Synergistic induction of CTGF by cytochalasin D and TGFβ-1 in primary human renal epithelial cells: Role of transcriptional regulators MKL1, YAP/TAZ and Smad2/3

Muehlich, Susanne; Rehm, Margot; Ebenau, Astrid; Goppelt‐Struebe, Margarete

doi:10.1016/j.cellsig.2016.10.002

Cited by 16 publications

(14 citation statements)

References 46 publications

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“…Pretreating A549 cells with 5 μM latrunculin for 15 min before adding TGF-β significantly decreased the abundance of pSmad (Supplemental Figure S2, B and C) compared with DMSO controls and blocked nuclear translocation of Smad2 (Supplemental Figure S2D). These findings conflict with a recent report that the actin filament disrupting drugs cytochalasin and latrunculin do not inhibit increased pSmad2 in renal tubular epithelial cells treated with TGF-β ( Muehlich et al., 2017 ).…”

Section: Resultscontrasting

confidence: 99%

Formin-dependent TGF-β signaling for epithelial to mesenchymal transition

Rana

Aloisio

Choi

et al. 2018

MBoC

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The role of distinct actin filament architectures in epithelial plasticity remains incompletely understood. We therefore determined roles for formins and the Arp2/3 complex, which are actin nucleators generating unbranched and branched actin filaments, respectively, in the process of epithelial to mesenchymal transition (EMT). In clonal lung, mammary, and renal epithelial cells, the formin activity inhibitor SMIFH2 but not the Arp2/3 complex activity inhibitor CK666 blocked EMT induced by TGF-β. SMIFH2 prevented the proximal signal of increased Smad2 phosphorylation and hence also blocked downstream EMT markers, including actin filament remodeling, decreased expression of the adherens junction protein E-cadherin, and increased expression of the matrix protein fibronectin and the transcription factor Snail. The short hairpin RNA silencing of formins DIAPH1 and DIAPH3 but not other formins phenocopied SMIFH2 effects and inhibited Smad2 phosphorylation and changes in Snail and cadherin expression. Formin activity was not necessary for the cell surface expression or dimerization of TGF-β receptors, or for nuclear translocation of TAZ, a transcription cofactor in Hippo signaling also regulated by TGF-β. Our findings reveal a previously unrecognized role for formin-dependent actin architectures in proximal TGF-β signaling that is necessary for Smad2 phosphorylation but not for cross-talk to TAZ.

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Section: Resultscontrasting

confidence: 99%

Formin-dependent TGF-β signaling for epithelial to mesenchymal transition

Rana

Aloisio

Choi

et al. 2018

MBoC

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“…Another pathway associated with cytoskeletal dynamics and sensing of ECM mechanical signals is the Hippo signalling pathway 184,185 . Inhibition of Rho and disruption of Factin results in pathway inactivation 186 and can lead to alterations in translocation of the transcription co-activators yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) between the cytoplasm and the nucleus 187 . These transcriptional co-activators, possibly interacting with SMAD3 from the TGFβ signalling pathway, might regulate fibroblast myofibroblast differentiation 188 .…”

Section: Mlp Titin and Associated Complexes In Cardiac Myocytes-myomentioning

confidence: 99%

Mechanical regulation of gene expression in cardiac myocytes and fibroblasts

et al. 2019

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The intact heart undergoes complex and multiscale remodelling processes in response to altered mechanical cues. Remodelling of the myocardium is regulated by a combination of myocyte and non-myocyte responses to mechanosensitive pathways, which can alter gene expression and therefore function in these cells. Cellular mechanotransduction and its downstream effects on gene expression are initially compensatory mechanisms during adaptations to the altered mechanical environment, but under prolonged and abnormal loading conditions, they can become maladaptive, leading to impaired function and cardiac pathologies. In this Review, we summarize mechanoregulated pathways in cardiac myocytes and fibroblasts that lead to altered gene expression and cell remodelling under physiological and pathophysiological conditions. Developments in systems modelling of the networks that regulate gene expression in response to mechanical stimuli should improve integrative understanding of their roles in vivo and help to discover new combinations of drugs and device therapies targeting mechanosignalling in heart disease. Physiological and pathological cardiac structural remodelling are commonly associated with chronic alterations in haemodynamics, chamber shape and myocardial mechanics that can initially compensate for, but ultimately exacerbate, the physical triggers of cardiac remodelling 1,2. Cell-mediated mechanotrans-duction responses are important regulators of adaptive and maladaptive myocyte and matrix remodelling 3. Mechanical loading also induces the release of factors such as angiotensin II, endothelin 1 and transforming growth

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“…Although the identity of the mechanosensor that initiates Hippo signaling is not clear, cytoskeletal dynamics are central for pathway activity. Thus, inhibition of Rho and disruption of F-actin results in pathway inactivation [207]. When Hippo signaling is absent, the transcription coactivators YAP and its paralog TAZ (transcriptional coactivator with PDZ-binding motif) can translocate between the cytoplasm and nucleus.…”

Section: Mechanotransduction By the Cytoskeleton: Actin’ On Nucleamentioning

confidence: 99%

The Soft- and Hard-Heartedness of Cardiac Fibroblasts: Mechanotransduction Signaling Pathways in Fibrosis of the Heart

Herum

Lunde

McCulloch

et al. 2017

JCM

140

123

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Cardiac fibrosis, the excessive accumulation of extracellular matrix (ECM), remains an unresolved problem in most forms of heart disease. In order to be successful in preventing, attenuating or reversing cardiac fibrosis, it is essential to understand the processes leading to ECM production and accumulation. Cardiac fibroblasts are the main producers of cardiac ECM, and harbor great phenotypic plasticity. They are activated by the disease-associated changes in mechanical properties of the heart, including stretch and increased tissue stiffness. Despite much remaining unknown, an interesting body of evidence exists on how mechanical forces are translated into transcriptional responses important for determination of fibroblast phenotype and production of ECM constituents. Such mechanotransduction can occur at multiple cellular locations including the plasma membrane, cytoskeleton and nucleus. Moreover, the ECM functions as a reservoir of pro-fibrotic signaling molecules that can be released upon mechanical stress. We here review the current status of knowledge of mechanotransduction signaling pathways in cardiac fibroblasts that culminate in pro-fibrotic gene expression.

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Synergistic induction of CTGF by cytochalasin D and TGFβ-1 in primary human renal epithelial cells: Role of transcriptional regulators MKL1, YAP/TAZ and Smad2/3

Cited by 16 publications

References 46 publications

Formin-dependent TGF-β signaling for epithelial to mesenchymal transition

Formin-dependent TGF-β signaling for epithelial to mesenchymal transition

Mechanical regulation of gene expression in cardiac myocytes and fibroblasts

The Soft- and Hard-Heartedness of Cardiac Fibroblasts: Mechanotransduction Signaling Pathways in Fibrosis of the Heart

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