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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Small molecules inhibiting the nuclear localization of YAP/TAZ for chemotherapeutics and chemosensitizers against breast cancers
Yusuke Oku,Naoyuki Nishiya,Toshiya Shito,Reiichiro Yamamoto,Yasufumi Yamamoto,Chihiro Oyama,Yoshimasa Uehara +6 more
TL;DR: Combinations of these compounds with each other or with other anti‐cancer drugs efficiently reduced cell proliferation of YAP/TAZ‐dependent breast cancer cells.
Journal ArticleDOI
Regulation of Hippo pathway transcription factor TEAD by p38 MAPK-induced cytoplasmic translocation
Kimberly C. Lin,Toshiro Moroishi,Zhipeng Meng,Han-Sol Jeong,Han-Sol Jeong,Steven W. Plouffe,Yoshitaka Sekido,Jiahuai Han,Hyun Woo Park,Hyun Woo Park,Kun-Liang Guan +10 more
TL;DR: It is shown that environmental stress promotes TEAD cytoplasmic translocation via p38 MAPK in a Hippo-independent manner and stress-induced TEAD inhibition predominates YAP-activating signals and selectively suppresses YAP's cancer cell growth.
Journal ArticleDOI
Phosphorylation of Angiomotin by Lats1/2 Kinases Inhibits F-actin Binding, Cell Migration, and Angiogenesis
Xiaoming Dai,Peilu She,Fangtao Chi,Ying Feng,Huan Liu,Daqing Jin,Yiqiang Zhao,Xiaocan Guo,Dandan Jiang,Kun-Liang Guan,Tao P. Zhong,Bin Zhao +11 more
TL;DR: A novel role of the Hippo pathway in angiogenesis is reported, with phosphorylation of angiomotin p130 isoform (AMOTp130) is phosphorylated on a conserved HXRXXS motif by Lats1/2 downstream of GPCR signaling.
Journal ArticleDOI
Emerging evidence on the role of the Hippo/YAP pathway in liver physiology and cancer.
TL;DR: This review focuses on the known roles for Hippo/YAP signaling in the liver and promising avenues for future study.
Journal ArticleDOI
Hippo Signaling Plays an Essential Role in Cell State Transitions during Cardiac Fibroblast Development.
Yang Xiao,Matthew C. Hill,Min Zhang,Thomas J. Martin,Yuka Morikawa,Suya Wang,Alexander R. Moise,Joshua D. Wythe,James F. Martin +8 more
TL;DR: Genetic and pharmacologic manipulation revealed that Yap inhibits fibroblast differentiation, prolonging a subepicardial-like cell state, and promotes expression of matricellular factors, such as Dpp4, that define ECM characteristics.
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.