Role of N-WASP in Endothelial Monolayer Formation and Integrity

Mooren, Olivia L.; Kim, Kyung Soon; Cooper, John A.

doi:10.1074/jbc.m115.668285

Cited by 7 publications

(14 citation statements)

References 35 publications

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“…The formation of plasma membrane protrusions is a complex molecular process, and depends on signals and mechanisms that involve the cytoskeleton and cytoskeleton-associated factors, as well as integral and peripheral membrane proteins (for reviews, see Bisi et al, 2013;Krause and Gautreau, 2014;Alblazi and Siar, 2015;Mooren et al, 2015;Grikscheit and Grosse, 2016;Tyler et al, 2016;Pizarro-Cerda et al, 2017;Schnoor et al, 2017b;Innocenti, 2018). Actin filament branching is a key process in protrusion formation and requires the actin-related protein complex Arp2/3, which needs to be activated by members of the WAVE/ WASP protein family (Pollard et al, 2000;Ti et al, 2011;Welch and Way, 2013;Pollard, 2016;Steffen et al, 2017).…”

Section: Molecular Control Of Jailmentioning

confidence: 99%

Putting VE-cadherin into JAIL for junction remodeling

Cao

Schnittler

2019

Journal of Cell Science

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Junction dynamics of endothelial cells are based on the integration of signal transduction, cytoskeletal remodeling and contraction, which are necessary for the formation and maintenance of monolayer integrity, but also enable repair and regeneration. The VE-cadherincatenin complex forms the molecular basis of the adherence junctions and cooperates closely with actin filaments. Several groups have recently described small actin-driven protrusions at the cell junctions that are controlled by the Arp2/3 complex, contributing to cell junction regulation. We identified these protrusions as the driving force for VE-cadherin dynamics, as they directly induce new VE-cadherin-mediated adhesion sites, and have accordingly referred to these structures as junction-associated intermittent lamellipodia (JAIL). JAIL extend over only a few microns and thus provide the basis for a subcellular regulation of adhesion. The local (subcellular) VE-cadherin concentration and JAIL formation are directly interdependent, which enables autoregulation. Therefore, this mechanism can contribute a subcellularly regulated adaptation of cell contact dynamics, and is therefore of great importance for monolayer integrity and relative cell migration during wound healing and angiogenesis, as well as for inflammatory responses. In this Review, we discuss the mechanisms and functions underlying these actin-driven protrusions and consider their contribution to the dynamic regulation of endothelial cell junctions.

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Section: Molecular Control Of Jailmentioning

confidence: 99%

Putting VE-cadherin into JAIL for junction remodeling

Cao

Schnittler

2019

Journal of Cell Science

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“…In line with our result, others have also observed the disruption of endothelial barrier function in N-WASP depleted cells. 49 The nature of N-WASP as a scaffolding protein enables N-WASP to bridge the actin cytoskeleton and cell junction organizations. Cells with N-WASP downregulation have been reported to present misshaped cell junctions.…”

Section: Discussionmentioning

confidence: 99%

“…23,57 TGF-β1 plays a critical role in mediating epithelial and endothelial permeability and development of pulmonary edema. 39,49,50 αvβ6 integrin is associated with inactive TGF-β1. Our data show an increased association of N-WASP with αvβ6 integrin, and increased TGF-β1 activation, in P aeruginosa-treated epithelial cells.…”

