The Role of Rho GTPases During Fibroblast Spreading, Migration, and Myofibroblast Differentiation in 3D Synthetic Fibrous Matrices

Rho GDP dissociation inhibitors (RhoGDIs) play important roles in various cellular processes, including cell migration, adhesion, and proliferation, by regulating the functions of the Rho GTPase family. Dissociation of Rho GTPases from RhoGDIs is necessary for their spatiotemporal activation and is dynamically regulated by several mechanisms, such as phosphorylation, sumoylation, and protein interaction. The expression of RhoGDIs has changed in many human cancers and become associated with the malignant phenotype, including migration, invasion, metastasis, and resistance to anticancer agents. Here, we review how RhoGDIs control the function of Rho GTPases by regulating their spatiotemporal activity and describe the regulatory mechanisms of the dissociation of Rho GTPases from RhoGDIs. We also discuss the role of RhoGDIs in cancer progression and their potential uses for therapeutic intervention.

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Maturation of a postsynaptic domain: Role of small Rho GTPases in organising nicotinic acetylcholine receptor aggregates at the vertebrate neuromuscular junction

Journal of Anatomy ◽

10.1111/joa.13526 ◽

2021 ◽

Author(s):

Angelymar Medina‐Moreno ◽

Juan Pablo Henríquez

Keyword(s):

Neuromuscular Junction ◽

Acetylcholine Receptor ◽

Nicotinic Acetylcholine Receptor ◽

Rho Gtpases ◽

Nicotinic Acetylcholine ◽

Small Rho Gtpases

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Role of Cation Channel TRPV4 in Mechanosensing, Myofibroblast Differentiation, and Pulmonary Fibrosis

Annals of the American Thoracic Society ◽

10.1513/annalsats.201411-531mg ◽

2015 ◽

Vol 12 (Supplement 1) ◽

pp. S74-S75

Author(s):

Shaik O. Rahaman ◽

Lisa M. Grove ◽

Brian D. Southern ◽

Rachel G. Scheraga ◽

Susamma Abraham ◽

...

Keyword(s):

Pulmonary Fibrosis ◽

Cation Channel ◽

Myofibroblast Differentiation

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Critical Role of Serum Response Factor in Pulmonary Myofibroblast Differentiation Induced by TGF-β

American Journal of Respiratory Cell and Molecular Biology ◽

10.1165/rcmb.2008-0288oc ◽

2009 ◽

Vol 41 (3) ◽

pp. 332-338 ◽

Cited By ~ 76

Author(s):

Nathan Sandbo ◽

Steven Kregel ◽

Sebastien Taurin ◽

Sangeeta Bhorade ◽

Nickolai O. Dulin

Keyword(s):

Serum Response Factor ◽

Critical Role ◽

Myofibroblast Differentiation ◽

Response Factor ◽

Serum Response

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TNF-α-Induced YAP/TAZ Activity Mediates Leukocyte-Endothelial Adhesion by Regulating VCAM1 Expression in Endothelial Cells

International Journal of Molecular Sciences ◽

10.3390/ijms19113428 ◽

2018 ◽

Vol 19 (11) ◽

pp. 3428 ◽

Cited By ~ 14

Author(s):

Hyun-Jung Choi ◽

Na-Eun Kim ◽

Byeong Kim ◽

Miran Seo ◽

Ji Heo

Keyword(s):

Endothelial Cells ◽

Rho Gtpases ◽

Leukocyte Adhesion ◽

Hippo Pathway ◽

Specific Inhibitor ◽

Vascular Diseases ◽

Adhesive Properties ◽

Sprouting Angiogenesis ◽

Tnf Α

YAP/TAZ, a transcriptional co-activator of Hippo pathway, has emerged as a central player in vessel homeostasis such as sprouting angiogenesis and vascular barrier stabilization, during development. However, the role of YAP/TAZ in pathological angiogenesis remains unclear. Here, we demonstrated that YAP/TAZ is a critical mediator in leukocyte-endothelial adhesion induced by the vascular inflammatory cytokine TNF-α. YAP/TAZ was dephosphorylated, translocated from the cytosol to the nucleus, and activated by TNF-α in endothelial cells. A specific inhibitor of Rho GTPases suppressed the TNF-α-induced dephosphorylation of YAP. Knockdown of YAP/TAZ using siRNA significantly reduced the expression of the leukocyte adhesion molecule VCAM1 induced by TNF-α. The adhesion of monocytes to endothelial cells was also markedly reduced by YAP/TAZ silencing. However, knockdown of YAP/TAZ did not affect TNF-α-induced NF-κB signaling. Overall, these results suggest that YAP/TAZ plays critical roles in regulating TNF-α-induced endothelial cell adhesive properties without affecting the NF-κB pathway, and implicate YAP/TAZ as a potential therapeutic target for treating inflammatory vascular diseases.

