Sphingosine 1-phosphate stimulates fibronectin matrix assembly through a Rho-dependent signal pathway

Fibronectin matrix assembly is a cell-dependent process mediated by cell su rface binding sites for the 70-kD N-terminal portion of fibronectin. We hav e shown that Rho-dependent cytoskeleton reorganization induced by lysophosp hatidic acid (LPA) or the microtubule-disrupting agent nocodazole increases fibronectin binding (Zhang et al, Mol Biol Cell 8:1415, 1997). Sphingosine 1-phosphate (S1P) is a bioactive sphingolipid implicated in mitogenesis an d cytoskeletal remodelling. Both LPA and S1P are present in increased amoun ts in serum as compared with plasma as a result of platelet activation. Add ition of S1P to human osteosarcoma MG63 cells or human foreskin fibroblasts increased cell-mediated binding and assembly of fibronectin. MG63 cells ex pressed the Edg-2 and Edg-4 G-protein-coupled receptors for bioactive lipid s, whereas foreskin fibroblasts expressed Edg-2, Edg-3, and Edg-4. The stim ulatory effect of S1P on the binding of fibronectin or the N-terminal 70-kD fragment of fibronectin was dynamic and due to increases in both the numbe r and affinity of binding sites. The stimulation of 70-kD fragment binding by nanomolar S1P, like stimulation of binding by LPA or nocodazole, was blo cked by inactivation of Rho with C3 exotoxin but not by pertussis toxin-med iated inactivation of Gi. These results indicate a common signal pathway le ading to control of cellular fibronectin matrix assembly by bioactive lipid s generated during blood coagulation. (C) 1999 by The American Society of H ematology.