis in the mechanotransduction systems studied by other laboratories. As the authors note, the precise mechanism by which YAP/TAZ activity is induced is not yet clear. It is not clear whether enhanced Rho activity can contribute to activation, and it may be more likely that Rho activity is necessary but not sufficient for YAP/TAZ action. Another question is whether mechanotransduction by other cell types besides epithelial and mesenchymal stem cells -- such as fibroblasts and circulating blood cells -- can also be mediated by YAP/TAZ. Another possibility raised by these findings is that YAP/TAZ-regulated growth factors, such as CTGF, TGF-beta 2, and FGF2, could be induced and mediate some downstream mechanotransduction effects.
If the generality and importance of this novel mediator of mechanotransduction are confirmed, it will be a major advance in our understanding of ways in which physical and mechanical inputs regulate cell biological functions.
Dupont, Morsut, Piccolo, and co-workers searched for a novel mechanotransduction pathway by screening signaling pathway signatures of gene expression that were activated in mouse mammary epithelial cells by a stiff substrate, e.g. possible activation of signatures for TGF-beta (transforming growth factor-beta), Ras, or other pathways. Quite surprisingly, they found that only YAP/TAZ target genes were upregulated. The activation of YAP/TAZ by substrate stiffness was characterized by nuclear retention of these proteins during mechanosensing, apparently modifying a process of continual cytoplasm-nucleus shuttling of the proteins to provide a novel, important link between mechanotransduction and transcriptional control. The authors provide evidence for the generality of this new form of regulation for at least four different cell types on two types of soft versus stiff substrate. In addition, they provide knockdown and overexpression data showing its powerful capacity to mediate the regulatory effects of substrate stiffness on mesenchymal stem cell differentiation.
What input information regulates this mechanotransduction process? The authors report that activation of YAP/TAZ is strongly correlated with cell spread area, a cellular feature that increases with increasing substrate stiffness. The authors provide evidence to confirm YAP/TAZ as a transducer of mechanotransduction by linking its regulation to known cellular mechanical responses: Rho activity, the presence of stress fibers, and cytoskeletal tension dependent on Rho kinase and myosin II contractility, but not protein synthesis, were all involved in YAP/TAZ activation.
Overall, the phenomena described by the authors point to YAP/TAZ as a central transcriptional mediator or transducer of mechanotransduction. These potentially exciting findings will need verification and further analysis in the mechanotransduction systems studied by other laboratories. As the authors note, the precise mechanism by which YAP/TAZ activity is induced is not yet clear. It is not clear whether enhanced Rho activity can contribute to activation, and it may be more likely that Rho activity is necessary but not sufficient for YAP/TAZ action. Another question is whether mechanotransduction by other cell types besides epithelial and mesenchymal stem cells -- such as fibroblasts and circulating blood cells -- can also be mediated by YAP/TAZ. Another possibility raised by these findings is that YAP/TAZ-regulated growth factors, such as CTGF, TGF-beta 2, and FGF2, could be induced and mediate some downstream mechanotransduction effects.
If the generality and importance of this novel mediator of mechanotransduction are confirmed, it will be a major advance in our understanding of ways in which physical and mechanical inputs regulate cell biological functions.
Acknowledgments
I thank Ryan Petrie and Matthew Kutys for their helpful comments on this evaluation.
Disclosures
None declared
Yamada K: F1000Prime Recommendation of [Dupont S et al., Nature 2011, 474(7350):179-83]. In F1000Prime, 27 Jun 2011; DOI: 10.3410/f.11206957.12614054. F1000Prime.com/11206957#eval12614054
28 Jun 2011
New Finding
DOI: 10.3410/f.11206957.12608054
This paper identifies a critical function for the Hippo pathway components Yes-associated protein (Yap) and transcriptional coactivator with PDZ-binding motif (Taz) in integrin-mediated mechanotransduction. It thereby defines a surprising new Hippo-independent role for these transcription factors in cell...Continue reading
This paper identifies a critical function for the Hippo pathway components Yes-associated protein (Yap) and transcriptional coactivator with PDZ-binding motif (Taz) in integrin-mediated mechanotransduction. It thereby defines a surprising new Hippo-independent role for these transcription factors in cell regulation by mechanical forces.
