Sphingosine-1-phosphate receptor S1P1 is regulated by direct interactions with P-Rex1, a Rac guanine nucleotide exchange factor

Sphingosine-1-phosphate (S1P) receptors S1P1 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 S1P1 function is based on agonists that promote changes on S1P1 expression at the plasma membrane. Here, we explored the hypothesis that cell surface expression and function of S1P1 are influenced by direct interactions with P-Rex1, a guanine nucleotide exchange factor for Rac. We demonstrate that P-Rex1-PDZ domains interact with S1P1-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. S1P1 trafficking to intracellular compartments is diminished by coexpression of P-Rex1. We conclude that S1P1 signaling linked to cell migration is facilitated by a functional interaction with P-Rex1 via a mechanism that involves the maintenance of S1P1 receptors at the cell membrane.