Rho GTPases mediated integrin αvβ3 activation in sphingosine-1-phosphate stimulated chemotaxis of endothelial cells

• DOI: 10.1007/s00418-008-0389-8
• Publication Date: 2008-02-04T11:24:45Z
• Authors: Lichun Wang; Jen-Fu Lee; Chen-Yong Lin; Menq-Jer Lee
• Keywords: rho GTP-Binding Proteins; 0301 basic medicine; Chemotaxis; Immunoblotting; Endothelial Cells; Fluorescent Antibody Technique; Integrin alphaVbeta3; Cell Line; Receptors, G-Protein-Coupled; 3. Good health; Cytoskeletal Proteins; Receptors, Lysosphingolipid; 03 medical and health sciences; Pertussis Toxin; Cell Movement; Sphingosine; Focal Adhesion Protein-Tyrosine Kinases; Cell Adhesion; Humans; Gene Silencing; Vitronectin; Lysophospholipids; RNA, Small Interfering

Integrins, a family of transmembrane heterodimeric polypeptides, mediate various biological responses including cell adhesion and migration. In this report, we show that sphingosine-1-phosphate (S1P) activates integrin alpha v beta 3 in endothelial cells (ECs) via the sphingosine-1-phosphate receptor subtype 1 (S1P1)-mediated signaling pathway. S1P treatment results in the activation of integrin alpha v beta 3 in the lamellipodia region of ECs, suggesting that integrin alpha v beta 3 plays a critical role in the S1P-stimulated chemotactic response of ECs. Indeed, S1P treatment induces the association of focal adhesion kinase (FAK) and cytoskeletal proteins with integrin alpha v beta 3, the ligation of alpha v and beta 3 subunits, as well as enhances endothelial migration on vitronectin-coated substrata. Knockdown endothelial S1P1 receptor, treatments with pertussis toxin or dominant-negative-Rho family GTPases abrogates the S1P-induced integrin alpha v beta 3 activation in ECs. Consequently, these treatments markedly inhibit the S1P-induced endothelial migratory response on vitronectin-coated substrata. Collectively, these data indicate that the S1P-mediated signaling via the S1P1/Gi/Rho GTPases pathway activates integrin alpha v beta 3, which is indispensable for S1P-stimulated chemotactic response of ECs.