Sphingosine‐1‐Phosphate Signaling via the EDG‐1 Family of G‐Protein‐Coupled Receptors

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Abstract
The bioactive lipid sphingosine‐1‐phosphate (SPP) is abundantly formed and released during the activation of platelets by thrombotic stimuli. Once exported, SPP interacts with the G‐protein‐coupled receptors (GPCR) of the EDG‐1 family. SPP binds to EDG‐1 with the dissociation constant of ∼8 nM and induces signal transduction events such as mitogen‐activated protein kinase (MAP kinase) activation, decrease of cAMP levels, remodeling of the actin cytoskeleton, among others. EDG‐1 is a prototypical member of a large family of GPCRs that interact with glycero‐ and sphingolysolipid phosphates, namely, SPP and lysophosphatidic acid (LPA). Three other GPCRs, trivially termed EDG‐3, EDG‐5, and EDG‐8, are also high‐affinity receptors for SPP. The four SPP receptor subtypes regulate different intracellular signal transduction pathways. In vascular endothelial cells, cooperative signaling between EDG‐1 and EDG‐3 subtypes of SPP receptors results in adherens junction assembly, cell survival, morphogenesis into capillary‐like networks, and angiogenesis. SPP acts distinctly, albeit cooperatively, with polypeptide angiogenic factors, resulting in the formation of mature neovessels. Thus SPP signaling as an extracellular mediator via the EDG‐1 family of GPCRs may be a heretofore unrecognized mechanism for the regulation of angiogenesis and vascular endothelial cell function.