title: Sphingosine-1-phosphate signaling regulates lamellipodia localization of cortactin complexes in endothelial cells.
abstract: Sphingosine-1-phosphate (S1P), a serum-borne lipid mediator, was demonstrated to be a potent chemoattractant of endothelial cells. It was recently shown that the colocalization of cortactin and actin related protein 2/3 (Arp2/3) in the lamellipodia is critical to S1P-induced endothelial chemotaxis. In this report, we describe that S1P-stimulated cortactin translocation to the cell periphery to form lamellipodia is specifically mediated by the endothelial S1P1 G-protein coupled receptor, and is regulated by G(i)-mediated Akt-dependent S1P1 receptor phosphorylation and Cdc42/Rac activation pathways. In contrast to Src-dependent fibroblast growth factor-induced cortactin translocation, tyrosine phosphorylation cascades are not required for S1P-mediated lamellipodia formation and chemotaxis. Furthermore, we also demonstrate that S1P signaling, via the G(i)/Akt/S1P1 phosphorylation/Rac pathway, regulates the cortactin-Arp2/3 complex formation, which ultimately results in membrane ruffling, formation of the lamellipodia and endothelial migration.
authors.affiliation: Gheens Center on Aging, Department of Microbiology and Immunology, University of Louisville Health Science Center, 580 S. Preston St., Louisville, KY 40202, USA.
authors.forename: Jen-Fu
authors.initials: JF
authors.lastname: Lee
authors.forename: Harunobu
authors.initials: H
authors.lastname: Ozaki
authors.forename: Xi
authors.initials: X
authors.lastname: Zhan
authors.forename: Eugenia
authors.initials: E
authors.lastname: Wang
authors.forename: Timothy
authors.initials: T
authors.lastname: Hla
authors.forename: Menq-Jer
authors.initials: MJ
authors.lastname: Lee
mesh_terms: D000818:Animals; D016466:CHO Cells; D002478:Cells, Cultured; D051356:Cortactin / Q000378:metabolism*; D006224:Cricetinae; D003412:Cricetulus; D042783:Endothelial Cells / Q000378:metabolism*; D005346:Fibroblast Growth Factors / Q000494:pharmacology; D005786:Gene Expression Regulation; D006801:Humans; D008246:Lysophospholipids / Q000378:metabolism / Q000494:pharmacology*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D021381:Protein Transport; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011554:Pseudopodia / Q000378:metabolism*; D015398:Signal Transduction; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D014161:Transduction, Genetic; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology
chemical_list: D051356:Cortactin; D008246:Lysophospholipids; D042461:Vascular Endothelial Growth Factor A; C060506:sphingosine 1-phosphate; D005346:Fibroblast Growth Factors; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D013110:Sphingosine