Pharmacological intervention of MKL/SRF signaling by CCG-1423 impedes endothelial cell migration and angiogenesis

Gau, David; Veon, William; Capasso, Teresa L.; Böttcher, Ralph T.; Shroff, Sanjeev G.; Roman, Beth L.; Roy, Partha

doi:10.1007/s10456-017-9560-y

Cited by 35 publications

(32 citation statements)

References 32 publications

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“…Pro-angiogenic growth factor stimulation promotes nuclear accumulation of MRTFA (Franco et al, 2013) and also forces angiogenesis stimulated through expression of MRTFA in the heart in mice (Hinkel et al, 2014). Finally, consistent with the pro-migratory and pro-angiogenic role of MRTF, the inhibitor of MRTF-SRF activity CCG-1423 suppresses migration of human dermal microvascular endothelial cells in vitro, angiogenic ability of human and mouse endothelial cells in vitro and ex vivo, and developmental angiogenesis in zebrafish embryos in vivo (Gau et al, 2017). • Epithelial cells: Loss of function of SRF reduces plasma membrane blebbing, whereas that of either MRTFA and SRF or MRTFB and SRF reduces entosis of mammary epithelial cells (Hinojosa et al, 2017).…”

Section: Mechanisms Of Mrtf-dependent Regulation Of Cell Migration Srmentioning

confidence: 54%

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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Section: Mechanisms Of Mrtf-dependent Regulation Of Cell Migration Srmentioning

confidence: 54%

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

Gau

Roy

2018

Journal of Cell Science

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“…While these 2D assays are sufficient to induce EC cord formation [76–78], they cannot reproduce the necessary cues for true lumen formation found in native, 3D tissues. Collagen sandwich assays surround EC within a 3D matrix by seeding the cells in monolayer on collagen I matrix and then covering them with a second layer of collagen [79].…”

Section: 3d Models Of Vascular Morphogenesismentioning

confidence: 99%

Consensus guidelines for the use and interpretation of angiogenesis assays

et al. 2018

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The formation of new blood vessels, or angiogenesis, is a complex process that plays important roles in growth and development, tissue and organ regeneration, as well as numerous pathological conditions. Angiogenesis undergoes multiple discrete steps that can be individually evaluated and quantified by a large number of bioassays. These independent assessments hold advantages but also have limitations. This article describes in vivo, ex vivo, and in vitro bioassays that are available for the evaluation of angiogenesis and highlights critical aspects that are relevant for their execution and proper interpretation. As such, this collaborative work is the first edition of consensus guidelines on angiogenesis bioassays to serve for current and future reference.

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“…Total cord length was quantified using the Angiogenesis plugin of ImageJ. The ex vivo aortic ring assay was performed using thoracic aortic segments from 9-to 11-week-old C57Bl/6 mice as described recently (24). At the end of the experiments, aortic rings were fixed with 3% (v/v) formalin for 30 min and stained with rhodamine-conjugated lectin (0.05 mg/ml) for 2 h at room temperature and washed before imaging at ϫ4 magnification.…”

Section: Angiogenesis Assaysmentioning

confidence: 99%

Structure-based virtual screening identifies a small-molecule inhibitor of the profilin 1–actin interaction

Gau¹,

Lewis²,

McDermott³

et al. 2018

Journal of Biological Chemistry

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Profilin 1 (Pfn1) is an important regulator of the actin cytoskeleton and plays a vital role in many actin-based cellular processes. Therefore, identification of a small-molecule intervention strategy targeted against the Pfn1-actin interaction could have broad utility in cytoskeletal research and further our understanding of the role of Pfn1 in actin-mediated biological processes. Based on an already resolved Pfn1-actin complex crystal structure, we performed structure-based virtual screening of small-molecule libraries to seek inhibitors of the Pfn1-actin interaction. We identified compounds that match the pharmacophore of the key actin residues of Pfn1-actin interaction and therefore have the potential to act as competitive inhibitors of this interaction. Subsequent biochemical assays identified two candidate compounds with nearly identical structures that can mitigate the effect of Pfn1 on actin polymerization As a further proof-of-concept test for cellular effects of these compounds, we performed proximity ligation assays in endothelial cells (ECs) to demonstrate compound-induced inhibition of Pfn1-actin interaction. Consistent with the important role of Pfn1 in regulating actin polymerization and various fundamental actin-based cellular activities (migration and proliferation), treatment of these compounds reduced the overall level of cellular filamentous (F) actin, slowed EC migration and proliferation, and inhibited the angiogenic ability of ECs both and In summary, this study provides the first proof of principle of small-molecule-mediated interference with the Pfn1-actin interaction. Our findings may have potential general utility for perturbing actin-mediated cellular activities and biological processes.

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Pharmacological intervention of MKL/SRF signaling by CCG-1423 impedes endothelial cell migration and angiogenesis

Cited by 35 publications

References 32 publications

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

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

Consensus guidelines for the use and interpretation of angiogenesis assays

Structure-based virtual screening identifies a small-molecule inhibitor of the profilin 1–actin interaction

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