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Vol. 18, Issue 6, 2346-2355, June 2007

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Induction of Vascular Permeability: PIX and GIT1 Scaffold the Activation of Extracellular Signal-regulated Kinase by PAK

Rebecca Stockton^*,, Jörg Reutershan^*, David Scott^*, John Sanders^*, Klaus Ley^*,,, and Martin Alexander Schwartz^*,,||

*Robert M. Berne Cardiovascular Research Center, and Departments of Biomedical Engineering, Molecular Physiology and Biological Physics, and ^||Microbiology, University of Virginia, Charlottesville, VA 22908

Submitted July 5, 2006; Revised March 26, 2007; Accepted March 30, 2007
Monitoring Editor: Anne Ridley

Increased permeability of blood vessels is an important component of inflammation, but in some circumstances it contributes to tissue injury and organ failure. Previous work showed that p21-activated kinase (PAK) is a critical regulator of endothelial cell–cell junctions through effects on myosin light chain phosphorylation and cell contractility. We now show that blocking PAK function inhibits fluid leak in a mouse model of acute lung injury. In cultured endothelial cells, induction of myosin light chain phosphorylation by PAK is mediated by mitogen-activated protein kinase kinase and extracellular signal-regulated kinase (Erk). Erk in lipopolysaccharide (LPS)-treated mouse lung is activated in a PAK-dependent manner in several cell types, most prominently vascular endothelium. Activation of Erk requires the integrity of the complex between PAK, PIX, and GIT1. Several means of disrupting this complex inhibit stimulation of vascular permeability in vitro. A cell-permeant peptide that blocks binding of PAK to PIX inhibits LPS-induced fluid leak in the mouse lung injury model. We conclude that the PAK–PIX–GIT1 complex is critical for Erk-dependent myosin phosphorylation and vascular permeability.

Present address: Department of Medicine, University of California, San Diego, La Jolla, CA 92093-0623.

Address correspondence to: Martin Alexander Schwartz (maschwartz{at}virginia.edu)

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