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 (SIP) receptors includes receptor isotype-specific, bimodal regulatory activity on cell migration. While Edg1 and Edg3 act as typical chemotactic receptors, Edg1 uniquely acts as a chemorepellant receptor. Consistent with this, Edg1 and Edg3, and Edgy 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 SIP. Edgy-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 SIP 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 SIP. Physiological and pathological roles for the repulsive activity of Edgy receptor remain to be clarified. (C) 2002 Elsevier Science B.V. All rights reserved.