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J. Biol. Chem., Vol. 281, Issue 39, 29190-29200, September 29, 2006

This Article Full Text Full Text (PDF) All Versions of this Article: 281/39/29190    most recent M604310200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lee, J.-F. Articles by Lee, M.-J. Search for Related Content PubMed PubMed Citation Articles by Lee, J.-F. Articles by Lee, M.-J. Social Bookmarking                      What's this?

Dual Roles of Tight Junction-associated Protein, Zonula Occludens-1, in Sphingosine 1-Phosphate-mediated Endothelial Chemotaxis and Barrier Integrity^*

Jen-Fu Lee, Qun Zeng, Harunobu Ozaki, Lichun Wang^¶, Arthur R. Hand^||, Timothy Hla^**, Eugenia Wang, and Menq-Jer Lee^¶1

From the Gheens Center on Aging, the ^¶Department of Microbiology and Immunology, and the Department of Biochemistry and Molecular Biology, University of Louisville Health Sciences Center, Louisville, Kentucky 40202, the Department of Cardiology, Keihanna Hospital, 1-2-1 Fujisakahigashi-cho, Hirakata, Osaka 573-0153, Japan, and the ^||Department of Pediatric Dentistry and the ^**Center for Vascular Biology, Department of Physiology, University of Connecticut Health Center, Farmington, Connecticut 06030

In this report, sphingosine-1-phosphate (S1P), a serum-borne bioactive lipid, is shown to activate tight-junction-associated protein Zonula Occludens-1 (ZO-1), which in turn plays a critical role in regulating endothelial chemotaxis and barrier integrity. After S1P stimulation, ZO-1 was redistributed to the lamellipodia and cell-cell junctions via the S1P1/G_i/Akt/Rac pathway. Similarly, both endothelial barrier integrity and cell motility were significantly enhanced in S1P-treated cells through the G_i/Akt/Rac pathway. Importantly, S1P-enhanced barrier integrity and cell migration were abrogated in ZO-1 knockdown cells, indicating ZO-1 is functionally indispensable for these processes. To investigate the underlying mechanisms, we demonstrated that cortactin plays a critical role in S1P-induced ZO-1 redistribution to the lamellipodia. In addition, S1P significantly induced the formation of endothelial tight junctions. ZO-1 and -catenin polypeptides were colocalized in S1P-induced junctional structures; whereas, cortactin was not observed in these regions. Together, these results suggest that S1P induces the formation of two distinct ZO-1 complexes to regulate two different endothelial functions: ZO-1/cortactin complexes to regulate chemotactic response and ZO-1/-catenin complexes to regulate endothelial barrier integrity. The concerted operation of these two ZO-1 complexes may coordinate two important S1P-mediated functions, i.e. migration and barrier integrity, in vascular endothelial cells.

Received for publication, May 5, 2006

^* This work was supported by National Institutes of Health Grants R01HL071071 (to M.-J. L.), R01HL067330 (to T. H.), and Department of Defense Grants 3R37AG007444 (to E. W.). 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.

¹ Recipient of the New Investigator Award of the Gheens Foundation, Louisville, KY. To whom correspondence should be addressed: University of Louisville Health Sciences Center, 580 S. Preston St. Louisville, KY 40202. Tel.: 502-852-7074; Fax: 502-852-2660; E-mail: menqjer.lee{at}louisville.edu.

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