Sphingosine 1‐phosphate promotes cell migration through the activation of Cdc42 in Edg‐6/S1P4‐expressing cells

s Background: Sphingosine 1‐phosphate (Sph‐1‐P) is a bioactive lipid mediator released from activated platelets, which regulates diverse signal transduction pathways via cell surface receptors. Recent studies have revealed that the seven‐transmembrane‐spanning receptors, Edg‐1, Edg‐3, Edg‐5, Edg‐6 and Edg‐8 are specific Sph‐1‐P receptors. Northern blot analysis has demonstrated that Edg‐6 is expressed in lymphocyte‐containing tissues such as spleen and lung. Little is known about the molecular mechanisms of Edg‐6 functions, probably because of the difficulties in expressing Edg‐6 on the cell surface. Results: Here, our studies revealed that N‐terminal FLAG‐tagged Edg‐6 or Edg‐6‐GFP fusion protein was expressed in the endoplasmic reticulum, but was not expressed on the cell surface. On the other hand, C‐terminally tagged Edg‐6 or both N‐terminally and C‐terminally tagged Edg‐6 was able to localize to the cell surface. Using these cells, we found that Sph‐1‐P induced cell migration through cell surface‐expressed Edg‐6 in a pertussis toxin‐sensitive manner. This motility was mediated through the activation of a member of the Rho family of small GTPases, Cdc42. Conclusion: These results support a role for Sph‐1‐P signalling via Edg‐6 in the pathways involved in cell motility.