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

Abstract

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.

Long non-coding RNAs link extracellular matrix gene expression to ischemic cardiomyopathy

“…The TGF-b signalling pathway has been shown essential for fibrosis and related gene expression. 30 We examined the expression levels of several TGF-b downstream targets that are involved in fibrosis and cell migration. We found that the expression of PAI-1, Snai1, and Snai2 was reduced when lncRNAs were inhibited ( Figure 7A).…”

The Aryl Hydrocarbon Receptor and Its Ligands Inhibit Myofibroblast Formation and Activation

“…Recently, b-catenin/Wnt signaling has been found to be crucial for myofibroblast formation in fibrotic diseases, such as pulmonary fibrosis and hypertrophic scar formation. 29,31 The importance of sustained b-catenin/Wnt signaling in fibrotic diseases is rapidly being realized, and developments to target this pathway in organ fibrosis are ongoing. 42 Although b-catenin/Wnt signaling is not currently being targeted to treat TED, our new findings and a recent report revealing increased Wnt pathway gene expression in TED tissue compared with control tissue suggests further investigation could be beneficial.…”

“…Smad2/3, MAPK/Erk, Akt, and b-catenin/Wnt signaling are known to be important in mediating myofibroblast formation. 7,29,30 Smad2/3, MAPK/Erk, and Akt signaling were investigated during and after TGF-beinduced orbital myofibroblast formation (time points ranged from 1 to 72 hours), and, interestingly, the AHR and AHR ligands had little effect on these pathways (data not shown). However, interesting effects of AHR ligands and AHR depletion on b-catenin/Wnt signaling during TGF-bedependent orbital myofibroblast formation were observed.…”

“…In b-catenin/Wnt signaling, Wnt family member proteins trigger phosphorylation of GSK3b, which in turn stabilize b-catenin proteins and allow b-catenin to translocate into the nucleus and activate transcription of Wnt-responsive genes, some of which are essential for myofibroblast formation. 29,31 Interestingly, TGF-b itself, without the need for Wnt, triggers phosphorylation of GSK3b to induce b-catenin nuclear translocation and activation. 32 To measure b-catenin/Wnt signaling, we analyzed phospho-GSK3b levels in orbital fibroblasts treated with or without TGF-b and the AHR ligands ITE and FICZ ( Figure 8A and Supplemental Figure S5).…”

The emerging role of YAP/TAZ in mechanotransduction

“…Is activation of YAP/TAZ associated with endothelial apoptosis and enhanced lipid uptake in the vessel wall? What is the role of other known signalling pathways interacting with YAP/TAZ such as the Wnt pathway that was recently shown to be regulated by blood flow (12)(13)(14)? …”