Investigation on physiological roles of sphingosine-1-phosphate signaling system using genetically engineered mice.

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We have identified sphingosine-1-phosphate(S1P) receptor isoform S1P_2 as the first G protein-coupled receptor that negatively regulates cell mobility. In the present study we demonstrated that endogenously expressed S1P_2 in mouse melanoma B16-F10 cells indeed mediated inhibition of cell migration and invasion in in vitro system. In addition, we found that pretreatment of B16 cells with S1P potently inhibited pulmonary metastasis in vivo in tail vein injection model, via endogenously expressed S1P_2. These results raises an intriguing possibility that S1P_2-selective agonist could serve as an inhibitor of tumor cell invasion and metastasis in a subset of human malignancies. In sharp contrast to S1P_2, we and others have demonstrated that S1P_1 and S1lP_3 mediates S1IP stimulation of cell migration, thereby acting as chemotactic receptors. Indeed, overexpression of either of the latter receptor isoforms in B16 melanoma cells resulted in stimulation of migration and invasion in vitro, and aggravation of lung metastasis in vivo in response to S1P treatment. In addition, we have recently found that S1P_1 mediated S1P stimulation of platelet-derived growth factor upregulation in cultured vascular smooth muscle rails, through die action of a transcription factor KLF5. The results may implicate pathophysiological role for S1P_1 in development of atherosclerosis. In an attempt to elucidate physiological role of S1P signaling system in vivo, we have created S1P_2 knockout mice and sphingosine kinase transgenic mice. Investigation on these genetically engineered mice is now underway.