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Essential role of Mecp2 in the regulation of myofibroblast differentiation

The FASEB Journal ◽

10.1096/fasebj.24.1_supplement.1027.3 ◽

2010 ◽

Vol 24 (S1) ◽

Author(s):

Biao Hu ◽

Mehrnaz Gharaee‐Kermani ◽

Zhe Wu ◽

Sem H. Phan

Keyword(s):

Essential Role ◽

Myofibroblast Differentiation

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Rho GTPases: Big Players in Breast Cancer Initiation, Metastasis and Therapeutic Responses

Cells ◽

10.3390/cells9102167 ◽

2020 ◽

Vol 9 (10) ◽

pp. 2167

Author(s):

Brock Humphries ◽

Zhishan Wang ◽

Chengfeng Yang

Keyword(s):

Breast Cancer ◽

Membrane Trafficking ◽

Rho Gtpases ◽

Migration And Invasion ◽

Breast Cancer Patients ◽

Cancer Initiation ◽

Cell Type Specific ◽

And Function ◽

Therapeutic Responses

Rho GTPases, a family of the Ras GTPase superfamily, are key regulators of the actin cytoskeleton. They were originally thought to primarily affect cell migration and invasion; however, recent advances in our understanding of the biology and function of Rho GTPases have demonstrated their diverse roles within the cell, including membrane trafficking, gene transcription, migration, invasion, adhesion, survival and growth. As these processes are critically involved in cancer initiation, metastasis and therapeutic responses, it is not surprising that studies have demonstrated important roles of Rho GTPases in cancer. Although the majority of data indicates an oncogenic role of Rho GTPases, tumor suppressor functions of Rho GTPases have also been revealed, suggesting a context and cell-type specific function for Rho GTPases in cancer. This review aims to summarize recent progresses in our understanding of the regulation and functions of Rho GTPases, specifically in the context of breast cancer. The potential of Rho GTPases as therapeutic targets and prognostic tools for breast cancer patients are also discussed.

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Trypanosoma cruzi Induces the PARP1/AP-1 Pathway for Upregulation of Metalloproteinases and Transforming Growth Factor β in Macrophages: Role in Cardiac Fibroblast Differentiation and Fibrosis in Chagas Disease

mBio ◽

10.1128/mbio.01853-20 ◽

2020 ◽

Vol 11 (6) ◽

Author(s):

Subhadip Choudhuri ◽

Nisha Jain Garg

Keyword(s):

Growth Factor ◽

Chagas Disease ◽

Transcriptional Activation ◽

Transforming Growth Factor ◽

Transforming Growth Factor Β ◽

Cardiac Fibroblast ◽

Myofibroblast Differentiation ◽

Content Type ◽

Parp1 Inhibitors

ABSTRACT Chagas disease (CD), caused by Trypanosoma cruzi, is a degenerative heart condition. In the present study, we investigated the role of poly [ADP-ribose] polymerase 1/activator protein 1 (PARP1/AP-1) in upregulation of profibrotic macrophages (Mϕ) and subsequent development of cardiac fibrosis in CD. We used in vitro and in vivo models of T. cruzi infection and chemical and genetic inhibition of Parp1 to examine the molecular mechanisms by which Mϕ might augment profibrotic events in CD. Cultured (RAW 264.7 and THP-1) Mϕ infected with T. cruzi and primary cardiac and splenic Mϕ of chronically infected mice exhibited a significant increase in the expression, activity, and release of metalloproteinases (MMP2, MMP9, and MMP12) and the cytokine transforming growth factor β (TGF-β). Mϕ release of MMPs and TGF-β signaled the cardiac fibroblast to myofibroblast differentiation, as evidenced by a shift from S100A4 to alpha smooth muscle actin (α-SMA) expression. Incubation of infected Mϕ with MMP2 and MMP9 inhibitors resulted in 60 to 74% decline in TGF-β release, and MMP9 and PARP1 inhibitors resulted in 57 to 70% decline in Mϕ TGF-β-driven cardiac fibroblast differentiation. Likewise, histological studies showed a 12- to 16-fold increase in myocardial expression of CD68 (Mϕ marker) and its colocalization with MMP9/TGF-β, galectin-3, and vimentin in wild-type mice with CD. In comparison, chronically infected Parp1−/− mice exhibited a >50% decline in myocardial levels of Mϕ and associated fibrosis markers. Further study showed that PARP1 synergized with c-Fos and JunB AP-1 family members for transcriptional activation of profibrotic response after T. cruzi infection. We conclude that PARP1 inhibition offers a potential therapy for controlling the T. cruzi-driven fibroblast differentiation in CD through modulation of the Mϕ signaling of the AP-1–MMP9–TGF-β pathway. IMPORTANCE Cardiomyopathy is the most important clinical manifestation of T. cruzi-driven CD. Recent studies have suggested the detrimental role of the matrix metalloproteinases MMP2 and MMP9 in extracellular matrix (ECM) degradation during cardiac remodeling in T. cruzi infection. Peripheral TGF-β levels are increased in clinically symptomatic CD patients over those in clinically asymptomatic seropositive individuals. We provide the first evidence that during T. cruzi infection, Mϕ release of MMP2 and MMP9 plays an active role in activation of TGF-β signaling of ECM remodeling and cardiac fibroblast-to-myofibroblast differentiation. We also determined that PARP1 signals c-Fos- and JunB-mediated AP-1 transcriptional activation of profibrotic gene expression and demonstrated the significance of PARP1 inhibition in controlling chronic fibrosis in Chagas disease. Our study provides a promising therapeutic approach for controlling T. cruzi-driven fibroblast differentiation in CD by PARP1 inhibitors through modulation of the Mϕ signaling of the AP-1–MMP9–TGF-β pathway.

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