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      YAP/TAZ upstream signals and downstream responses

      research-article
      1 , 1 , 1 , 2 , *
      Nature cell biology

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          Abstract

          Cell behavior is strongly influenced by physical, mechanical contacts between cells and their extracellular matrix. We review how the transcriptional regulators YAP/TAZ integrate mechanical cues with the response to soluble signals and metabolic pathways to control multiple aspects of cell behavior, including proliferation, cell plasticity and stemness essential for tissue regeneration. Corruption of cell-environment interplay leads to aberrant YAP/TAZ activation that is instrumental for multiple diseases, including cancer.

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          Most cited references99

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          Regulation of the Hippo-YAP pathway by G-protein-coupled receptor signaling.

          The Hippo pathway is crucial in organ size control, and its dysregulation contributes to tumorigenesis. However, upstream signals that regulate the mammalian Hippo pathway have remained elusive. Here, we report that the Hippo pathway is regulated by G-protein-coupled receptor (GPCR) signaling. Serum-borne lysophosphatidic acid (LPA) and sphingosine 1-phosphophate (S1P) act through G12/13-coupled receptors to inhibit the Hippo pathway kinases Lats1/2, thereby activating YAP and TAZ transcription coactivators, which are oncoproteins repressed by Lats1/2. YAP and TAZ are involved in LPA-induced gene expression, cell migration, and proliferation. In contrast, stimulation of Gs-coupled receptors by glucagon or epinephrine activates Lats1/2 kinase activity, thereby inhibiting YAP function. Thus, GPCR signaling can either activate or inhibit the Hippo-YAP pathway depending on the coupled G protein. Our study identifies extracellular diffusible signals that modulate the Hippo pathway and also establishes the Hippo-YAP pathway as a critical signaling branch downstream of GPCR. Copyright © 2012 Elsevier Inc. All rights reserved.
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            Local force and geometry sensing regulate cell functions.

            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.
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              Why don't we get more cancer? A proposed role of the microenvironment in restraining cancer progression.

              Tumors are like new organs and are made of multiple cell types and components. The tumor competes with the normal microenvironment to overcome antitumorigenic pressures. Before that battle is won, the tumor may exist within the organ unnoticed by the host, referred to as 'occult cancer'. We review how normal tissue homeostasis and architecture inhibit progression of cancer and how changes in the microenvironment can shift the balance of these signals to the procancerous state. We also include a discussion of how this information is being tailored for clinical use.
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                Author and article information

                Journal
                100890575
                21417
                Nat Cell Biol
                Nat. Cell Biol.
                Nature cell biology
                1465-7392
                1476-4679
                9 October 2018
                26 July 2018
                August 2018
                01 February 2019
                : 20
                : 8
                : 888-899
                Affiliations
                [1 ]Department of Molecular Medicine (DMM), University of Padua School of Medicine, viale Colombo 3, 35126 Padua, Italy
                [2 ]IFOM - the FIRC Institute of Molecular Oncology
                Author notes
                [* ]To whom correspondence should be addressed. Stefano Piccolo, Department of Molecular Medicine, viale Colombo 3, 35100 Padua, Italy, TEL 0039049 8276098, FAX 0039049 8276079, piccolo@ 123456bio.unipd.it
                Article
                PMC6186418 PMC6186418 6186418 ems79996
                10.1038/s41556-018-0142-z
                6186418
                30050119
                3bd6db58-4078-4f9c-a135-0e26f50e878c
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