Sphingosine 1-phosphate activates nuclear factor-κB through Edg receptors

Sphingosine I-phosphate (SIP) exerts a variety of actions as a second messenger or as an agonist that binds to one or more members of the Edg family of G protein-coupled receptors. By using human embryonic kidney 293 cells, we show that SIP activates nuclear factor-kappaB (NF-kappaB) in a receptor-dependent fashion. Edg-3 and Edg-5, which are coupled to G(i), G(q), and G(13), affect activation of NF-kappaB, whereas Edg-1, which is coupled to Gi alone, does not. We find that the activation of NF-kappaB requires protein kinase C and Ca2+, probably downstream of Gq, but that the activation of Rho alone by SIP, whether through Gq or G13, does not translate into the activation of NF-kappaB. GOT has little effect of its own but potentiates the activation of NF-kappaB achieved through other G proteins. We conclude that the activation of NF-kappaB by SIP is a receptor-mediated process that relies primarily on the activation of a phospholipase C by Gq and secondarily on effector regulation through other G proteins.