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      Potential Role of Exercise in Regulating YAP and TAZ During Cardiomyocytes Aging

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          Abstract

          Adaptation of cardiac muscle to regular exercise results in morphological and structural changes known as physiological cardiac hypertrophy, to which the Hippo signaling pathway might have contributed. Two major terminal effectors in the Hippo signaling pathway are Yes-associated protein (YAP) and its homolog transcriptional coactivator with PDZ-binding motif (TAZ). The latest studies have reported the role of YAP and TAZ in different life stages, such as in fetal, neonatal, and adult hearts. Their regulation might involve several mechanisms and effectors. One of the possible coregulators is exercise. Exercise plays a role in cardiomyocyte hypertrophic changes during different stages of life, including in aged hearts. YAP/TAZ signaling pathway has a role in physiological cardiac hypertrophy induced by exercise and is associated with cardiac remodelling. Thus, it can be believed that exercise has roles in activating the signaling pathway of YAP and TAZ in aged cardiomyocytes. However, the studies regarding the roles of YAP and TAZ during cardiomyocyte aging are limited. The primary purpose of this review is to explore the response of cardiovascular aging to exercise via signaling pathway of YAP and TAZ.

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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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            Mechanisms of Hippo pathway regulation

            In this review, Meng et al. focus on recent developments in our understanding of the molecular actions of the core Hippo kinase cascade and discuss key open questions in Hippo pathway regulation and function.
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              A coordinated phosphorylation by Lats and CK1 regulates YAP stability through SCF(beta-TRCP).

              The Yes-associated protein (YAP) transcription coactivator is a key regulator of organ size and a candidate human oncogene. YAP is inhibited by the Hippo pathway kinase cascade, at least in part via phosphorylation of Ser 127, which results in YAP 14-3-3 binding and cytoplasmic retention. Here we report that YAP is phosphorylated by Lats on all of the five consensus HXRXXS motifs. Phosphorylation of Ser 381 in one of them primes YAP for subsequent phosphorylation by CK1delta/epsilon in a phosphodegron. The phosphorylated phosphodegron then recruits the SCF(beta-TRCP) E3 ubiquitin ligase, which catalyzes YAP ubiquitination, ultimately leading to YAP degradation. The phosphodegron-mediated degradation and the Ser 127 phosphorylation-dependent translocation coordinately suppress YAP oncogenic activity. Our study identified CK1delta/epsilon as new regulators of YAP and uncovered an intricate mechanism of YAP regulation by the Hippo pathway via both S127 phosphorylation-mediated spatial regulation (nuclear-cytoplasmic shuttling) and the phosphodegron-mediated temporal regulation (degradation).
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                Author and article information

                Journal
                Curr Cardiol Rev
                Curr Cardiol Rev
                CCR
                Current Cardiology Reviews
                Bentham Science Publishers
                1573-403X
                1875-6557
                16 September 2022
                16 September 2022
                : 18
                : 5
                : CCR-18-5-E040422203084
                Affiliations
                deptPostgraduate Program of Biomedical Science, PMDSU Program Batch V , Universitas Padjajaran , Bandung, , Indonesia;
                deptDepartment of Clinical Skills, Faculty of Medicine , Maranatha Christian University , Bandung, , Indonesia;
                deptDepartment of Physical Medicine and Rehabilitation , Unggul Karsa Medika Hospital , Bandung, , Indonesia;
                deptDepartment of Anatomy, Faculty of Medicine , Maranatha Christian University , Bandung, , Indonesia;
                deptDepartment of Histology, Faculty of Medicine , Maranatha Christian University , Bandung, , Indonesia;
                deptDepartment of Physiology, Faculty of Medicine , Maranatha Christian University , Bandung, , Indonesia;
                deptDepartment of Physical Medicine and Rehabilitation, Faculty of Medicine , Universitas Padjadjaran/Dr. Hasan Sadikin General Hospital , Bandung, , Indonesia;
                deptDepartment of Pharmacology, Faculty of Medicine , Maranatha Christian University , Bandung, , Indonesia;
                deptPhysiology Molecular, Biological Activity Division , Central Laboratory , Bandung, , Indonesia;
                deptDepartment of Biomedical Science, Faculty of Medicine, Universitas Padjadjaran Bandung, Sumedang , Indonesia
                Author notes
                [* ]Address correspondence to this author at the Postgraduate Doctoral Program Faculty of Medicine, Universitas Padjadjaran, Bandung, West Java, 40161; Department of Physical Medicine and Rehabilitation, Unggul Karsa Medika Hospital, Bandung, West Java, 40218; Department of Clinical Skills, Faculty of Medicine, Maranatha Christian University, Bandung, West Java, 40164, Indonesia; Tel/Fax: +62222012186, +62222017621; Email: y_nni@ 123456yahoo.com
                Article
                CCR-18-5-E040422203084
                10.2174/1573403X18666220404152924
                9896415
                35379136
                00e04d4d-0797-4261-a5f4-7256f0ac9305
                © 2022 Bentham Science Publishers

                This is an open access article licensed under the terms of the Creative Commons Attribution-Non-Commercial 4.0 International Public License (CC BY-NC 4.0) ( https://creativecommons.org/licenses/by-nc/4.0/), which permits unrestricted, non-commercial use, distribution and reproduction in any medium, provided the work is properly cited.

                History
                : 08 July 2021
                : 03 January 2022
                : 26 January 2022
                Categories
                Cardiology

                Cardiovascular Medicine
                aging,cardiomyocyte,cardiac hypertrophy,exercise,yap,taz
                Cardiovascular Medicine
                aging, cardiomyocyte, cardiac hypertrophy, exercise, yap, taz

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