Building Blood Vessels—One Rho GTPase at a Time

Barlow, Haley R.; Cleaver, Ondine

doi:10.3390/cells8060545

Cited by 33 publications

(20 citation statements)

References 120 publications

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“…This allows new blood vessels to form within the tumor, alleviates nutrient deficiency and promotes metastasis. As Rho GTPases function within specific vascular cell types, and some Rho GTPases are also expressed in diseased vessels [ 67 ], recent studies have shown that Rho GTPases are important for angiogenesis.…”

Section: Rho Gtpases In Primary Tumor Growth and Angiogenesismentioning

confidence: 99%

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

Humphries

Wang

Yang

2020

Cells

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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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Section: Rho Gtpases In Primary Tumor Growth and Angiogenesismentioning

confidence: 99%

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

Humphries

Wang

Yang

2020

Cells

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“…Upon activation, αvβ3 integrin initiates a signaling cascade in which an important role is played by rat sarcoma (Ras)-related C3 botulinum toxin substrate 1 (Rac1) that belongs to the Rho proteins, which are a dynamic group of GTPases participating in a multitude of cellular activities and functions. From their effects on the expression of angiogenic factors to their role in the integrin signaling pathways and endothelial cell morphogenesis, Rho proteins prove to be an important part of the angiogenesis machinery [74]. Little is known about uPAR interaction with αvβ3 integrin although there are some indications that αvβ3 integrin is implicated in regulatory functions mediated by the uPAR system.…”

Section: Upar-co-receptor Interactionmentioning

confidence: 99%

The uPAR System as a Potential Therapeutic Target in the Diseased Eye

Cammalleri

Monte

Pavone

et al. 2019

Cells

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Dysregulation of vascular networks is characteristic of eye diseases associated with retinal cell degeneration and visual loss. Visual impairment is also the consequence of photoreceptor degeneration in inherited eye diseases with a major inflammatory component, but without angiogenic profile. Among the pathways with high impact on vascular/degenerative diseases of the eye, a central role is played by a system formed by the ligand urokinase-type plasminogen activator (uPA) and its receptor uPAR. The uPAR system, although extensively investigated in tumors, still remains a key issue in vascular diseases of the eye and even less studied in inherited retinal pathologies such as retinitis pigmantosa (RP). Its spectrum of action has been extended far beyond a classical pro-angiogenic function and has emerged as a central actor in inflammation. Preclinical studies in more prevalent eye diseases characterized by neovascular formation, as in retinopathy of prematurity, wet macular degeneration and rubeosis iridis or vasopermeability excess as in diabetic retinopathy, suggest a critical role of increased uPAR signaling indicating the potentiality of its modulation to counteract neovessel formation and microvascular dysfunction. The additional observation that the uPAR system plays a major role in RP by limiting the inflammatory cascade triggered by rod degeneration rises further questions about its role in the diseased eye.

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“…The role of HSP27 phosphorylation in the regulation of endothelial permeability remains controversial [ 25 , 26 , 27 , 28 , 29 ]. In addition, small Rho GTPases are crucial orchestrators of actin organization and contractility [ 23 , 30 ]. RhoA promotes stress fibers contraction, while Rac1 reinforces IEJs’ anchorage to the plasma membrane by promoting the development of a cortical actin network [ 31 , 32 ].…”

Section: Introductionmentioning

confidence: 99%

α1AMP-Activated Protein Kinase Protects against Lipopolysaccharide-Induced Endothelial Barrier Disruption via Junctional Reinforcement and Activation of the p38 MAPK/HSP27 Pathway

Angé

Castanares-Zapatero

Poortere

et al. 2020

IJMS

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Vascular hyperpermeability is a determinant factor in the pathophysiology of sepsis. While, AMP-activated protein kinase (AMPK) is known to play a role in maintaining endothelial barrier function in this condition. Therefore, we investigated the underlying molecular mechanisms of this protective effect. α1AMPK expression and/or activity was modulated in human dermal microvascular endothelial cells using either α1AMPK-targeting small interfering RNA or the direct pharmacological AMPK activator 991, prior to lipopolysaccharide (LPS) treatment. Western blotting was used to analyze the expression and/or phosphorylation of proteins that compose cellular junctions (zonula occludens-1 (ZO-1), vascular endothelial cadherin (VE-Cad), connexin 43 (Cx43)) or that regulate actin cytoskeleton (p38 MAPK; heat shock protein 27 (HSP27)). Functional endothelial permeability was assessed by in vitro Transwell assays, and quantification of cellular junctions in the plasma membrane was assessed by immunofluorescence. Actin cytoskeleton remodeling was evaluated through actin fluorescent staining. We consequently demonstrate that α1AMPK deficiency is associated with reduced expression of CX43, ZO-1, and VE-Cad, and that the drastic loss of CX43 is likely responsible for the subsequent decreased expression and localization of ZO-1 and VE-Cad in the plasma membrane. Moreover, α1AMPK activation by 991 protects against LPS-induced endothelial barrier disruption by reinforcing cortical actin cytoskeleton. This is due to a mechanism that involves the phosphorylation of p38 MAPK and HSP27, which is nonetheless independent of the small GTPase Rac1. This results in a drastic decrease of LPS-induced hyperpermeability. We conclude that α1AMPK activators that are suitable for clinical use may provide a specific therapeutic intervention that limits sepsis-induced vascular leakage.

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Building Blood Vessels—One Rho GTPase at a Time

Cited by 33 publications

References 120 publications

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

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

The uPAR System as a Potential Therapeutic Target in the Diseased Eye

α1AMP-Activated Protein Kinase Protects against Lipopolysaccharide-Induced Endothelial Barrier Disruption via Junctional Reinforcement and Activation of the p38 MAPK/HSP27 Pathway

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