The phosphorylated derivative of the immunosuppressant FFY720 interacts with and modulates the function of sphingosine-1-phosphate (S1P)-receptors. We observed a significant reduction of endothelial surface binding of a S1P(1)-specific antibody after FrY720 treatment of 6 h and longer, which was associated with a reduced healing after mechanic injury, impaired angiogenesis and enhanced adhesion molecule expression. IFTY720 (5 h) had no impact on the expression of SIP1-or S1P(3)-encoding transcripts. Notably, pre-treatment of cells with FTY720 for only 30 min, which did not reduce S1P, surface expression, inhibited the rapid S1P- and SEW2871- (a S1P(1) agonist) induced cortical actin formation and cell migration. FTY720 was effective at concentrations as low as 5 nM. FFY720 at therapeutic concentrations may be harmful by impairing important endothelial functions. Interestingly, FTY720 inhibited endothelial actin remodelling and cell migration without decreasing SI P, surface expression. (c) 2008 Elsevier Inc. All rights reserved.