The ability of cells to sense forces applied through integrins is a key determinant of cell growth, survival and differentiation. The Hippo pathway was previously defined as a regulator of cell growth downstream of cell-cell interactions. The current manuscript shows that Yap and Taz are important mediators of mechanical signaling that regulate growth and differentiation in response to cytoskeletal tension or extracellular matrix rigidity, independent of the upstream Hippo pathway.
The ability of cells to sense forces applied through integrins is a key determinant of cell growth, survival and differentiation. The Hippo pathway was previously defined as a regulator of cell growth downstream of cell-cell interactions. The current manuscript shows that Yap and Taz are important mediators of mechanical signaling that regulate growth and differentiation in response to cytoskeletal tension or extracellular matrix rigidity, independent of the upstream Hippo pathway.
Disclosures
None declared
Schwartz M: F1000Prime Recommendation of [Dupont S et al., Nature 2011, 474(7350):179-83]. In F1000Prime, 28 Jun 2011; DOI: 10.3410/f.11206957.12608054. F1000Prime.com/11206957#eval12608054
07 Jul 2011
New Finding
DOI: 10.3410/f.11206957.12854059
Yes-associated protein (YAP) and transcription co-activator with PDZ domain (TAZ) are two transcription factors that mediate the Hippo signaling, a signaling pathway that controls organ size through regulation of apoptosis and proliferation. In this paper, Dupont and colleagues provide compelling evidence...Continue reading
Yes-associated protein (YAP) and transcription co-activator with PDZ domain (TAZ) are two transcription factors that mediate the Hippo signaling, a signaling pathway that controls organ size through regulation of apoptosis and proliferation. In this paper, Dupont and colleagues provide compelling evidence for a Hippo-independent regulation of YAP/TAZ signaling by mechanosensation.
Using public microarray data from mouse mammary epithelial cells embedded in high-density collagen gels (associated with increased ligand density and stiffness) versus low-density collagen gels, the authors found a significant number of YAP/TAZ target genes were regulated by collagen density/stiffness. The authors then showed that restricting cell spreading or decreasing substrate stiffness reduced nuclear translocation of YAP/TAZ and transcription of the target genes CTGF and ANKRD1, and YAP/TAZ signaling appeared to depend on Rho/ROCK activity and stress fiber formation. Furthermore, manipulations of YAP/TAZ signaling directed cells between apoptosis versus proliferation and osteogenic versus adipogenic differentiation in a similar way as previously reported Rho/ROCK manipulations (please see refs {1,2}, on which Christopher Chen appears as an author).
Although compelling evidence is provided that YAP/TAZ signaling is another mechanoregulated pathway, the mechanism of how forces are transduced into such signals remains undefined. In this paper, evidence suggests regulation by cytoskeletal tension at the nuclear membrane wherein low tension conditions inhibit YAP/TAZ nuclear cytoplasmatic export. If true, then it will be important to know if this mechanism is unique for YAP/TAZ transcription factors only, or for many others. When confirmed by other groups, mechanoregulation of YAP/TAZ signaling will become an important research topic as YAP/TAZ interacts with other major developmental signaling pathways such as transforming growth factor-beta (TGF-beta) and Wnt signaling.
Using public microarray data from mouse mammary epithelial cells embedded in high-density collagen gels (associated with increased ligand density and stiffness) versus low-density collagen gels, the authors found a significant number of YAP/TAZ target genes were regulated by collagen density/stiffness. The authors then showed that restricting cell spreading or decreasing substrate stiffness reduced nuclear translocation of YAP/TAZ and transcription of the target genes CTGF and ANKRD1, and YAP/TAZ signaling appeared to depend on Rho/ROCK activity and stress fiber formation. Furthermore, manipulations of YAP/TAZ signaling directed cells between apoptosis versus proliferation and osteogenic versus adipogenic differentiation in a similar way as previously reported Rho/ROCK manipulations (please see refs {1,2}, on which Christopher Chen appears as an author).
