Subtype-specific differential regulation of Rho family G proteins and cell migration by the Edg family sphingosine-1-phosphate receptors.

One of the striking activities of the Edg family sphingosine-1-phosphate (S1P) receptors includes receptor isotype-specific, bimodal regulatory activity on cell migration. While Edg1 and Edg3 act as typical chemotactic receptors, Edg5 uniquely acts as a chemorepellant receptor. Consistent with this, Edg1 and Edg3, and Edg5 regulate the activity of the Rho family GTPase Rac positively and negatively, respectively. Thus, Edg isotype-specific, differential regulatory activities on Rac seem to be important as mechanisms underlying the bimodal regulation of cell migration by S1P. Edg5-mediated Rac inhibition involves stimulation of Rac-GTPase-activating protein (GAP) activity, rather than inhibition of Rac-guanine nucleotide exchange factor (GEF) activity. Many cell types including vascular smooth muscle and endothelial cells express more than a single S1P receptor isotype. In these cells, it appears that an integration of the Edg isotype-selective, positive and negative signals on cellular Rac activity is a critical determinant for eventual direction of regulation on cell motility by S1P. Physiological and pathological roles for the repulsive activity of Edg5 receptor remain to be clarified.