Asef controls vascular endothelial permeability and barrier recovery in the lung.
Bottom Line: Molecular inhibition of Asef attenuated HGF-induced peripheral accumulation of cortactin, formation of lamellipodia-like structures, and enhancement of VE-cadherin adherens junctions and compromised HGF-protective effect against thrombin-induced RhoA GTPase activation, Rho-dependent cytoskeleton remodeling, and EC permeability.This effect was lost in Asef(-/-) mice.This study shows for the first time the role of Asef in HGF-mediated protection against endothelial hyperpermeability and lung injury.
Affiliation: Section of Pulmonary and Critical Care Medicine, Department of Medicine, University of Chicago, Chicago, IL 60637.Show MeSH
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Mentions: Potential effect of EC confluence on Asef-dependent peripheral cortactin activation and actin cytoskeletal remodeling was further tested. Activation of cortactin in response to HGF was reflected by cortactin phosphorylation and accumulation in cell-peripheral lamellipodia-like structures and was observed in both sparse and dense EC monolayers (Figure 3, D and E). These effects were markedly attenuated by Asef knockdown in both sparse and dense EC cultures. Cortactin translocation was also accompanied by increased F-actin accumulation at cell peripheral compartments (Figure 4A). Inspection of subcortical F-actin accumulation at different cell regions revealed that HGF-induced cortical F-actin accumulation in lamellipodia-like structures was observed in regions with intercellular gaps (inset 1 in Figure 4A) but also in the regions of established cell–cell contacts (inset 2 in Figure 4, A and B). HGF-induced cortical actin dynamics was inhibited by Asef knockdown (Figure 4, A and B). These data show that HGF-induced Asef activity stimulates cortical cytoskeletal dynamics in a cell contact–independent manner.
Affiliation: Section of Pulmonary and Critical Care Medicine, Department of Medicine, University of Chicago, Chicago, IL 60637.