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      Recent advances in the role of Yes‐associated protein in dermatosis

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          Abstract

          Background

          Dermatosis is a general term for diseases of the skin and skin appendages including scleroderma, psoriasis, bullous disease, atopic dermatitis, basal cell carcinoma, squamous cell carcinoma, and melanoma. These diseases affect millions of individuals globally and are a serious public health concern. However, the pathogenesis of skin diseases is not fully understood, and treatments are not optimal. Yes‐associated protein (YAP) is a transcriptional coactivator that plays a role in the regulation of gene transcription and signal transduction.

          Aims

          To study the role of Yes‐associated protein in skin diseases.

          Materials and Methods

          The present review summarizes recent advances in our understanding of the role of YAP in skin diseases, current treatments that target YAP, and potential avenues for novel therapies.

          Results

          Abnormal YAP expression has been implicated in occurrence and development of dermatosis. YAP regulates the cell homeostasis, proliferation, differentiation, apoptosis, angiopoiesis, and epithelial‐to‐mesenchymal transition, among other processes. As well as, it serves as a potential target in many biological processes for treating dermatosis.

          Conclusions

          The effects of YAP on the skin are complex and require multidimensional investigational approaches. YAP functions as an oncoprotein that can promote the occurrence and development of cancer, but there is currently limited information on the therapeutic potential of YAP inhibition for cancer treatment. Additional studies are also needed to clarify the role of YAP in the development and maturation of dermal fibroblasts; skin barrier function, homeostasis, aging, and melanin production; and dermatosis.

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          Most cited references93

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          Elucidation of a universal size-control mechanism in Drosophila and mammals.

          Coordination of cell proliferation and cell death is essential to attain proper organ size during development and for maintaining tissue homeostasis throughout postnatal life. In Drosophila, these two processes are orchestrated by the Hippo kinase cascade, a growth-suppressive pathway that ultimately antagonizes the transcriptional coactivator Yorkie (Yki). Here we demonstrate that a single phosphorylation site in Yki mediates the growth-suppressive output of the Hippo pathway. Hippo-mediated phosphorylation inactivates Yki by excluding it from the nucleus, whereas loss of Hippo signaling leads to nuclear accumulation and therefore increased Yki activity. We further delineate a mammalian Hippo signaling pathway that culminates in the phosphorylation of YAP, the mammalian homolog of Yki. Using a conditional YAP transgenic mouse model, we demonstrate that the mammalian Hippo pathway is a potent regulator of organ size, and that its dysregulation leads to tumorigenesis. These results uncover a universal size-control mechanism in metazoan.
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            The Crumbs complex couples cell density sensing to Hippo-dependent control of the TGF-β-SMAD pathway.

            The Hippo pathway senses cell density information to control tissue growth by regulating the localization of the transcriptional regulators TAZ and YAP (TAZ/YAP). TAZ/YAP also regulate TGF-β-SMAD signaling, but whether this role is linked to cell density sensing is unknown. Here we demonstrate that TAZ/YAP dictate the localization of active SMAD complexes in response to cell density-mediated formation of polarity complexes. In high-density cell cultures, the Hippo pathway drives cytoplasmic localization of TAZ/YAP, which sequesters SMAD complexes, thereby suppressing TGF-β signaling. We show that during mouse embryogenesis, this is reflected by differences in TAZ/YAP localization, which define regions of active SMAD2/3 complexes. Interfering with TAZ/YAP phosphorylation drives nuclear accumulation of TAZ/YAP and SMAD2/3. Furthermore, we demonstrate that the Crumbs polarity complex interacts with TAZ/YAP, which relays cell density information by promoting TAZ/YAP phosphorylation, cytoplasmic retention, and suppressed TGF-β signaling. Accordingly, disruption of the Crumbs complex enhances TGF-β signaling and predisposes cells to TGF-β-mediated epithelial-to-mesenchymal transitions. Copyright © 2010 Elsevier Inc. All rights reserved.
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              Mechanosignaling through YAP and TAZ drives fibroblast activation and fibrosis.

              Pathological fibrosis is driven by a feedback loop in which the fibrotic extracellular matrix is both a cause and consequence of fibroblast activation. However, the molecular mechanisms underlying this process remain poorly understood. Here we identify yes-associated protein (YAP) (homolog of drosophila Yki) and transcriptional coactivator with PDZ-binding motif (TAZ) (also known as Wwtr1), transcriptional effectors of the Hippo pathway, as key matrix stiffness-regulated coordinators of fibroblast activation and matrix synthesis. YAP and TAZ are prominently expressed in fibrotic but not healthy lung tissue, with particularly pronounced nuclear expression of TAZ in spindle-shaped fibroblastic cells. In culture, both YAP and TAZ accumulate in the nuclei of fibroblasts grown on pathologically stiff matrices but not physiologically compliant matrices. Knockdown of YAP and TAZ together in vitro attenuates key fibroblast functions, including matrix synthesis, contraction, and proliferation, and does so exclusively on pathologically stiff matrices. Profibrotic effects of YAP and TAZ operate, in part, through their transcriptional target plasminogen activator inhibitor-1, which is regulated by matrix stiffness independent of transforming growth factor-β signaling. Immortalized fibroblasts conditionally expressing active YAP or TAZ mutant proteins overcome soft matrix limitations on growth and promote fibrosis when adoptively transferred to the murine lung, demonstrating the ability of fibroblast YAP/TAZ activation to drive a profibrotic response in vivo. Together, these results identify YAP and TAZ as mechanoactivated coordinators of the matrix-driven feedback loop that amplifies and sustains fibrosis.
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                Author and article information

                Contributors
                vipyz@126.com
                Journal
                Skin Res Technol
                Skin Res Technol
                10.1111/(ISSN)1600-0846
                SRT
                Skin Research and Technology
                John Wiley and Sons Inc. (Hoboken )
                0909-752X
                1600-0846
                27 February 2023
                March 2023
                : 29
                : 3 ( doiID: 10.1111/srt.v29.3 )
                : e13285
                Affiliations
                [ 1 ] Department of Dermatology The First Affiliated Hospital of Kunming Medical University Kunming China
                Author notes
                [*] [* ] Correspondence

                Zhi Yang, Department of Dermatology, The First Affiliated Hospital of Kunming Medical University, No. 295 Xichang Rd, Kunming 650032, Yunnan Province, China.

                Email: vipyz@ 123456126.com

                Article
                SRT13285
                10.1111/srt.13285
                10155855
                36973973
                a0b4cef4-185f-43d6-b00f-ddd7134aef9d
                © 2023 The Authors. Skin Research and Technology published by John Wiley & Sons Ltd.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.

                History
                : 18 December 2022
                : 22 December 2022
                Page count
                Figures: 2, Tables: 1, Pages: 9, Words: 6688
                Funding
                Funded by: Yunnan Province Clinical Center for Skin Immune Diseases
                Award ID: ZX2019‐03‐02
                Funded by: Yunnan Province High‐level Health Technology Talent (Academic Leader)
                Award ID: D‐2018‐033
                Categories
                Original Article
                Original Articles
                Custom metadata
                2.0
                March 2023
                Converter:WILEY_ML3GV2_TO_JATSPMC version:6.2.8 mode:remove_FC converted:03.05.2023

                dermatosis,hippo signaling pathway,signal transduction,skin physiology,yes‐associated protein

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