MRTFs‐ master regulators of EMT

Gasparics, Ákos; Sebe, Attila

doi:10.1002/dvdy.24544

Cited by 38 publications

(34 citation statements)

References 126 publications

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“…63 Mkl2/TGF-b pathway is required for the maturation and stabilization of embryonic vasculature, [63][64][65] but also for the myofibroblast transformation and EMT induction. 66,67 The enhanced TGF-b signaling taking place in vasculature leads to the endothelial-mesenchymal transition (EndMT), a process that has many similarities with EMT. 68,69 The transformed endothelial cells have high vascular permeability, further driving inflammation and by thus perpetuating the incomplete repair state.…”

Section: Discussionmentioning

confidence: 99%

SWATH-MS Proteomic Analysis of Oxygen-Induced Retinopathy Reveals Novel Potential Therapeutic Targets

Vähätupa

Nättinen

Jylhä

et al. 2018

Invest. Ophthalmol. Vis. Sci.

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Section: Discussionmentioning

confidence: 99%

SWATH-MS Proteomic Analysis of Oxygen-Induced Retinopathy Reveals Novel Potential Therapeutic Targets

Vähätupa

Nättinen

Jylhä

et al. 2018

Invest. Ophthalmol. Vis. Sci.

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“…We will then discuss the role of MRTFs in cell motility, emphasizing their canonical SRFdependent functions, as well as emerging SRF-independent functions, in both physiological and pathological contexts. Readers are also encouraged to refer to several excellent general reviews on MRTF-SRF signaling (Cen et al, 2004;Gasparics and Sebe, 2018;Hendzel, 2014;Olson and Nordheim, 2010;Pipes et al, 2006;Posern and Treisman, 2006).…”

Section: Introductionmentioning

confidence: 99%

SRF'ing and SAP'ing – the role of MRTF proteins in cell migration

Gau

Roy

2018

Journal of Cell Science

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Actin-based cell migration is a fundamental cellular activity that plays a crucial role in a wide range of physiological and pathological processes. An essential feature of the remodeling of actin cytoskeleton during cell motility is the de novo synthesis of factors involved in the regulation of the actin cytoskeleton and cell adhesion in response to growth-factor signaling, and this aspect of cell migration is critically regulated by serum-response factor (SRF)mediated gene transcription. Myocardin-related transcription factors (MRTFs) are key coactivators of SRF that link actin dynamics to SRF-mediated gene transcription. In this Review, we provide a comprehensive overview of the role of MRTF in both normal and cancer cell migration by discussing its canonical SRF-dependent as well as its recently emerged SRF-independent functions, exerted through its SAP domain, in the context of cell migration. We conclude by highlighting outstanding questions for future research in this field.

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“…The nature of the link between MRTF, actin, and α-SMA transcription is well-established from previous studies. MRTFs contain a basic region (B1) and an adjacent Glu-rich domain through which they associate with SRF (10,45), and an N-terminal domain (NTD) that contains three Arg-Pro-X-X-X-Glu-Leu (RPEL) motifs that mediate MRTF binding with G-actin. At baseline, when levels of actin polymerization are low, monomeric G-actins bind to MRTF via the RPEL motifs and sequester MRTF in the cytoplasm.…”

Section: Discussionmentioning

confidence: 99%

CD44 inhibits α-SMA gene expression via a novel G-actin/MRTF mediated pathway that requires TGFβR/p38MAPK activity in murine skin fibroblasts

Wang

Mack

Maytin

2019

Preprint

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Well-regulated differentiation of fibroblasts into myofibroblasts (MF) is critical for skin wound healing. Neoexpression of α-smooth muscle actin (α-SMA), an established marker for MF differentiation, is driven by TGFβ receptor (TGFβR)-mediated signaling. Hyaluronan (HA) and its receptor CD44 may also participate in this process. To further understand this process, primary mouse skin fibroblasts were isolated and treated in vitro with recombinant TGF-β1 (rTGF-β1) to induce α-SMA expression. CD44 expression was also increased. Paradoxically, CD44 knockdown by RNA interference (RNAi) led to increased α-SMA expression and α-SMA-containing stress fibers. Removal of extracellular HA or inhibition of HA synthesis had no effect on α-SMA levels, suggesting a dispensable role for HA. Exploration of mechanisms linking CD44 knockdown to α-SMA induction, using RNAi and chemical inhibitors, revealed a requirement for non-canonical TGFβR signaling through p38MAPK. Decreased monomeric G-actin but increased filamentous F-actin following CD44 RNAi suggested a possible role for Myocardin-related Transcription Factor (MRTF), a known regulator of α-SMA transcription and itself being regulated by G-actin binding. CD44 RNAi promoted nuclear accumulation of MRTF and the binding to its transcriptional cofactor, SRF. MRTF knockdown abrogated the increased α-SMA expression caused by CD44 RNAi, suggesting that MRTF is required for CD44-mediated regulation of α-SMA. Finally, chemical inhibition of p38MAPK reversed nuclear MRTF accumulation after rTGF-β1 addition or CD44 RNAi, revealing a central requirement for p38MAPK in both cases. We concluded that CD44 regulates α-SMA gene expression through cooperation between two intersecting signaling pathways, one mediated by Gactin/MRTF and the other via TGFβR/p38MAPK.

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MRTFs‐ master regulators of EMT

Cited by 38 publications

References 126 publications

SWATH-MS Proteomic Analysis of Oxygen-Induced Retinopathy Reveals Novel Potential Therapeutic Targets

SWATH-MS Proteomic Analysis of Oxygen-Induced Retinopathy Reveals Novel Potential Therapeutic Targets

SRF'ing and SAP'ing – the role of MRTF proteins in cell migration

CD44 inhibits α-SMA gene expression via a novel G-actin/MRTF mediated pathway that requires TGFβR/p38MAPK activity in murine skin fibroblasts

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