Sphingosine-1-phosphate (S1P) receptors S1P(1) are emerging molecular targets for the treatment of cancer, Vascular and immune diseases, due to their pivotal role in cell migration and survival of immune and endothelial cells. A therapeutic strategy to control S1P(1) function is based on agonists that promote changes on S1P(1) expression at the plasma membrane. Here, we explored the hypothesis that cell Surface expression and function of S1P(1) are influenced by direct interactions with P-Rexl, a guanine nucleotide exchange factor for Rac. We demonstrate that P-Rex1-PDZ domains interact with S1P(1)-carboxyl terminal tail and full length receptor monomers and dimers. Endothelial cells transfected with P-Rex1-PDZ domains show an increased migratory response to S1P. S1P(1) trafficking to intracellular compartments is diminished by coexpression of P-Rex1. We conclude that S1P(1) signaling linked to cell migration is facilitated by a functional interaction with P-Rexl via a mechanism that involves the maintenance of S1P(1) receptors at the cell membrane. (C) 2009 Elsevier Inc. All rights reserved.