Abstract
Sugimoto et al. investigated sphingosine-1-phosphate (S1P)-mediated effects on cell motility and discovered evidence for simultaneous activation of opposing signals mediated through individual S1P receptor isotypes. S1P acts through guanine-nucleotide-binding protein (G protein)-coupled receptors (GPCRs) to stimulate or inhibit cell migration. Two GPCR isotypes, S1P 1 and S1P 3 , stimulate migration through G i -dependent activation of the small guanosine triphosphatase Rac, whereas S1P 2 blocks chemotaxis by inhibiting Rac. Both S1P 2 and S1P 3 stimulate RhoA. Aluminum fluoride (AlF 4 - ), which activates G proteins, mimicked S1P in stimulating Rho but inhibiting Rac and chemotaxis in Chinese hamster ovary (CHO) cells expressing S1P 2 . The authors used pharmacological analysis, combined with transient expression of COOH-terminal peptides of G protein α subunits (Gα), to implicate Gα 12 and Gα 13 in S1P 2 -mediated inhibition of cell migration, inhibition of Rac, and stimulation of RhoA. S1P 2 coimmunoprecipitated with Gα 12 and Gα 13 . CHO cells expressing mutant receptors consisting of Gα sequences fused to the S1P 2 COOH-terminal showed S1P-dependent inhibition of Rac activation, inhibition of chemotaxis, and activation of RhoA. Pharmacological analysis combined with expression of Rho mutants implicated Rho in S1P 2 -mediated inhibition of chemotaxis and of Rac. Whereas overexpressing Gα 12 and Gα 13 potentiated inhibition of chemotaxis mediated by AlF 4 - and S1P, overexpressing Gα i countered S1P-dependent inhibition of Rac and cell migration. In CHO cells expressing S1P 1 or S1P 3 , S1P stimulated chemotaxis and Rac. After inactivation of G i with pertussis toxin, however, S1P inhibited Rac and chemotaxis. Thus, both classes of S1P receptor activate distinct signaling pathways with opposing effects on Rac and on cell migration that are integrated into the overall response. N. Sugimoto, N. Takuwa, H. Okamoto, S. Sakurada, Y. Takuwa, Inhibitory and stimulatory regulation of Rac and cell motility by the G 12/13 -Rho and G i pathways integrated downstream of a single G protein-coupled sphingosine-1-phosphate receptor isoform. Mol. Cell. Biol. 23 , 1534-1545 (2003). [Abstract] [Full Text]
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