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

Chichger, Havovi; Braza, Julie; Duong, Huetran; Harrington, Elizabeth O.

doi:10.1165/rcmb.2013-0489oc

Cited by 24 publications

(20 citation statements)

References 63 publications

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“…Cationic liposomes encapsulating cDNA encoding Rab4 wt , Rab4 Q67L , Rab4 S22N , or GFP were injected into the retro-orbital vein of C57/BL6 mice. Previous studies with cationic liposomes demonstrate that overexpression is observed at 48 hours after injection of cDNA for proteins of varying molecular weight from 27 to 78 kD; however, it is likely that protein overexpression occurs throughout the lung, and not specifically in endothelial cells (11,21,23,24). At 44 hours after liposome injection, mice were exposed to the live bacteria, P. aeruginosa strain PA103, via intratracheal injection, for a further 4 hours and pulmonary edema formation was assessed by lung wet-to-dry ratio.…”

Section: Discussionmentioning

confidence: 99%

Select Rab GTPases Regulate the Pulmonary Endothelium via Endosomal Trafficking of Vascular Endothelial-Cadherin

Chichger

Braza

Duong

et al. 2016

Am J Respir Cell Mol Biol

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Pulmonary edema occurs in settings of acute lung injury, in diseases, such as pneumonia, and in acute respiratory distress syndrome. The lung interendothelial junctions are maintained in part by vascular endothelial (VE)-cadherin, an adherens junction protein, and its surface expression is regulated by endocytic trafficking. The Rab family of small GTPases are regulators of endocytic trafficking. The key trafficking pathways are regulated by Rab4, -7, and -9. Rab4 regulates the recycling of endosomes to the cell surface through a rapid-shuttle process, whereas Rab7 and -9 regulate trafficking to the late endosome/lysosome for degradation or from the trans-Golgi network to the late endosome, respectively. We recently demonstrated a role for the endosomal adaptor protein, p18, in regulation of the pulmonary endothelium through enhanced recycling of VE-cadherin to adherens junction. Thus, we hypothesized that Rab4, -7, and -9 regulate pulmonary endothelial barrier function through modulating trafficking of VE-cadherin-positive endosomes. We used Rab mutants with varying activities and associations to the endosome to study endothelial barrier function in vitro and in vivo. Our study demonstrates a key role for Rab4 activation and Rab9 inhibition in regulation of vascular permeability through enhanced VE-cadherin expression at the interendothelial junction. We further showed that endothelial barrier function mediated through Rab4 is dependent on extracellular signal-regulated kinase phosphorylation and activity. Thus, we demonstrate that Rab4 and -9 regulate VE-cadherin levels at the cell surface to modulate the pulmonary endothelium through extracellular signal-regulated kinase-dependent and -independent pathways, respectively. We propose that regulating select Rab GTPases represents novel therapeutic strategies for patients suffering with acute respiratory distress syndrome.

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Section: Discussionmentioning

confidence: 99%

Select Rab GTPases Regulate the Pulmonary Endothelium via Endosomal Trafficking of Vascular Endothelial-Cadherin

Chichger

Braza

Duong

et al. 2016

Am J Respir Cell Mol Biol

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“…SHP2 inhibition reduced basal monolayer resistance in PAECs and promoted an increase in phosphorylated VE-cadherin and β -catenin as measured by IP and phosphotyrosine Western blot [ 142 ]. More recently, it was shown that both LPS and thrombin treatment induced a reduction in lung SHP2 activity and association with FAK [ 187 ]. Further, liposomal delivery of a constitutively active (D61A) SHP2 mutant reduced pulmonary edema in mice challenged with LPS or Pseudomonas aeruginosa [ 187 ], suggesting that SHP2 plays an important role in preventing acute lung injury.…”

