Sphingosine-1-phosphate Signaling


Pathway Description

Sphingolipids represent a complex group of lipids that have recently emerged as new class of signal transducers in eukaryotic cells. Sphingolipids are found in all mammalian cells, mostly located in the plasma membrane. They all contain a long chain base - the sphingoid base (mostly sphingosine) - as a backbone linked to a fatty acid by an amide bond, thus forming ceramide. Addition of a phosphocholine substituent or sugar to ceramide gives rise to the major sphingolipid sphingomyelin (SM), or to glycosphingolipids, respectively. Ceramide is also produced by the breakdown of sphingolipids by glycosidases (for glycolipid degradation) and sphingomyelinases.The bioactive sphingosine-1-phosphate (S-1P), a sphingolipid metabolite, has been linked to a wide spectrum of biological processes, among which cell growth, survival, and motility are prominent. The cellular levels of S-1P are controlled by its formation from sphingosine through the activity of SPHK and by its degradation by S-1P lyase and dephosphorylation by S-1P phosphatases. In the basal state, this balance between S-1P generation and degradation results in low cellular levels of S-1P. The most well known actions of S-1P are mediated by plasma membrane GPCRs. Similar to other important phospholipid mediators, S-1P exerts dual actions in cells: it acts intracellularly as a second messenger and extracellularly as a ligand for a family of GPCRs originally known as the EDG1 family of proteins but were recently renamed S1PRs. S1PR1 and S1PR5 are coupled mainly to Gαi, S1PR2 is coupled to all G-proteins, S1PR3 is coupled to Gαi, Gαq and Gα12/13, and S1PR4 activates Gαi and Gα12 but not Gαs or Gαq/11.

Stimulation of these receptors results in either activation or inhibition of members of the Rho family of small GTPases, most prominently Rho and Rac. Activated Rho induces the formation of stress fibers, while activated Rac induces formation of the cortical actin network. Activation of S1PR1 promotes this latter function of Rac, whereas activation of S1PR2 inhibits it thereby preventing Rac-induced chemotaxis and membrane ruffling. However, the binding of S-1P to S1PR2 or S1PR3 triggers Rho-mediated stress fiber assembly. Downstream of heterotrimeric G-proteins, the S1PRs regulate FAK and c-Src which are important for cadherin stimulation and cytoskeletal rearrangements. Whereas binding of S1P to S1PR1 mediates cortical actin assembly and Rac activation, binding to S1PR2 and S1PR3 induces stress fiber formation and activation of Rho. S1PR2 negatively regulates Rac activity, thereby inhibiting cell migration. S-1P also has second messenger functions important for calcium homeostasis, cell growth and suppression of apoptosis. S-1P activates PYK2, which has been identified as a Ca2+ and PKC-regulated effector of GPCRs, resulting in the activation of ERKs. Conversely, binding of PDGF to the PDGFR activates and recruits SPHK1 to the cell's leading edge, producing S-1P which spatially and temporally stimulates S1PR1 in an autocrine or paracrine manner. S-1P in turn activates its receptors leading to recruitment and/or activation of downstream signaling molecules, including c-Src, FAK, PI3K, AKT and Rac which are important for cell migration and PLC/AC-mediated calcium signaling. Some specific effects of intracellular S-1P include activation of ERK1/2, stimulation of DNA binding activity of NF-κB, and inhibition of caspases. S1PR5 is expressed predominantly by oligodendrocytes and/or fibrous astrocytes and is the only one that mediates anti-proliferative effects. It has the most unusual signaling properties. Moreover, S-1P regulates angiogenesis or new blood vessel formation, which is critical for tumor progression. Furthermore, S-1P can act in an autocrine and/or paracrine fashion to regulate blood vessel formation.