Attenuation of cell motility observed with high doses of sphingosine 1‐phosphate or phosphorylated FTY720 involves RGS2 through its interactions with the receptor S1P

Sphingosine 1‐phosphate (S1P) stimulation enhances cell motility via the G‐protein coupled S1P receptor S1P1. This ligand‐induced, receptor‐mediated cell motility follows a typical bell‐shaped dose–response curve, that is, stimulation with low concentrations of S1P enhances cell motility, whereas excess ligand stimulation does not enhance it. So far, the attenuation of the response at higher ligand concentrations has not been explained. We report here that S1P1 interacts with the regulator of G protein signaling (RGS)‐2 protein, which is a GTPase‐activating protein (GAP) for heterotrimeric G proteins, in a concentration dependent manner. The RGS2–S1P1 complex dissociated at higher ligand concentrations, yet it was unaffected at low concentrations, suggesting that the dissociated RGS2 is involved in the concurrent decrease of cell motility. In RGS2 knockdown cells, the decrease of cell motility induced by high ligand concentrations was rescued. S1P1 internalization was not implicated in the attenuation of the response. Similar results were observed upon stimulation with the phosphorylated form of FTY720 (FTYP), which is an S1P1 agonist. In conclusion, the suppressed response in cell motility induced by excess S1P or FTYP via S1P1 is regulated by RGS2 functioning through a mechanism that is independent of S1P1 internalization.