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      The Roles of YAP/TAZ and the Hippo Pathway in Healthy and Diseased Skin

      review-article
      Author(s): 1 , 2 , *
      Publication date (Electronic):
      Journal: Cells
      Publisher: MDPI
      Keywords: Hippo signalling, skin development, stem cells, skin cancer, fibroblasts, fibrosis, wound healing

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          Abstract

          Skin is the largest organ of the human body. Its architecture and physiological functions depend on diverse populations of epidermal cells and dermal fibroblasts. Reciprocal communication between the epidermis and dermis plays a key role in skin development, homeostasis and repair. While several stem cell populations have been identified in the epidermis with distinct locations and functions, there is additional heterogeneity within the mesenchymal cells of the dermis. Here, we discuss the current knowledge of how the Hippo pathway and its downstream effectors Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) contribute to the maintenance, activation and coordination of the epidermal and dermal cell populations during development, homeostasis, wound healing and cancer.

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

          Fa-Xing Yu, Bin Zhao, Nattapon Panupinthu … (2012)
          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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            YAP/TAZ incorporation in the β-catenin destruction complex orchestrates the Wnt response.

            Luca Azzolin, Tito Panciera, Sandra Soligo … (2014)
            The Hippo transducers YAP/TAZ have been shown to play positive, as well as negative, roles in Wnt signaling, but the underlying mechanisms remain unclear. Here, we provide biochemical, functional, and genetic evidence that YAP and TAZ are integral components of the β-catenin destruction complex that serves as cytoplasmic sink for YAP/TAZ. In Wnt-ON cells, YAP/TAZ are physically dislodged from the destruction complex, allowing their nuclear accumulation and activation of Wnt/YAP/TAZ-dependent biological effects. YAP/TAZ are required for intestinal crypt overgrowth induced by APC deficiency and for crypt regeneration ex vivo. In Wnt-OFF cells, YAP/TAZ are essential for β-TrCP recruitment to the complex and β-catenin inactivation. In Wnt-ON cells, release of YAP/TAZ from the complex is instrumental for Wnt/β-catenin signaling. In line, the β-catenin-dependent maintenance of ES cells in an undifferentiated state is sustained by loss of YAP/TAZ. This work reveals an unprecedented signaling framework relevant for organ size control, regeneration, and tumor suppression. Copyright © 2014 Elsevier Inc. All rights reserved.
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              Distinct fibroblast lineages determine dermal architecture in skin development and repair

              Ryan R. Driskell, Beate M Lichtenberger, Esther Hoste … (2013)
              Fibroblasts are the major mesenchymal cell type in connective tissue and deposit the collagen and elastic fibers of the extracellular matrix (ECM) 1 . Even within a single tissue fibroblasts exhibit remarkable functional diversity, but it is not known whether this reflects the existence of a differentiation hierarchy or is a response to different environmental factors. Here we show, using transplantation assays and lineage tracing, that the fibroblasts of skin connective tissue arise from two distinct lineages. One forms the upper dermis, including the dermal papilla that regulates hair growth and the arrector pili muscle (APM), which controls piloerection. The other forms the lower dermis, including the reticular fibroblasts that synthesise the bulk of the fibrillar ECM, and the pre-adipocytes and adipocytes of the hypodermis. The upper lineage is required for hair follicle formation. In wounded adult skin, the initial wave of dermal repair is mediated by the lower lineage and upper dermal fibroblasts are recruited only during re-epithelialisation. Epidermal beta-catenin activation stimulates expansion of the upper dermal lineage, rendering wounds permissive for hair follicle formation. Our findings explain why wounding is linked to formation of ECM-rich scar tissue that lacks hair follicles 2-4 . They also form a platform for discovering fibroblast lineages in other tissues and for examining fibroblast changes in ageing and disease.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Cells
                Journal ID (iso-abbrev): Cells
                Journal ID (publisher-id): cells
                Title: Cells
                Publisher: MDPI
                ISSN (Electronic): 2073-4409
                Publication date (Electronic): 03 May 2019
                Publication date Collection: May 2019
                Volume: 8
                Issue: 5
                Electronic Location Identifier: 411
                Affiliations
                [1 ]Centre for Endocrinology, William Harvey Research Institute, Barts and The London School of Medicine, Queen Mary University of London, London EC1M 6BQ, UK; e.rognoni@ 123456qmul.ac.uk
                [2 ]Department of Biology and Biochemistry & Centre for Therapeutic Innovation, University of Bath, Claverton Down, Bath BA2 7AY, UK
                Author notes
                [* ]Correspondence: g.walko@ 123456bath.ac.uk ; Tel.: +44-(0)1225-38-6261
                Author information
                https://orcid.org/0000-0001-6050-2860
                https://orcid.org/0000-0002-8504-1738
                Article
                Publisher ID: cells-08-00411
                DOI: 10.3390/cells8050411
                PMC ID: 6562585
                PubMed ID: 31058846
                SO-VID: 268f9082-a173-4a3b-a7f1-473e5faa2f60
                Copyright © © 2019 by the authors.
                License:

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                Date received : 22 March 2019
                Date accepted : 30 April 2019
                Categories
                Subject: Review

                Keywords: hippo signalling,skin development,stem cells,skin cancer,fibroblasts,fibrosis,wound healing
                Data availability:
                Keywords: hippo signalling, skin development, stem cells, skin cancer, fibroblasts, fibrosis, wound healing

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