Regulation of RhoA Activity by Adhesion Molecules and Mechanotransduction

Marjoram, Robin J.; Lessey, Elizabeth C.; Burridge, Keith

doi:10.2174/1566524014666140128104541

Cited by 92 publications

(80 citation statements)

References 123 publications

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“…Mechanotransduction depends largely on a variety of cell-matrix adhesion molecules, such as integrins, cadherins, and intercellular adhesion molecule-1. 45 During cell adhesion, external mechanical force promotes clustering of integrins and then leads to recruitment of focal complexes at the inner side of the cell membrane. 46 Focal adhesion kinase (FAK) phosphorylation further activates RhoA and actin filaments.…”

Section: Discussionmentioning

confidence: 99%

The Role of the RhoA/ROCK Signaling Pathway in Mechanical Strain-Induced Scleral Myofibroblast Differentiation

Yuan

et al. 2018

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. Biomechanical properties changes and a-smooth muscle actin (a-SMA) overexpression are involved in myopia scleral remodeling. However, interactions between altered tissue biomechanics and cellular signaling that sustain scleral remodeling have not been well defined. We determine the mechanisms of mechanotransduction in the regulation of a-SMA expression during myopia scleral remodeling.METHODS. Guinea pigs were used to establish a form-deprivation myopia (FDM) model. Protein profiles in myopic sclera were examined using tandem mass spectrometry. Ras homolog gene family member A (RhoA) and a-SMA expressions were confirmed using quantitative (q) RT-PCR and Western blotting. Scleral fibroblasts were cultured and subjected to 4% cyclic strain. Levels of RhoA, rho-associated protein kinase-2 (ROCK2), myocardin-related transcription factor-A (MRTF-A), serum response factor (SRF), and a-SMA were determined by qRT-PCR and Western blotting in groups with or without the RhoA siRNA or ROCK inhibitor Y27632. MRTF-A and a-SMA were evaluated by confocal immunofluorescent microscopy and myofibroblasts were enumerated using flow cytometry.RESULTS. mRNA and protein levels of RhoA and a-SMA were significantly increased in the FDM eyes after 4 weeks of form-deprivation treatment. The 4% static strain increased expressions of RhoA, ROCK2, MRTF-A, SRF, and a-SMA as well as nuclear translocalization of MRTF-A in scleral fibroblasts compared to those without strain stimulation. Additionally, the percentage of myofibroblasts increased after strain stimulation. Conversely, inhibition of RhoA or ROCK2 reversed the strain-induced a-SMA expression and myofibroblast ratio.CONCLUSIONS. Mechanical strain activated RhoA signaling and scleral myofibroblast differentiation. Strain also mediated myofibroblast differentiation via the RhoA/ROCK2-MRTF-A/SRF pathway. These findings provided evidence for a mechanical strain-induced RhoA/ROCK2 pathway that may contribute to myopia scleral remodeling.

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Section: Discussionmentioning

confidence: 99%

The Role of the RhoA/ROCK Signaling Pathway in Mechanical Strain-Induced Scleral Myofibroblast Differentiation

Yuan

et al. 2018

Invest. Ophthalmol. Vis. Sci.

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“…These differences may also be mediated by variations in upstream regulators of ROCK such as podoplanin and the different Rho GTPases as well as other pathways downstream of ROCK that include ezrin and moesin that also regulate invadopodia [53, 85, 102–104]. In particular, RhoA is known to regulate force sensing pathways including actomyosin contractility [105–107] as well as invasive migration and/or metastasis by cancer cells [108–110], while RhoC has been found to promote invadopodia activity locally through the LIMK-cofilin pathway [17, 34, 85]. Furthermore, podoplanin mediates ECM degradation by invadopodia through a ROCK-LIMK-cofilin pathway that is regulated by RhoC [104].…”

Section: Discussionmentioning

confidence: 99%

Matrix rigidity differentially regulates invadopodia activity through ROCK1 and ROCK2

Jerrell

Parekh

2016

Biomaterials

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ROCK activity increases due to ECM rigidity in the tumor microenvironment and promotes a malignant phenotype via actomyosin contractility. Invasive migration is facilitated by actin-rich adhesive protrusions known as invadopodia that degrade the ECM. Invadopodia activity is dependent on matrix rigidity and contractile forces suggesting that mechanical factors may regulate these subcellular structures through ROCK-dependent actomyosin contractility. However, emerging evidence indicates that the ROCK1 and ROCK2 isoforms perform different functions in cells suggesting that alternative mechanisms may potentially regulate rigidity-dependent invadopodia activity. In this study, we found that matrix rigidity drives ROCK signaling in cancer cells but that ROCK1 and ROCK2 differentially regulate invadopodia activity through separate signaling pathways via contractile (NM II) and non-contractile (LIMK) mechanisms. These data suggest that the mechanical rigidity of the tumor microenvironment may drive ROCK signaling through distinct pathways to enhance the invasive migration required for cancer progression and metastasis.

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“…One is the increase in cellular motility driven by podoplanin interacting with the ERM proteins-Rho GTPases axis; the second is what we call "effective cohesiveness" in the cells. Effective cohesiveness designates a sensor mechanism or metabolite that would integrate the overall adhesive properties of a cell, and could be regulated by transcriptional and epigenetic mechanisms, protein stability, presence in the plasma membrane and context-specific mechanisms (like, for instance, the properties of the extracellular matrix) (Adhikary et al, 2014;Boulter et al, 2012;Engl et al, 2014;Friedl et al, 2014;Gueron et al, 2014;Marjoram et al, 2014;McGrail et al, 2014;Murali and Rajalingam, 2014;Orgaz et al, 2014;Sadok and Marshall, 2014;Thiery et al, 2012;50 Zegers and Friedl, 2014). If podoplanin is expressed in a cellular context with low effective cohesiveness, it will promote mesenchymal motility that will end up in EMT.…”

Section: Role Of Podoplanin In Emtmentioning

confidence: 99%