Conditional deletion of FAK in mice endothelium disrupts lung vascular barrier function due to destabilization of RhoA and Rac1 activities

Schmidt, Tracy Thennes; Tauseef, Mohammad; Yue, Lili; Bonini, Marcelo G.; Göthert, Joachim R; Shen, Tang‐Long; Guan, Jun‐Lin; Predescu, Sanda; Sadikot, Ruxana T.; Mehta, Dolly

doi:10.1152/ajplung.00094.2013

Cited by 52 publications

(67 citation statements)

References 49 publications

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“…In a recent study, we had shown SHP2 inhibition to promote pulmonary barrier dysfunction through the enhanced tyrosine phosphorylation of AJ protein constituents, VE-cadherin, b-catenin, and p190RhoGAP, as well as activation of RhoA (5). Our previous findings suggested SHP2 to act at the level of endothelial intercellular junctions to regulate endothelial monolayer permeability (5 (34) showed that the knockdown of FAK in the mouse endothelium promoted lung edema and cell infiltration through the impairment of VE-cadherin surface expression and AJ formation. Further studies demonstrated that disruption of FAK signaling caused dysfunction of AJs (12,29,35), and have implicated the kinase activity of FAK as vital in maintaining endothelial cell barrier function and localization of VE-cadherin at AJs via select phosphorylation of VE-cadherin Y 658 (36).…”

Section: Discussionmentioning

confidence: 99%

SH2 Domain-Containing Protein Tyrosine Phosphatase 2 and Focal Adhesion Kinase Protein Interactions Regulate Pulmonary Endothelium Barrier Function

Chichger

Braza

Duong

et al. 2015

Am J Respir Cell Mol Biol

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Enhanced protein tyrosine phosphorylation is associated with changes in vascular permeability through formation and dissolution of adherens junctions and regulation of stress fiber formation. Inhibition of the protein tyrosine phosphorylase SH2 domaincontaining protein tyrosine phosphatase 2 (SHP2) increases tyrosine phosphorylation of vascular endothelial cadherin and b-catenin, resulting in disruption of the endothelial monolayer and edema formation in the pulmonary endothelium. Vascular permeability is a hallmark of acute lung injury (ALI); thus, enhanced SHP2 activity offers potential therapeutic value for the pulmonary vasculature in diseases such as ALI, but this has not been characterized. To assess whether SHP2 activity mediates protection against edema in the endothelium, we assessed the effect of molecular activation of SHP2 on lung endothelial barrier function in response to the edemagenic agents LPS and thrombin. Both LPS and thrombin reduced SHP2 activity, correlated with decreased focal adhesion kinase (FAK) phosphorylation (Y 397 and Y 925 ) and diminished SHP2 protein-protein associations with FAK. Overexpression of constitutively active SHP2 (SHP2 D61A ) enhanced baseline endothelial monolayer resistance and completely blocked LPSand thrombin-induced permeability in vitro and significantly blunted pulmonary edema formation induced by either endotoxin (LPS) or Pseudomonas aeruginosa exposure in vivo. Chemical inhibition of FAK decreased SHP2 protein-protein interactions with FAK concomitant with increased permeability; however, overexpression of SHP2 D61A rescued the endothelium and maintained FAK activity and FAK-SHP2 protein interactions. Our data suggest that SHP2 activation offers the pulmonary endothelium protection against barrier permeability mediators downstream of the FAK signaling pathway. We postulate that further studies into the promotion of SHP2 activation in the pulmonary endothelium may offer a therapeutic approach for patients suffering from ALI.Keywords: endothelium; SH2 domain-containing protein tyrosine phosphatase 2; pulmonary edema; acute lung injury; focal adhesion kinase Clinical RelevanceThis work studies the mechanism through which SHP2 activation protects the endothelial barrier against injury. In settings of acute lung injury, activation of SHP2 may offer a novel therapeutic approach to treat pulmonary edema.Acute respiratory distress syndrome (ARDS) is a complex syndrome associated with severe arterial hypoxemia. Onset of ARDS results from several predisposing factors, such as pneumonia, pancreatitis, sepsis, and trauma. At present, patients suffering from ARDS are treated with mechanical ventilation; however, there are insufficient treatment options available, and

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Section: Discussionmentioning

confidence: 99%

SH2 Domain-Containing Protein Tyrosine Phosphatase 2 and Focal Adhesion Kinase Protein Interactions Regulate Pulmonary Endothelium Barrier Function

