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MBC in Press, published online ahead of print April 11, 2007
Mol. Biol. Cell 10.1091/mbc.E06-07-0584

A more recent version of this article appeared on June 1, 2007
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Submitted on July 5, 2006
Revised on March 26, 2007
Accepted on March 30, 2007

Induction of Vascular Permeability: {beta}PIX and GIT1 Scaffold the Activation of Erk by PAK

Rebecca Stockton,*{dagger} Jörg Reutershan,* David Scott,* John Sanders,* Klaus Ley,*{ddagger}{sect} and Martin Alexander Schwartz*{ddagger}||

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

Monitoring Editor: Anne Ridley

Increased permeability of blood vessels is an important component of inflammation but in some circumstances 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 MEK and Erk. Erk in 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.

{dagger}Present address: Department of Medicine, University of California, San Diego, CA.

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




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