Although compelling evidence is provided that YAP/TAZ signaling is another mechanoregulated pathway, the mechanism of how forces are transduced into such signals remains undefined. In this paper, evidence suggests regulation by cytoskeletal tension at the nuclear membrane wherein low tension conditions inhibit YAP/TAZ nuclear cytoplasmatic export. If true, then it will be important to know if this mechanism is unique for YAP/TAZ transcription factors only, or for many others. When confirmed by other groups, mechanoregulation of YAP/TAZ signaling will become an important research topic as YAP/TAZ interacts with other major developmental signaling pathways such as transforming growth factor-beta (TGF-beta) and Wnt signaling.
References
1.
An inhibitory role for FAK in regulating proliferation: a link between limited adhesion and RhoA-ROCK signaling.
J Cell Biol 2006 Jul 17; 2(174):277-88
PMID: 16847103
2.
Cell shape, cytoskeletal tension, and RhoA regulate stem cell lineage commitment.
Dev Cell 2004 Apr; 4(6):483-95
PMID: 15068789
Disclosures
None declared
Chen C and Eyckmans J: F1000Prime Recommendation of [Dupont S et al., Nature 2011, 474(7350):179-83]. In F1000Prime, 07 Jul 2011; DOI: 10.3410/f.11206957.12854059. F1000Prime.com/11206957#eval12854059
18 Jul 2011
New Finding
DOI: 10.3410/f.11206957.13069054
In this fascinating new study, the authors provided compelling evidence to support a role for YAP/TAZ in mechanotransduction.
It has been known for some time that the extracellular matrix influences cell behavior through both direct interaction and mechanical forces. The most famous example is probably...Continue reading
It has been known for some time that the extracellular matrix influences cell behavior through both direct interaction and mechanical forces. The most famous example is probably...Continue reading
In this fascinating new study, the authors provided compelling evidence to support a role for YAP/TAZ in mechanotransduction.
It has been known for some time that the extracellular matrix influences cell behavior through both direct interaction and mechanical forces. The most famous example is probably the mesenchymal stem cells, which differentiate toward different lineages according to the stiffness of the substrate. However, the underlying mechanism of how cells respond to the environmental cues is less well known. By comparing the gene expression profiles, the authors found that components of the Hippo pathway, namely YAP and TAZ, are involved in mechanotransduction of several cell types, including mesenchymal stem cells, endothelial cells, and epithelial cells. Remarkably, it is the geometry of the cell, rather than the interaction with the matrix per se, that directs YAP/TAZ into the nucleus to regulate downstream gene expression. Interestingly, Rho and stress fiber, not the overall amount of actin polymer, are important mediators that promote the nuclear localization of YAP/TAZ. The authors favor the idea that the mechanotransduction pathway is independent of the Hippo pathway.
Additional experiments will help to clarify whether the mechano-pathway could inhibit the Hippo pathway to allow the translocation of YAP/TAZ into the nucleus. This paper has made a significant step toward the understanding of the mechanotransduction signaling pathway.
It has been known for some time that the extracellular matrix influences cell behavior through both direct interaction and mechanical forces. The most famous example is probably the mesenchymal stem cells, which differentiate toward different lineages according to the stiffness of the substrate. However, the underlying mechanism of how cells respond to the environmental cues is less well known. By comparing the gene expression profiles, the authors found that components of the Hippo pathway, namely YAP and TAZ, are involved in mechanotransduction of several cell types, including mesenchymal stem cells, endothelial cells, and epithelial cells. Remarkably, it is the geometry of the cell, rather than the interaction with the matrix per se, that directs YAP/TAZ into the nucleus to regulate downstream gene expression. Interestingly, Rho and stress fiber, not the overall amount of actin polymer, are important mediators that promote the nuclear localization of YAP/TAZ. The authors favor the idea that the mechanotransduction pathway is independent of the Hippo pathway.
