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Signaling in Fibrosis: TGF-β, WNT, and YAP/TAZ Converge

Chronic organ injury leads to fibrosis and eventually organ failure. Fibrosis is characterized by excessive synthesis, remodeling, and contraction of extracellular matrix produced by myofibroblasts. Myofibroblasts are the key cells in the pathophysiology of fibrotic disorders and their differentiati...

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Autores principales: Piersma, Bram, Bank, Ruud A., Boersema, Miriam
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4558529/
https://www.ncbi.nlm.nih.gov/pubmed/26389119
http://dx.doi.org/10.3389/fmed.2015.00059
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author Piersma, Bram
Bank, Ruud A.
Boersema, Miriam
author_facet Piersma, Bram
Bank, Ruud A.
Boersema, Miriam
author_sort Piersma, Bram
collection PubMed
description Chronic organ injury leads to fibrosis and eventually organ failure. Fibrosis is characterized by excessive synthesis, remodeling, and contraction of extracellular matrix produced by myofibroblasts. Myofibroblasts are the key cells in the pathophysiology of fibrotic disorders and their differentiation can be triggered by multiple stimuli. To develop anti-fibrotic therapies, it is of paramount importance to understand the molecular basis of the signaling pathways contributing to the activation and maintenance of myofibroblasts. Several signal transduction pathways, such as transforming growth factor (TGF)-β, Wingless/Int (WNT), and more recently yes-associated protein 1 (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ) signaling, have been linked to the pathophysiology of fibrosis. Activation of the TGF-β1-induced SMAD complex results in the upregulation of genes important for myofibroblast function. Similarly, WNT-stabilized β-catenin translocates to the nucleus and initiates transcription of its target genes. YAP and TAZ are two transcriptional co-activators from the Hippo signaling pathway that also rely on nuclear translocation for their functioning. These three signal transduction pathways have little molecular similarity but do share one principle: the cytosolic/nuclear regulation of its transcriptional activators. Past research on these pathways often focused on the isolated cascades without taking other signaling pathways into account. Recent developments show that parts of these pathways converge into an intricate network that governs the activation and maintenance of the myofibroblast phenotype. In this review, we discuss the current understanding on the signal integration between the TGF-β, WNT, and YAP/TAZ pathways in the development of organ fibrosis. Taking a network-wide view on signal transduction will provide a better understanding on the complex and versatile processes that underlie the pathophysiology of fibrotic disorders.
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spelling pubmed-45585292015-09-18 Signaling in Fibrosis: TGF-β, WNT, and YAP/TAZ Converge Piersma, Bram Bank, Ruud A. Boersema, Miriam Front Med (Lausanne) Medicine Chronic organ injury leads to fibrosis and eventually organ failure. Fibrosis is characterized by excessive synthesis, remodeling, and contraction of extracellular matrix produced by myofibroblasts. Myofibroblasts are the key cells in the pathophysiology of fibrotic disorders and their differentiation can be triggered by multiple stimuli. To develop anti-fibrotic therapies, it is of paramount importance to understand the molecular basis of the signaling pathways contributing to the activation and maintenance of myofibroblasts. Several signal transduction pathways, such as transforming growth factor (TGF)-β, Wingless/Int (WNT), and more recently yes-associated protein 1 (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ) signaling, have been linked to the pathophysiology of fibrosis. Activation of the TGF-β1-induced SMAD complex results in the upregulation of genes important for myofibroblast function. Similarly, WNT-stabilized β-catenin translocates to the nucleus and initiates transcription of its target genes. YAP and TAZ are two transcriptional co-activators from the Hippo signaling pathway that also rely on nuclear translocation for their functioning. These three signal transduction pathways have little molecular similarity but do share one principle: the cytosolic/nuclear regulation of its transcriptional activators. Past research on these pathways often focused on the isolated cascades without taking other signaling pathways into account. Recent developments show that parts of these pathways converge into an intricate network that governs the activation and maintenance of the myofibroblast phenotype. In this review, we discuss the current understanding on the signal integration between the TGF-β, WNT, and YAP/TAZ pathways in the development of organ fibrosis. Taking a network-wide view on signal transduction will provide a better understanding on the complex and versatile processes that underlie the pathophysiology of fibrotic disorders. Frontiers Media S.A. 2015-09-03 /pmc/articles/PMC4558529/ /pubmed/26389119 http://dx.doi.org/10.3389/fmed.2015.00059 Text en Copyright © 2015 Piersma, Bank and Boersema. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Medicine
Piersma, Bram
Bank, Ruud A.
Boersema, Miriam
Signaling in Fibrosis: TGF-β, WNT, and YAP/TAZ Converge
title Signaling in Fibrosis: TGF-β, WNT, and YAP/TAZ Converge
title_full Signaling in Fibrosis: TGF-β, WNT, and YAP/TAZ Converge
title_fullStr Signaling in Fibrosis: TGF-β, WNT, and YAP/TAZ Converge
title_full_unstemmed Signaling in Fibrosis: TGF-β, WNT, and YAP/TAZ Converge
title_short Signaling in Fibrosis: TGF-β, WNT, and YAP/TAZ Converge
title_sort signaling in fibrosis: tgf-β, wnt, and yap/taz converge
topic Medicine
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4558529/
https://www.ncbi.nlm.nih.gov/pubmed/26389119
http://dx.doi.org/10.3389/fmed.2015.00059
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