Journal ArticleDOI
Role of YAP/TAZ in mechanotransduction
Sirio Dupont,Leonardo Morsut,Mariaceleste Aragona,Elena Enzo,Stefano Giulitti,Michelangelo Cordenonsi,Francesca Zanconato,Jimmy Le Digabel,Mattia Forcato,Silvio Bicciato,Nicola Elvassore,Stefano Piccolo +11 more
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TLDR
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.read more
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Journal ArticleDOI
RAP2 mediates mechanoresponses of the Hippo pathway
Zhipeng Meng,Yunjiang Qiu,Kimberly C. Lin,Aditya Kumar,Jesse K. Placone,Cao Fang,Kuei Chun Wang,Shicong Lu,Margaret Pan,Audrey W. Hong,Toshiro Moroishi,Toshiro Moroishi,Min Luo,Min Luo,Steven W. Plouffe,Yarui Diao,Zhen Ye,Hyun Woo Park,Hyun Woo Park,Xiaoqiong Wang,Fa-Xing Yu,Shu Chien,Cun-Yu Wang,Bing Ren,Bing Ren,Adam J. Engler,Kun-Liang Guan +26 more
TL;DR: The Ras-related GTPase RAP2 is a key intracellular signal transducer by which extracellular matrix rigidity controls mechanosensitive cellular activities through YAP and TAZ, thereby defining a mechanosignalling pathway from ECM stiffness to the nucleus.
Journal ArticleDOI
TGF-β-Induced Endothelial-Mesenchymal Transition in Fibrotic Diseases
TL;DR: The role of the TGF-β signaling pathway and EndMT in the development of fibrotic diseases are summarized and their therapeutic potential is discussed.
Journal ArticleDOI
Substrate Rigidity Regulates Human T Cell Activation and Proliferation
Roddy S. O’Connor,Xueli Hao,Keyue Shen,Keenan T. Bashour,Tatiana Akimova,Wayne W. Hancock,Lance C. Kam,Michael C. Milone +7 more
TL;DR: The results reveal that the rigidity of the substrate used to immobilize T cell stimulatory ligands is an important and previously unrecognized parameter influencing T cell activation, proliferation, and Th differentiation.
Journal ArticleDOI
Yap- and Cdc42-dependent nephrogenesis and morphogenesis during mouse kidney development
Antoine Reginensi,Rizaldy P. Scott,Alex Gregorieff,Mazdak Bagherie-Lachidan,Mazdak Bagherie-Lachidan,Chaeuk Chung,Dae-Sik Lim,Tony Pawson,Jeff Wrana,Helen McNeill,Helen McNeill +10 more
TL;DR: It is proposed that Yap responds to Cdc42-dependent signals in nephron progenitor cells to activate a genetic program required to shape the functioning nephrons, in a manner independent of regulation of cell proliferation and apoptosis.
Journal ArticleDOI
Mechanosensitivity and compositional dynamics of cell-matrix adhesions.
TL;DR: An overview of the compositional dynamics of cell–matrix adhesions is provided, the most prevalent functional domains in adhesome proteins are discussed and concepts about mechanosensing mechanisms that operate at the adhesion site are reviewed.
References
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Journal ArticleDOI
Matrix elasticity directs stem cell lineage specification.
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.
Journal ArticleDOI
Geometric control of cell life and death.
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.
Journal ArticleDOI
Cell shape, cytoskeletal tension, and rhoa regulate stem cell lineage commitment
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.
Journal ArticleDOI
Inactivation of YAP oncoprotein by the Hippo pathway is involved in cell contact inhibition and tissue growth control
Bin Zhao,Xiaomu Wei,Weiquan Li,Ryan S. Udan,Ryan S. Udan,Qian Yang,Joungmok Kim,Joungmok Kim,Joe Xie,Tsuneo Ikenoue,Jindan Yu,Li Li,Li Li,Pan Zheng,Keqiang Ye,Arul M. Chinnaiyan,Georg Halder,Georg Halder,Zhi Chun Lai,Kun-Liang Guan,Kun-Liang Guan +20 more
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.
Journal ArticleDOI
Local force and geometry sensing regulate cell functions.
Viola Vogel,Michael P. Sheetz +1 more
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.