Sphingosine-1-phosphate receptor S1P1 is regulated by direct interactions with P-Rex1, a Rac guanine nucleotide exchange factor.
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-Rex1, 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-Rex1 via a mechanism that involves the maintenance of S1P(1) receptors at the cell membrane.
Ledezma-Sánchez
Benjamín Alejandro
BA
Department of Pharmacology, Center for Research and Advanced Studies of the National Polytechnic Institute (CINVESTAV-IPN), Av Instituto Politécnico Nacional 2508, Col San Pedro Zacatenco, 07360 Apartado Postal 14-740, 07000 México, DF México.
García-Regalado
Alejandro
A
Guzmán-Hernández
María Luisa
ML
Vázquez-Prado
José
J
D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D002465:Cell Movement; D042783:Endothelial Cells / Q000378:metabolism / Q000502:physiology; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism*; D006801:Humans; D054731:PDZ Domains; D055503:Protein Multimerization; D049349:Receptors, Lysosphingolipid / Q000378:metabolism*
D020662:Guanine Nucleotide Exchange Factors; C453280:PREX1 protein, human; D049349:Receptors, Lysosphingolipid