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HGF attenuates thrombin‐induced endothelial permeability by Tiaml‐mediated activation of the Rac pathway and by Tiam1/Rac‐dependent inhibition of the Rho pathway
Author(s) -
Birukova Anna A.,
Alekseeva Elena,
Mikaelyan Arsen,
Birukov Konstantin G.
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.06-7660com
Subject(s) - cortactin , microbiology and biotechnology , guanine nucleotide exchange factor , small interfering rna , chemistry , myosin light chain kinase , hepatocyte growth factor , gtpase , rac gtp binding proteins , rac1 , actin cytoskeleton , signal transduction , phosphorylation , paracellular transport , thrombin , cytoskeleton , biology , immunology , cell , permeability (electromagnetism) , biochemistry , transfection , platelet , receptor , gene , membrane
Reorganization of the endothelial cell (EC) cytoskeleton and cell adhesive complexes provides a structural basis for increased vascular permeability implicated in the pathogenesis of many diseases, including asthma, sepsis, and acute respiratory distress syndrome (ARDS). We have recently described the barrier‐protective effects of hepatocyte growth factor (HGF) on the human pulmonary EC. In the present study, we explored the involvement of Rac‐GTPase and Rac‐specific nucleotide exchange factor Tiam1 in the mechanisms of EC barrier protection by HGF. HGF protected EC monolayers from thrombin‐induced hy‐perpermeability, disruption of intercellular junctions, and formation of stress fibers and paracellular gaps by inhibiting thrombin‐induced activation of Rho GTPase, Rho association with nucleotide exchange factor p115‐RhoGEF, and myosin light chain phosphorylation, which was opposed by stimulation of Rac‐dependent signaling. The pharmacological Rac inhibitor or silencing RNA (siRNA) based depletion of either Rac or Tiam1 significantly attenuated HGF‐induced peripheral translocation of Rac effector cortactin, cortical actin ring formation, and EC barrier enhancement. Moreover, Tiam1 knockdown using the siRNA approach, attenuated the protective effect of HGF against throm‐bin‐induced activation of Rho signaling, monolayer disruption, and EC hyperpermeability. This study demonstrates the Tiam1/Rac‐dependent mechanism of HGF‐induced EC barrier protection and provides novel mechanistic insights into regulation of EC permeabilityvia dynamic interactions between Rho‐ and Tiam1/Rac‐medi‐ated pathways.—Birukova, A., Alekseeva, E., Mikaelyan, A., and Birukov, K. G. HGF attenuates thrombin‐induced endothelial permeability by Tiam1‐mediated activation of the Rac pathway and by Tiam1/Rac‐dependent inhibition of the Rho pathway. FASEB J. 21, 2776–2786 (2007)