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J. Biol. Chem., Vol. 279, Issue 23, 24692-24700, June 4, 2004

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Pulmonary Endothelial Cell Barrier Enhancement by Sphingosine 1-Phosphate

ROLES FOR CORTACTIN AND MYOSIN LIGHT CHAIN KINASE^*

Steven M. Dudek, Jeffrey R. Jacobson, Eddie T. Chiang, Konstantin G. Birukov, Peiyi Wang, Xi Zhan¶, and Joe G. N. Garcia||

From the Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205 and the ^¶Department of Experimental Pathology, Holland Laboratory, American Red Cross, Rockville, Maryland 20855

We recently reported the critical importance of Rac GTPase-dependent cortical actin rearrangement in the augmentation of pulmonary endothelial cell (EC) barrier function by sphingosine 1-phosphate (S1P). We now describe functional roles for the actin-binding proteins cortactin and EC myosin light chain kinase (MLCK) in mediating this response. Antisense down-regulation of cortactin protein expression significantly inhibits S1P-induced barrier enhancement in cultured human pulmonary artery EC as measured by transendothelial electrical resistance (TER). Immunofluorescence studies reveal rapid, Rac-dependent translocation of cortactin to the expanded cortical actin band following S1P challenge, where colocalization with EC MLCK occurs within 5 min. Adenoviral overexpression of a Rac dominant negative mutant attenuates TER elevation by S1P. S1P also induces a rapid increase in cortactin tyrosine phosphorylation (within 30 s) critical to subsequent barrier enhancement, since EC transfected with a tyrosine-deficient mutant cortactin exhibit a blunted TER response. Direct binding of EC MLCK to the cortactin Src homology 3 domain appears essential to S1P barrier regulation, since cortactin blocking peptide inhibits both S1P-induced MLC phosphorylation and peak S1P-induced TER values. These data support novel roles for the cytoskeletal proteins cortactin and EC MLCK in mediating lung vascular barrier augmentation evoked by S1P.

Received for publication, December 22, 2003 , and in revised form, March 30, 2004.

^* This work was supported by National Institutes of Health (NIH) Grants P01 HL 58064, R01 68071 (to J. G. N. G.), R01 HL 52753-09, and R01 CA 91984-01, Department of Defense Grant DAMD 17-01-1-0125, American Heart Association Grant 0040135N (to X. Z.), and an American Heart Association grant-in-aid (to K. G. B.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Supported by the Four Schools Physician-Scientist Program, National Research Service Award HL 10403, and NIH Grant KO8 HL70013-01.

^|| To whom correspondence should be addressed: Johns Hopkins Division of Pulmonary and Critical Care Medicine, 1830 Monument St., Rm. 527, Baltimore, MD 21205. Tel.: 443-287-3343; Fax: 443-287-3349; E-mail: drgarcia{at}jhmi.edu.

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