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: As a complementary approach to experiments with Asef knockdown, we performed ectopic expression of HA-tagged wild-type Asef or its constitutively activated (CA-Asef) or dominant-negative (DN-Asef) mutant (Kawasaki et al., 2003). Overexpression of wild-type Asef further enhanced EC peripheral actin remodeling in response to HGF in comparison to HGF-stimulated nontransfected cells (Figure 5A). In turn, expression of activated Asef mutant in nonstimulated cells reproduced peripheral actin cytoskeletal rearrangement observed in nontransfected ECs treated with HGF (Figure 5B). Similar to Asef knockdown experiments, the expression of dominant-negative Asef abrogated HGF-induced formation of lamellipodia-like structures and peripheral actin rim (Figure 5C). Expression of dominant-negative Asef mutant suppressed the HGF-induced activation of Rac1 GTPase in pulmonary ECs (Figure 5D).
Affiliation: Section of Pulmonary and Critical Care Medicine, Department of Medicine, University of Chicago, Chicago, IL 60637.