Regulation of sphingosine 1-phosphate-induced endothelial cytoskeletal rearrangement and barrier enhancement by S1P 1 receptor, PI3 kinase, Tiam1/Rac1, and α-actinin Patrick A. Singleton, Steven M. Dudek, Eddie T. Chiang and Joe G. N. Garcia 1 Division of Pulmonary and Critical Care Medicine, Center for Translational Respiratory Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA 1 Correspondence: Johns Hopkins University, Baltimore, MD 21224, USA. E-mail: drgarcia@jhmi.edu Endothelial cell (EC) barrier dysfunction results in increased vascular permeability observed in inflammation, tumor angiogenesis, and atherosclerosis. The platelet-derived phospholipid sphingosine-1-phosphate (S1P) decreases EC permeability in vitro and in vivo and thus has obvious therapeutic potential. We examined S1P-mediated human pulmonary artery EC signaling and barrier regulation in caveolin-enriched microdomains (CEM). Immunoblotting from S1P-treated EC revealed S1P-mediated rapid recruitment (1 µM, 5 min) to CEMs of the S1P receptors S1P 1 and S1P 3 , p110 PI3 kinase α and ß catalytic subunits, the Rac1 GEF, Tiam1, and α-actinin isoforms 1 and 4. Immunoprecipitated p110 PI3 kinase catalytic subunits from S1P-treated EC exhibited PIP 3 production in CEMs. Immunoprecipitation of S1P receptors from CEM fractions revealed complexes containing Tiam1 and S1P 1 . PI3 kinase inhibition (LY294002 ) attenuated S1P-induced Tiam1 association with S1P 1 , Tiam1/Rac1 activation, α-actinin-1/4 recruitment, and EC barrier enhancement. Silencing of either S1P 1 or Tiam1 expression resulted in the loss of S1P-mediated Rac1 activation and α-actinin-1/4 recruitment to CEM. Finally, silencing S1P 1 , Tiam1, or both α-actinin isoforms 1/4 inhibits S1P-induced cortical F-actin rearrangement and S1P-mediated barrier enhancement. Taken together, these results suggest that S1P-induced recruitment of S1P 1 to CEM fractions promotes PI3 kinase-mediated Tiam1/Rac1 activation required for α-actinin-1/4-regulated cortical actin rearrangement and EC barrier enhancement.—Singleton, P. A., Dudek, S. M., Chiang, E. T., Garcia, J. G. N. Regulation of sphingosine 1-phosphate-induced endothelial cytoskeletal rearrangement and barrier enhancement by S1P 1 receptor, PI3 kinase, Tiam1/Rac1 and α-actinin. Key Words: cytoskeleton • S1P • S1P 1 /Edg1 receptor • Tiam1 • PI3 kinase • α-actinin
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Regulation of sphingosine 1-phosphate-induced endothelial cytoskeletal rearrangement and barrier enhancement by S1P1 receptor, PI3 kinase, Tiam1/Rac1, and α-actinin
Singleton, Patrick A.; Dudek, Steven M.; Chiang, Eddie T.; Garcia, Joe G. N.
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, Volume 19 (12): 1646
Fed of American Socs for Experimental Biology – Oct 1, 2005
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