Section: Discussionmentioning

confidence: 99%

Neuronal Wiskott‐Aldrich syndrome protein regulatesPseudomonas aeruginosa‐induced lung vascular permeability through the modulation of actin cytoskeletal dynamics

et al. 2020

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Pulmonary edema associated with increased vascular permeability is a severe complication of Pseudomonas (P.) aeruginosa‐induced acute lung injury. The mechanisms underlying P aeruginosa‐induced vascular permeability are not well understood. In the present study, we investigated the role of neuronal Wiskott Aldrich syndrome protein (N‐WASP) in modulating P aeruginosa‐induced vascular permeability. Using lung microvascular endothelial and alveolar epithelial cells, we demonstrated that N‐WASP downregulation attenuated P aeruginosa‐induced actin stress fiber formation and prevented paracellular permeability. P aeruginosa‐induced dissociation between VE‐cadherin and β‐catenin, but increased association between N‐WASP and VE‐cadherin, suggesting a role for N‐WASP in promoting P aeruginosa‐induced adherens junction rupture. P aeruginosa increased N‐WASP‐Y256 phosphorylation, which required the activation of Rho GTPase and focal adhesion kinase. Increased N‐WASP‐Y256 phosphorylation promotes N‐WASP and integrin αVβ6 association as well as TGF‐β‐mediated permeability across alveolar epithelial cells. Inhibition of N‐WASP‐Y256 phosphorylation by N‐WASP‐Y256F overexpression blocked N‐WASP effects in P aeruginosa‐induced actin stress fiber formation and increased paracellular permeability. In vivo, N‐WASP knockdown attenuated the development of pulmonary edema and improved survival in a mouse model of P aeruginosa pneumonia. Together, our data demonstrate that N‐WASP plays an essential role in P aeruginosa‐induced vascular permeability and pulmonary edema through the modulation of actin cytoskeleton dynamics.

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“…The expression pattern for both genes is unaffected in the lower density cohort but was consistently up-regulated in the higher density cohort. Wiskott-Aldrich syndrome protein (WASP) is a key regulator of endothelial cell-cell junctions and cytoskeleton dynamics and helps form and maintain the integrity and function of EC monolayers [ 35 ]. Moreover, WASP organizes actin and vascular epithelium-cadherins at EC junctions, and hence is vital for the assembly of vascular structures [ 35 – 37 ].…”

Section: Discussionmentioning

confidence: 99%

Metabolic shift in density-dependent stem cell differentiation

et al. 2017

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BackgroundVascular progenitor cells (VPCs) derived from embryonic stem cells (ESCs) are a valuable source for cell- and tissue-based therapeutic strategies. During the optimization of endothelial cell (EC) inductions from mouse ESCs using our staged and chemically-defined induction methods, we found that cell seeding density but not VEGF treatment between 10 ng/mL and 40 ng/mL was a significant variable directing ESCs into FLK1+ VPCs during stage 1 induction. Here, we examine potential contributions from cell-to-cell signaling or cellular metabolism in the production of VPCs from ESCs seeded at different cell densities.MethodsUsing 1D 1H-NMR spectroscopy, transcriptomic arrays, and flow cytometry, we observed that the density-dependent differentiation of ESCs into FLK1+ VPCs positively correlated with a shift in metabolism and cellular growth.ResultsSpecifically, cell differentiation correlated with an earlier plateauing of exhaustive glycolysis, decreased lactate production, lower metabolite consumption, decreased cellular proliferation and an increase in cell size. In contrast, cells seeded at a lower density of 1,000 cells/cm2 exhibited increased rates of glycolysis, lactate secretion, metabolite utilization, and proliferation over the same induction period. Gene expression analysis indicated that high cell seeding density correlated with up-regulation of several genes including cell adhesion molecules of the notch family (NOTCH1 and NOTCH4) and cadherin family (CDH5) related to vascular development.ConclusionsThese results confirm that a distinct metabolic phenotype correlates with cell differentiation of VPCs.

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Role of N-WASP in Endothelial Monolayer Formation and Integrity

Cited by 7 publications

References 35 publications

Putting VE-cadherin into JAIL for junction remodeling

Putting VE-cadherin into JAIL for junction remodeling

Neuronal Wiskott‐Aldrich syndrome protein regulatesPseudomonas aeruginosa‐induced lung vascular permeability through the modulation of actin cytoskeletal dynamics

Metabolic shift in density-dependent stem cell differentiation

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