Chichger

Braza

Duong

et al. 2015

Am J Respir Cell Mol Biol

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“…125 Inhibition of Rac with Clostridium sordellii toxin (a specific inhibitor of Rac) caused AJ disruption in cultured endothelial cells and increased L p of rat venular microvessels, 126 implicating Rac in promoting barrier function by stabilizing AJs. Schmidt et al 127 recently showed that a fine balance between the activities of RhoA and Rac1 GTPases is required for maintaining AJs in mice lungs. They showed, using a mouse model lacking endothelial focal adhesion kinase (FAK , described 128 showed that the re-annealing of AJs following the increase in endothelial permeability by thrombin required the activation of Cdc42.…”

Section: Role Of Rho-gtpasesmentioning

confidence: 99%

“…129 Role of FAK FAK, a 120-kD nonreceptor tyrosine kinase, regulates turnover of focal adhesion formation by binding to focal adhesion proteins, such as vinculin, talin, and paxillin. 2,127 Global as well as endothelial cell-specific deletion of FAK induces lethality in embryos because of improper formation of blood vessels. Several studies have shown that FAK maintains basal endothelial barrier function and induces resealing of endothelial junctions following the increase in endothelial permeability by thrombin or H 2 O 2 .…”

Section: Role Of Rho-gtpasesmentioning

confidence: 99%

“…131 However, expression of dominant negative FAK or kinase-dead FAK mutant in endothelial cells prevented AJ disruption in response to VEGF or oxidants, indicating FAK infact disrupts the barrier function. 132 To resolve the role of FAK in regulating lung vascular barrier function, Schmidt et al 127 generated tamoxifen-inducible endothelial-specific FAK knockout mice. These authors showed that loss of EC-FAK induced diffuse lung hemorrhage and increased transvascular albumin influx, edema, and neutrophil accumulation in the lung due to disruption of AJs.…”

Section: Role Of Rho-gtpasesmentioning

confidence: 99%

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Mechanisms Regulating Endothelial Permeability

et al. 2014

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The endothelial monolayer partitioning underlying tissue from blood components in the vessel wall maintains tissue fluid balance and host defense through dynamically opening intercellular junctions. Edemagenic agonists disrupt endothelial barrier function by signaling the opening of the intercellular junctions leading to the formation of protein-rich edema in the interstitial tissue, a hallmark of tissue inflammation that, if left untreated, causes fatal diseases, such as acute respiratory distress syndrome. In this review, we discuss how intercellular junctions are maintained under normal conditions and after stimulation of endothelium with edemagenic agonists. We have focused on reviewing the new concepts dealing with the alteration of adherens junctions after inflammatory stimulus.

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“…The honor roll includes Drs. Christina Alvira (19), Lyubov Brueggemann (4), Adrian R. West (55), Julia E. Rager (43), James Londino (25), Ezra Roan (44), and Tracy Schmidt (46). Congratulations to these outstanding young scientists.…”

Section: Our Publishing Philosophymentioning

confidence: 99%

A critical review of the American Journal of Physiology-Lung Cellular and Molecular Physiology: 2012–2015

Matalon

2014

American Journal of Physiology-Lung Cellular and Molecular Phys

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I have had the privilege of serving as Editor-in-Chief of the American Journal of Physiology: Lung Cellular and Molecular Physiology from 1/1/2012 to 1/1/2015 and have been reappointed for another 3-year term. When I took over as editor, I published an editorial in AJP-Lung in which I highlighted my vision and outlined the tasks to be accomplished to transform AJP-Lung into “The best place to publish basic, translational, and hypothesis-driven clinical lung research.” Herein I review our accomplishments during the first term. As promised, we review each article submitted to this journal and our reviews always help the quality and impact of every paper. We recognized the contributions of junior authors by establishing a number of awards and increased the visibility of AJP-Lung by establishing Facebook and Blog electronic pages and sponsoring symposia in scientific meetings. Our impact factor increased from 3.523 in 2011 to 4.041 in 2012 and, thanks to our calls for papers, we are receiving large numbers of high-quality papers in all aspects of pulmonary cell biology and lung diseases. The best is yet to come.

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Conditional deletion of FAK in mice endothelium disrupts lung vascular barrier function due to destabilization of RhoA and Rac1 activities

Abstract: Conditional deletion of FAK in mice endothelium disrupts lung vascular barrier function due to destabilization of RhoA and Rac1 activities.

Cited by 52 publications

References 49 publications

SH2 Domain-Containing Protein Tyrosine Phosphatase 2 and Focal Adhesion Kinase Protein Interactions Regulate Pulmonary Endothelium Barrier Function

SH2 Domain-Containing Protein Tyrosine Phosphatase 2 and Focal Adhesion Kinase Protein Interactions Regulate Pulmonary Endothelium Barrier Function

Mechanisms Regulating Endothelial Permeability

A critical review of the American Journal of Physiology-Lung Cellular and Molecular Physiology: 2012–2015

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