CHEMOTAXIS S1Ping in Two Directions

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, S1P₁ and S1P₃, stimulate migration through G_i-dependent activation of the small guanosine triphosphatase Rac, whereas S1P₂ blocks chemotaxis by inhibiting Rac. Both S1P₂ and S1P₃ stimulate RhoA. Aluminum fluoride (AlF₄^-), which activates G proteins, mimicked S1P in stimulating Rho but inhibiting Rac and chemotaxis in Chinese hamster ovary (CHO) cells expressing S1P₂. The authors used pharmacological analysis, combined with transient expression of COOH-terminal peptides of G protein subunits (G), to implicate G₁₂ and G₁₃ in S1P₂-mediated inhibition of cell migration, inhibition of Rac, and stimulation of RhoA. S1P₂ coimmunoprecipitated with G₁₂ and G₁₃. CHO cells expressing mutant receptors consisting of G sequences fused to the S1P₂ 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 S1P₂-mediated inhibition of chemotaxis and of Rac. Whereas overexpressing G₁₂ and G₁₃ potentiated inhibition of chemotaxis mediated by AlF₄^- and S1P, overexpressing G_i countered S1P-dependent inhibition of Rac and cell migration. In CHO cells expressing S1P₁ or S1P₃, 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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