Sphingosine 1-phosphate-induced cell proliferation, survival, and related signaling events mediated by G protein-coupled receptors Edg3 and Edg5

Sphingosine l-phosphate (S1P) regulates cell proliferation, apoptosis, moti lity, and neurite retraction. Contradictory reports propose that S1P acts a s either an intracellular second messenger or an extracellular ligand for c ell-surface receptors. Hence, the precise signaling mechanisms mediating th e diverse cellular effects of S1P remain to be determined. Here, we investi gate whether S1P stimulation of cell. proliferation, survival, and related signaling events can be mediated by the recently cloned Edg family members of G protein-coupled receptors. We observed that S1P treatment significantl y increased proliferation of HTC4 hepatoma cells stably transfected with hu man S1P receptor Edg3 or Edg5, which was attributable to stimulation of cel l growth and inhibition of apoptosis caused by serum starvation. Edg3 and E dg5 transduced S1P-evoked signaling events relevant to cell proliferation a nd survival, including activation of the ERK/MAP kinases, and immediate-ear ly induction of c-Jun and c-Fos. Transcriptional activation of reporter gen es for the c-fos promoter and the serum response element by Edg3 and Edg5 t ransfected in Jurkat cells was inhibited by pertussis toxin and C3 exoenzym e, implicating G(i/o)- and Rho-dependent pathways. Our data also indicated that Edg3 and Edg5 mediated the serum response element activation through t ranscriptional factors Elk-1 and serum response factor. Thus, specific G pr otein-coupled receptors Edg3 and Edg5 account for, at least in part, S1P-in duced cell proliferation, survival, and related signaling events.