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: The HGF-induced endothelial barrier protective response is associated with activation of Rac1 GTPase signaling, but the precise mechanisms of Rac1 activation remain elusive. We found that HGF induced activation of Rac1 (Figure 1A), which was associated with rapid stimulation of Asef nucleotide exchange activity toward Rac1 observed at 2–10 min after HGF addition (Figure 1B). Western blot analysis showed comparable levels of Asef expression in both human lung microvascular and pulmonary artery EC cultures. These data suggest the role for Asef-dependent signaling mechanisms in ECs from different vascular beds. HGF-induced activation of Asef guanine nucleotide exchange activity toward Rac1 was abrogated by cell pretreatment with the pharmacological inhibitor of HGF receptor c-Met (Figure 1C). Activation of Asef by HGF also led to Asef translocation to the cell membrane fraction (Figure 1D), with preferential accumulation at the cell periphery as visualized by immunofluorescence staining with Asef antibody (Figure 1E).
Affiliation: Section of Pulmonary and Critical Care Medicine, Department of Medicine, University of Chicago, Chicago, IL 60637.