Signaling mechanisms for positive and negative regulation of cell motility by sphingosine-1-phosphate receptors

Abstract

Sphingosine-1-phosphate (S1P) exerts positive and negative effects on cell migration apparently in a cell-type-dependent manner. Our data suggest that the bimodal actions of S1P on cell migration is due to receptor subtype-specific positive and negative regulation of Rho family GTPase, Rac; S1P1 and S1P3 mediate Rac stimulation and chemotaxis whereas S1P2 mediates Rac inhibition and chemorepulsion. The stimulatory effects of S1P 1 and S1P3 on Rac and, subsequently on migration, are mediated by Gi. The inhibitory effect of SlP2 acts on G12/13 and Rho. S1P exerts inhibitory effects on some tumor cell migration and invasion via S1P2. S1P2 also mediates the inhibition of hematogenous metastasis. In contrast, exogenously expressed S1P1 has the reverse effect, it stimulates invasion and metastasis. S1P also exerts a similar bimodal action on vascular endothelial cells and, thereby, angiogenesis. The examples suggest that control of S1P receptor activity using a receptor subtype-specific agonist and antagonist may have beneficial effects on disorders, including cancer, and vascular diseases. © Springer-Verlag Tokyo 2006. All rights reserved.