Additional experiments will help to clarify whether the mechano-pathway could inhibit the Hippo pathway to allow the translocation of YAP/TAZ into the nucleus. This paper has made a significant step toward the understanding of the mechanotransduction signaling pathway.
Disclosures
None declared
Zheng Y and Liu Z: F1000Prime Recommendation of [Dupont S et al., Nature 2011, 474(7350):179-83]. In F1000Prime, 18 Jul 2011; DOI: 10.3410/f.11206957.13069054. F1000Prime.com/11206957#eval13069054
28 Jul 2011
New Finding
DOI: 10.3410/f.11206957.13331054
This exceptional paper provides evidence that Yes-associated protein/transcriptional co-activator with PDZ-binding motif (YAP/TAZ), known transcriptional mediators of the Hippo pathway, have an additional function of relaying signaling from mechanical cues, such as cell matrix-dependent tension, to...Continue reading
This exceptional paper provides evidence that Yes-associated protein/transcriptional co-activator with PDZ-binding motif (YAP/TAZ), known transcriptional mediators of the Hippo pathway, have an additional function of relaying signaling from mechanical cues, such as cell matrix-dependent tension, to the nucleus. The discovered signaling pathway is mediated by Rho GTPases and actin cytoskeleton, yet is insensitive to the amount of filamentous actin. Curiously, the effects of mechanotransduction on YAP/TAZ did not require the LATS kinases, other known components of the Hippo pathway.
The identified novel role for YAP/TAZ in mechanotransduction is biologically relevant, since both proteins are required for extracellular matrix and shape-dependent cell differentiation and proliferation. I fully agree with the previous evaluations that this study raises a number of novel questions and provides a foundation for further analysis of how mechanical sensing of the environment changes cell behavior both in vitro and in vivo.
The identified novel role for YAP/TAZ in mechanotransduction is biologically relevant, since both proteins are required for extracellular matrix and shape-dependent cell differentiation and proliferation. I fully agree with the previous evaluations that this study raises a number of novel questions and provides a foundation for further analysis of how mechanical sensing of the environment changes cell behavior both in vitro and in vivo.
Disclosures
None declared
Sokol S: F1000Prime Recommendation of [Dupont S et al., Nature 2011, 474(7350):179-83]. In F1000Prime, 28 Jul 2011; DOI: 10.3410/f.11206957.13331054. F1000Prime.com/11206957#eval13331054
28 Jul 2011
New Finding
DOI: 10.3410/f.11206957.13409056
This paper identifies the Yes-associated protein/transcriptional coactivator with PDZ-binding motif (YAP/TAZ) transcriptional regulators as a common end point of force-mediated signalling. It has been long appreciated that mechanical force can alter phenotype in a multitude of biological systems, but...Continue reading
This paper identifies the Yes-associated protein/transcriptional coactivator with PDZ-binding motif (YAP/TAZ) transcriptional regulators as a common end point of force-mediated signalling. It has been long appreciated that mechanical force can alter phenotype in a multitude of biological systems, but the mechanisms had proven elusive.
Striking features of this report include: (a) the very highly selective upregulation of YAP/TAZ in response to substrate stiffness (see Supplementary Figure 2 in the paper) – the initial observation on which the study is based; (b) the demonstration that YAP/TAZ activation in response to substrate stiffness takes place in multiple cell types; and (c) that YAP/TAZ activation is apparently independent of the Hippo pathway, which has previously been reported as the upstream activation mechanism for YAP/TAZ.
Taken together, the data point to the remarkable conclusion, that of YAP/TAZ as a convergence point for mechanosensing. Perhaps unsurprisingly, RhoA activation is implicated upstream of YAP/TAZ, but the pathway remains largely undefined and a major priority for future studies.
