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The Role of Focal Adhesion Kinase in Sphingosine‐1‐Phosphate Induced Endothelial Barrier Enhancement
Author(s) -
Thennes Tracy Lynn,
Konstantoulaki Maria,
Mehta Dolly
Publication year - 2008
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/fasebj.22.1_supplement.1178.1
Subject(s) - focal adhesion , microbiology and biotechnology , adherens junction , barrier function , sphingosine 1 phosphate , ptk2 , rac1 , endothelial stem cell , actin cytoskeleton , rhoa , sphingosine , chemistry , s1pr1 , paxillin , cell junction , cell adhesion , biology , signal transduction , cadherin , cytoskeleton , cell , biochemistry , vascular endothelial growth factor a , cancer research , protein kinase c , mitogen activated protein kinase kinase , receptor , in vitro , vascular endothelial growth factor , vegf receptors
Dynamic interactions between adherens junctions and cell‐matrix adhesions mediated by actin cytoskeleton regulate endothelial barrier function. Barrier‐enhancing agonist, sphingosine‐1‐phosphate (S1P), by binding its S1P receptor1 (S1P‐1) on the endothelial cell surface enhance endothelial monolayer integrity by Rac1‐mediated stabilization of intercellular junctions and by promoting cell‐matrix adhesions at focal adhesions complexes (FACs). Focal adhesion kinase (FAK) regulates the cell‐matrix adhesive contact at focal adhesion sites. We address the possibility that S1P via FAK‐induces Rac1 activation which in turn signals lamellopodia formation to promote cell‐cell interactions and endothelial barrier enhancement. We show that S1P induces FAK activation, as evidenced by phosphorylation on tyrosine residues 397 and 576 in endothelial cells, in association with enhancement of endothelial barrier function. In YFP‐actin mutant transducing cells S1P induced robust lamellopodia formation, consistent with the role of Rac1 in strengthening intercellular junctions. Inhibition of FAK by transduction of dominant negative FAK mutant (FRNK) markedly suppressed basal Rac1 activity. FRNK expression also increased basal endothelial permeability as measured by determining transendothelial monolayer resistance and S1P could not restored it to the level seen in control cells. These findings suggest that S1P induced FAK activation may play an important role in Rac1 mediated endothelial barrier enhancement.