A critical role for Lyn kinase in strengthening endothelial integrity and barrier function

Han, Jing‐Yan; Zhang, Guoying; Welch, Emily J.; Li, Ying; Fu, Jing; Vogel, Stephen M.; Lowell, Clifford A.; Du, Xiaoping; Cheresh, David A.; Malik, Asrar B.; Li, Zhenyu

doi:10.1182/blood-2013-03-491423

Cited by 61 publications

(51 citation statements)

References 54 publications

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“…The EC-expressed TLR4 plays a pivotal role in mediating the increased vascular permeability stimulated by LPS, which has been shown in many previous studies [2,41] and LPSinduced vascular permeability is often applied in the researches of endothelial integrity and barrier function [23] in tumor or inflammatory diseases. Therefore, we use LPS to stimulate HUVECs constructing the increasing vascular permeability model.…”

Section: Discussionmentioning

confidence: 95%

Wogonin inhibits LPS-induced vascular permeability via suppressing MLCK/MLC pathway

Huang

Luo

et al. 2015

Vascular Pharmacology

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Section: Discussionmentioning

confidence: 95%

Wogonin inhibits LPS-induced vascular permeability via suppressing MLCK/MLC pathway

Huang

Luo

et al. 2015

Vascular Pharmacology

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“…G protein bg-dependent FAK activation localized the kinase to the AJ to promote resealing of the junctions and restore barrier function (22). Likewise, Han and colleagues (48) observed that small interfering RNA knockdown of FAK in human umbilical vein endothelial cells resulted in VE-cadherin breakdown at the endothelial cell border. Thus, the protective effect of FAK activation on the pulmonary vasculature, after SHP2 activation, may be mediated by the localization of FAK-SHP2 protein-protein interactions at the focal adhesion complexes, as well as AJs, in the endothelial cell.…”

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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“…This was surprising, as Lyn is thought to be expressed primarily in hematopoietic cells. Lyn has been reported to be present in other epithelial cell types (35)(36)(37)(38). Lyn is unique in that it initiates both activating and inhibitory signaling in hematopoietic cells, with the inhibitory signaling role being dominant (25 Human airway epithelial cells have been reported to express TLR1-6 and -9 (39).…”

Section: Discussionmentioning

confidence: 99%

Immune Defense Protein Expression in Highly Purified Mouse Lung Epithelial Cells

Sinha

Lowell

2016

Am J Respir Cell Mol Biol

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Lung epithelial cells play critical roles in initiating and modulating immune responses during pulmonary infection or injury. To better understand the spectrum of immune response-related proteins present in lung epithelial cells, we developed an improved method of isolating highly pure primary murine alveolar type (AT) II cells and murine tracheal epithelial cells (mTECs) using negative selection for a variety of lineage markers and positive selection for epithelial cell adhesion molecule (EpCAM), a pan-epithelial cell marker. This method yielded 2-3 3 10 6 ATII cells/mouse lung and 1-2 3 10 4 mTECs/trachea that were highly pure (.98%) and viable (.98%).Using these preparations, we found that both ATII cells and mTECs expressed the Lyn tyrosine kinase, which is best studied as an inhibitory kinase in hematopoietic cells. However, we found little or no expression of Syk in either ATII cells or mTECs, which is in contrast to earlier published reports. Both cell types expressed C-type lectin receptors, anaphylatoxin receptors, and various Toll-like receptors (TLRs). In addition, stimulation of ATII cells with TLR ligands led to secretion of various cytokines and chemokines.Interestingly, lyn 2/2 ATII cells were hyperresponsive to TLR3 stimulation, suggesting that, as in hematopoietic cells, Lyn might be playing an inhibitory role in ATII cells. In conclusion, the improved isolation method reported here, along with expression profiles of various immune defense proteins, will help refocus investigations of immune-related signaling events in pulmonary epithelium.

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A critical role for Lyn kinase in strengthening endothelial integrity and barrier function

Abstract: Key Points In contrast to c-Src and Yes, Lyn stabilizes endothelial junctions through interaction and phosphorylation of FAK.

Cited by 61 publications

References 54 publications

Wogonin inhibits LPS-induced vascular permeability via suppressing MLCK/MLC pathway

Wogonin inhibits LPS-induced vascular permeability via suppressing MLCK/MLC pathway

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

Immune Defense Protein Expression in Highly Purified Mouse Lung Epithelial Cells

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