Striking features of this report include: (a) the very highly selective upregulation of YAP/TAZ in response to substrate stiffness (see Supplementary Figure 2 in the paper) – the initial observation on which the study is based; (b) the demonstration that YAP/TAZ activation in response to substrate stiffness takes place in multiple cell types; and (c) that YAP/TAZ activation is apparently independent of the Hippo pathway, which has previously been reported as the upstream activation mechanism for YAP/TAZ.
Taken together, the data point to the remarkable conclusion, that of YAP/TAZ as a convergence point for mechanosensing. Perhaps unsurprisingly, RhoA activation is implicated upstream of YAP/TAZ, but the pathway remains largely undefined and a major priority for future studies.
Disclosures
None declared
Humphries M: F1000Prime Recommendation of [Dupont S et al., Nature 2011, 474(7350):179-83]. In F1000Prime, 28 Jul 2011; DOI: 10.3410/f.11206957.13409056. F1000Prime.com/11206957#eval13409056
29 Jul 2011
New Finding
DOI: 10.3410/f.11206957.13447060
Extracellular matrix (ECM) physical cues are sensed by cells to further transduce signals controlling cell shape. Dupont et al. describe a breakthrough in cell mechanotransduction investigation by showing a model using Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif...Continue reading
Extracellular matrix (ECM) physical cues are sensed by cells to further transduce signals controlling cell shape. Dupont et al. describe a breakthrough in cell mechanotransduction investigation by showing a model using Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) to relay mechanical cues in a Rho-dependent, but Hippo-independent, manner.
Importantly, this new finding indicates YAP and TAZ as downstream nuclear players, responding to cytoskeletal tension, in the cellular mechanotransduction machinery.
Importantly, this new finding indicates YAP and TAZ as downstream nuclear players, responding to cytoskeletal tension, in the cellular mechanotransduction machinery.
Disclosures
None declared
Ginsberg M and Liu J: F1000Prime Recommendation of [Dupont S et al., Nature 2011, 474(7350):179-83]. In F1000Prime, 29 Jul 2011; DOI: 10.3410/f.11206957.13447060. F1000Prime.com/11206957#eval13447060
02 Aug 2011
New Finding
DOI: 10.3410/f.11206957.13355059
This paper provides a molecular link between extracellular matrix (ECM) elasticity and cell tension sensing at the membrane to transcriptional effects in the nucleus. Mechanotransduction and the sensing of force are important in a number of disease states, including cancer where an increase in ECM stiffness...Continue reading
This paper provides a molecular link between extracellular matrix (ECM) elasticity and cell tension sensing at the membrane to transcriptional effects in the nucleus. Mechanotransduction and the sensing of force are important in a number of disease states, including cancer where an increase in ECM stiffness can promote cancer progression.
Cells are able to link external physical forces and ECM elasticity to biochemical changes and changes in cell behaviour. This paper shows that the YAP/TAZ family of transcription factors is regulated by ECM stiffness and cell geometry. YAP/TAZ are retained in the nucleus in stiff ECM conditions and on increased cell spreading, and the transcriptional activity of YAP/TAZ requires Rho and cytoskeletal tension. YAP and TAZ are transcription factors in the Hippo pathway; however, their tension sensing activity was shown to be independent of the Hippo cascade. The molecular mechanism linking Rho/ROCK signalling and activation of the YAP/TAZ transcription factors is still to be elucidated. The biological relevance of these transcription factors was signified by a requirement for YAP/TAZ by mesenchymal stem cells to differentiate into osteoblasts in a stiff ECM.
This study connects nicely with recent work from Keith Burridge {1} that provides an additional piece in the mechanotransduction jigsaw. Guilluy et al. identified that following force application to cells, the Rho GEFs LARG and GEF-HI link activated integrins with RhoA. It will be interesting to see if these GEFs are involved in the regulation of YAP/TAZ transcription factors.