Section: The Other Side Of the Coin: Tyrosine Phosphatasesmentioning

confidence: 99%

Regulation of Endothelial Adherens Junctions by Tyrosine Phosphorylation

Adam

2015

Mediators of Inflammation

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Endothelial cells form a semipermeable, regulated barrier that limits the passage of fluid, small molecules, and leukocytes between the bloodstream and the surrounding tissues. The adherens junction, a major mechanism of intercellular adhesion, is comprised of transmembrane cadherins forming homotypic interactions between adjacent cells and associated cytoplasmic catenins linking the cadherins to the cytoskeleton. Inflammatory conditions promote the disassembly of the adherens junction and a loss of intercellular adhesion, creating openings or gaps in the endothelium through which small molecules diffuse and leukocytes transmigrate. Tyrosine kinase signaling has emerged as a central regulator of the inflammatory response, partly through direct phosphorylation and dephosphorylation of the adherens junction components. This review discusses the findings that support and those that argue against a direct effect of cadherin and catenin phosphorylation in the disassembly of the adherens junction. Recent findings indicate a complex interaction between kinases, phosphatases, and the adherens junction components that allow a fine regulation of the endothelial permeability to small molecules, leukocyte migration, and barrier resealing.

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“…Liposomes were prepared as described elsewhere (36,37). In brief, dimethyldioctadecylammonium bromide and cholesterol were mixed in chloroform, then chloroform was evaporated by using a rotary evaporator under vacuum at 37°C until a thin lipid film formed.…”

Section: Liposome Preparationmentioning

confidence: 99%

Endothelial cell SHP‐2 negatively regulates neutrophil adhesion and promotes transmigration by enhancing ICAM‐1–VE‐cadherin interaction

et al. 2017

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Intercellular adhesion molecule-1 (ICAM-1) mediates the firm adhesion of leukocytes to endothelial cells and initiates subsequent signaling that promotes their transendothelial migration (TEM). Vascular endothelial (VE)-cadherin plays a critical role in endothelial cell-cell adhesion, thereby controlling endothelial permeability and leukocyte transmigration. This study aimed to determine the molecular signaling events that originate from the ICAM-1-mediated firm adhesion of neutrophils that regulate VE-cadherin's role as a negative regulator of leukocyte transmigration. We observed that ICAM-1 interacts with Src homology domain 2-containing phosphatase-2 (SHP-2), and SHP-2 down-regulation silencing of small interfering RNA in endothelial cells enhanced neutrophil adhesion to endothelial cells but inhibited neutrophil transmigration. We also found that VE-cadherin associated with the ICAM-1-SHP-2 complex. Moreover, whereas the activation of ICAM-1 leads to VE-cadherin dissociation from ICAM-1 and VE-cadherin association with actin, SHP-2 down-regulation prevented ICAM-1-VE-cadherin association and promoted VE-cadherin-actin association. Furthermore, SHP-2 down-regulation promoted LPS-induced neutrophil recruitment in mouse lung but delayed neutrophil extravasation. These results suggest that SHP-2- association with ICAM-1-mediates ICAM-1-induced Src activation and modulates VE-cadherin switching association with ICAM-1 or actin, thereby negatively regulating neutrophil adhesion to endothelial cells and enhancing their TEM.-Yan, M., Zhang, X., Chen, A., Gu, W., Liu, J., Ren, X., Zhang, J., Wu, X., Place, A. T., Minshall, R. D., Liu, G. Endothelial cell SHP-2 negatively regulates neutrophil adhesion and promotes transmigration by enhancing ICAM-1-VE-cadherin interaction.

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

Cited by 24 publications

References 63 publications

Select Rab GTPases Regulate the Pulmonary Endothelium via Endosomal Trafficking of Vascular Endothelial-Cadherin

Select Rab GTPases Regulate the Pulmonary Endothelium via Endosomal Trafficking of Vascular Endothelial-Cadherin

Regulation of Endothelial Adherens Junctions by Tyrosine Phosphorylation

Endothelial cell SHP‐2 negatively regulates neutrophil adhesion and promotes transmigration by enhancing ICAM‐1–VE‐cadherin interaction

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