Molecular biological analysis of the lipid morphogen sphingosine-1-phosphate

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We tried to determine physiological and pathological roles of the sphingosine-1-phosphate (S1P)/Edg receptor axis, by using gene targeting and transgenic techniques and cell biological analysis.We generated Edg5 knockout mice, by the standard method. We found that mice homozygous for null mutation of Edg5 receptor gene are born, accordingly to the Mendelian law. Gross abnormality in the appearance and behavior of Edg5-/- mice is not observed. After birth, approximately 40 % of Edg5-/- mice die within 1 month. The reason of this increased mortality in the early stage is not known at present. Adult Edg5-/- mice display slightly lower blood pressure. Sphingosine kinase is a rate-limiting enzyme for the production of S1P. In sphingosine kinase-transgenic mice, the wound-healing process is promoted compared to wild type mice.Edg5 has unique activities to suppress cell migration and cellular Rac, different from Edg1 or Edg3, which both inhibit Rac activity cell migration. We found for the first time that Edg5 couples to inhibition of Rac via G12/13 and the small GTPase Rho. We observed that Edg5 exerts inhibition of cell motility and invasion of tumor cells, resulting in suppression of metastasis in vivo.