Cells are able to link external physical forces and ECM elasticity to biochemical changes and changes in cell behaviour. This paper shows that the YAP/TAZ family of transcription factors is regulated by ECM stiffness and cell geometry. YAP/TAZ are retained in the nucleus in stiff ECM conditions and on increased cell spreading, and the transcriptional activity of YAP/TAZ requires Rho and cytoskeletal tension. YAP and TAZ are transcription factors in the Hippo pathway; however, their tension sensing activity was shown to be independent of the Hippo cascade. The molecular mechanism linking Rho/ROCK signalling and activation of the YAP/TAZ transcription factors is still to be elucidated. The biological relevance of these transcription factors was signified by a requirement for YAP/TAZ by mesenchymal stem cells to differentiate into osteoblasts in a stiff ECM.
This study connects nicely with recent work from Keith Burridge {1} that provides an additional piece in the mechanotransduction jigsaw. Guilluy et al. identified that following force application to cells, the Rho GEFs LARG and GEF-HI link activated integrins with RhoA. It will be interesting to see if these GEFs are involved in the regulation of YAP/TAZ transcription factors.
Disclosures
None declared
Sahai E and Manning C: F1000Prime Recommendation of [Dupont S et al., Nature 2011, 474(7350):179-83]. In F1000Prime, 02 Aug 2011; DOI: 10.3410/f.11206957.13355059. F1000Prime.com/11206957#eval13355059
30 Aug 2011
New Finding
DOI: 10.3410/f.11206957.14256054
Substrate stiffness influences multiple cellular behavior such as pluripotency, proliferation, or differentiation. Dupont et al. unraveled a yet-unknown role for the Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) in modulating mechano-transduction forces dictated...Continue reading
Substrate stiffness influences multiple cellular behavior such as pluripotency, proliferation, or differentiation. Dupont et al. unraveled a yet-unknown role for the Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) in modulating mechano-transduction forces dictated by substrate stiffness or by cell geometry.
The authors provide robust evidence that YAP/TAZ act independently from the Hippo pathway and point to small GTPase Rho as mediator of the signal. The paper raises a variety of interesting questions, such as - how can the YAP/TAZ signaling be modulated to improve stem cell engraftment in the context of transplantation studies? How is YAP/TAZ signaling altered in a model of cancer metastasis? What genes or genomic regions are preferentially regulated by YAP/TAZ? Is Rho signaling directly modulating YAP/TAZ activity, perhaps through its downstream kinases, or are other players involved in the non-canonical regulation of YAP/TAZ? The use of genetic models and further in vivo studies will help in elucidating the role of YAP/TAZ in shaping cellular behavior in response to substrate stiffness.
The authors provide robust evidence that YAP/TAZ act independently from the Hippo pathway and point to small GTPase Rho as mediator of the signal. The paper raises a variety of interesting questions, such as - how can the YAP/TAZ signaling be modulated to improve stem cell engraftment in the context of transplantation studies? How is YAP/TAZ signaling altered in a model of cancer metastasis? What genes or genomic regions are preferentially regulated by YAP/TAZ? Is Rho signaling directly modulating YAP/TAZ activity, perhaps through its downstream kinases, or are other players involved in the non-canonical regulation of YAP/TAZ? The use of genetic models and further in vivo studies will help in elucidating the role of YAP/TAZ in shaping cellular behavior in response to substrate stiffness.
Disclosures
None declared
Rudnicki M and Pasut A: F1000Prime Recommendation of [Dupont S et al., Nature 2011, 474(7350):179-83]. In F1000Prime, 30 Aug 2011; DOI: 10.3410/f.11206957.14256054. F1000Prime.com/11206957#eval14256054
F1000Prime Recommendations, Dissents and Comments for [Dupont S et al., Nature 2011, 474(7350):179-83]. In F1000Prime, 19 May 2013; F1000Prime.com/11206957
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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.
DOI: 10.1038/nature10137
PMID: 21654799
