Fate-determining mechanisms in epithelial–myofibroblast transition: major inhibitory role for Smad3

Masszi, András; Speight, Pam; Charbonney, Emmanuel; Lodyga, Monika; Nakano, Hiroyasu; Szászi, Katalin; Kapùs, András

doi:10.1083/jcb.200906155

Cited by 116 publications

(183 citation statements)

References 70 publications

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“…Hic-5 interacts with SMAD-family members, altering their stability, and could regulate the biphasic differentiation by terminating this early SMADdependent phase and enabling the later MRTF-A-SRF phase (Charbonney et al, 2011;Masszi et al, 2010;Wang et al, 2008Wang et al, , 2005. The reported negative regulation of SMAD7 by Hic-5 might also partially explain the recent finding that Hic-5-knockout mice are resistant to the development of liver fibrosis (Lei et al, 2016).…”

Section: Discussionmentioning

confidence: 59%

“…One way in which SMADs are thought to regulate the induction of contractile genes important for myofibroblast differentiation is by regulating the expression and function of MRTF-A (Charbonney et al, 2011;Masszi et al, 2010;Mihira et al, 2012;Morita et al, 2007;Scharenberg et al, 2014). We observed that MRTF-A levels were significantly lower in SMAD3-depleted NHDFs at 48 h post treatment (Fig.…”

Section: Hic-5 Expression In Myofibroblasts In Vivomentioning

confidence: 50%

“…In fact, SMAD3 and MRTF-A are known to interact as a transcriptionally active complex during epithelial-mesenchymal transition (EMT) (Morita et al, 2007). Indeed, it has been suggested that myofibroblast differentiation is biphasic with an early SMADdependent phase that induces genes, which aid in stress fiber growth (Sandbo et al, 2011), and then a later contractile phase governed by MRTF-A and SRF (Charbonney et al, 2011;Masszi et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

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Hic-5 is required for myofibroblast differentiation by regulating mechanically dependent MRTF-A nuclear accumulation

Varney

Betts

Zheng

et al. 2016

Journal of Cell Science

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How mechanical cues from the extracellular environment are translated biochemically to modulate the effects of TGF-β on myofibroblast differentiation remains a crucial area of investigation. We report here that the focal adhesion protein, Hic-5 (also known as TGFB1I1), is required for the mechanically dependent generation of stress fibers in response to TGF-β. Successful generation of stress fibers promotes the nuclear localization of the transcriptional co-factor MRTF-A (also known as MKL1), and this correlates with the mechanically dependent induction of α smooth muscle actin (α-SMA) and Hic-5 in response to TGF-β. As a consequence of regulating stress fiber assembly, Hic-5 is required for the nuclear accumulation of MRTF-A and the induction of α-SMA as well as cellular contractility, suggesting a crucial role for Hic-5 in myofibroblast differentiation. Indeed, the expression of Hic-5 was transient in acute wounds and persistent in pathogenic scars, and Hic-5 colocalized with α-SMA expression in vivo. Taken together, these data suggest that a mechanically dependent feed-forward loop, elaborated by the reciprocal regulation of MRTF-A localization by Hic-5 and Hic-5 expression by MRTF-A, plays a crucial role in myofibroblast differentiation in response to TGF-β.

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Section: Discussionmentioning

confidence: 59%

Section: Hic-5 Expression In Myofibroblasts In Vivomentioning

confidence: 50%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Hic-5 is required for myofibroblast differentiation by regulating mechanically dependent MRTF-A nuclear accumulation

Varney

Betts

Zheng

et al. 2016

Journal of Cell Science

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“…Smads have been shown to activate SMC differentiation from several different progenitors (22,26,43,44) although Smad3 was recently reported to inhibit MRTF-induced ACTA2 expression in epithelial-myofibroblast transition (45). It appears that only Smad3, but not Smad2, mediates the suppression of Myocd expression.…”

Section: Discussionmentioning

confidence: 99%

Smad3-mediated Myocardin Silencing

Xie

Miano

et al. 2011

Journal of Biological Chemistry

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“…Ref. 38). Forty-eight hours after transfection, HA-ERK2 was precipitated through the tag from lysates of untreated or TNF-␣-treated cells.…”

Section: Tnf-␣-induced Erk and Rhoa Activation Is Src-dependent-mentioning

confidence: 99%

The Epidermal Growth Factor Receptor Mediates Tumor Necrosis Factor-α-induced Activation of the ERK/GEF-H1/RhoA Pathway in Tubular Epithelium

Kakiashvili¹,

Dan²,

Vandermeer

et al. 2011

Journal of Biological Chemistry

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Tumor necrosis factor (TNF)-␣ induces cytoskeleton and intercellular junction remodeling in tubular epithelial cells; the underlying mechanisms, however, are incompletely explored. We have previously shown that ERK-mediated stimulation of the RhoA GDP/GTP exchange factor GEF-H1/Lfc is critical for TNF-␣-induced RhoA stimulation. Here we investigated the upstream mechanisms of ERK/GEF-H1 activation. Surprisingly, TNF-␣-induced ERK and RhoA stimulation in tubular cells were prevented by epidermal growth factor receptor (EGFR) inhibition or silencing. TNF-␣ also enhanced phosphorylation of the EGFR. EGF treatment mimicked the effects of TNF-␣, as it elicited potent, ERK-dependent GEF-H1 and RhoA activation. Moreover, EGF-induced RhoA activation was prevented by GEF-H1 silencing, indicating that GEF-H1 is a key downstream effector of the EGFR. The TNF-␣-elicited EGFR, ERK, and RhoA stimulation were mediated by the TNF-␣ convertase enzyme (TACE) that can release EGFR ligands. Further, EGFR transactivation also required the tyrosine kinase Src, as Src inhibition prevented TNF-␣-induced activation of the EGFR/ERK/ GEF-H1/RhoA pathway. Importantly, a bromodeoxyuridine (BrdU) incorporation assay and electric cell substrate impedance-sensing (ECIS) measurements revealed that TNF-␣ stimulated cell growth in an EGFR-dependent manner. In contrast, TNF-␣-induced NFB activation was not prevented by EGFR or Src inhibition, suggesting that TNF-␣ exerts both EGFR-dependent and -independent effects. In summary, in the present study we show that the TNF-␣-induced activation of the ERK/GEF-H1/RhoA pathway in tubular cells is mediated through Src-and TACE-dependent EGFR activation. Such a mechanism could couple inflammatory and proliferative stimuli and, thus, may play a key role in the regulation of wound healing and fibrogenesis.

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Fate-determining mechanisms in epithelial–myofibroblast transition: major inhibitory role for Smad3

Abstract: Smad3 inhibits activation of the smooth muscle actin promoter and functions as a timer for myogenic programming in the epithelium.

Cited by 116 publications

References 70 publications

Hic-5 is required for myofibroblast differentiation by regulating mechanically dependent MRTF-A nuclear accumulation

Hic-5 is required for myofibroblast differentiation by regulating mechanically dependent MRTF-A nuclear accumulation

Smad3-mediated Myocardin Silencing

The Epidermal Growth Factor Receptor Mediates Tumor Necrosis Factor-α-induced Activation of the ERK/GEF-H1/RhoA Pathway in Tubular Epithelium

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