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: Several actin-binding proteins, including the Arp2/3 complex, p21Arc, PAK1, and cortactin, control peripheral actin polymerization and cortical actin structure (Borisy and Svitkina, 2000; Weed and Parsons, 2001). Cortactin is an actin-binding activator of peripheral actin polymerization (Uruno et al., 2001). Translocation of cortactin to the cell periphery is mediated by Rac1 and blocked in cells with inhibited Rac1 activity (Weed et al., 1998). Rac1 activation is also required for cortactin tyrosine phosphorylation and activation of actin cytoskeletal dynamics such as membrane ruffling and lamellipodia formation (Vouret-Craviari et al., 2002; Head et al., 2003; Ammer and Weed, 2008). Involvement of Asef in HGF-induced peripheral cytoskeletal dynamics was first evaluated by analysis of cortactin membrane translocation, which indicates cortactin activation (Uruno et al., 2001; Dudek et al., 2004). HGF stimulated cortactin translocation to the membrane fraction; this effect was attenuated by Asef knockdown (Figure 3A). Rac1 activation triggers signaling pathways leading to increased cortactin tyrosine phosphorylation (Head et al., 2003). Indeed, we observed HGF-induced increase in cortactin phosphorylation at Tyr-421, which was markedly attenuated by Asef knockdown (Figure 3B).
Affiliation: Section of Pulmonary and Critical Care Medicine, Department of Medicine, University of Chicago, Chicago, IL 60637.