S-1P Stimulated Signaling
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S-1P Stimulated Signaling
Various lipid molecules serve as second messengers for transducing signals from the cell surface to the cell interior and trigger specific cellular responses. Sphingolipids represent a complex group of lipids that have recently emerged as new transducers in eukaryotic cells. Sphingolipids are found in all mammalian cells and are mostly located in the plasma membrane. They all contain as a backbone a long-chain base - the sphingoid base (mostly sphingosine) - 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 SM (sphingomyelin) or to glycosphingolipids, respectively. Ceramide is also produced by breakdown of all sphingolipids by glycosidases (for glycolipid degradation) and Sphingomyelinases. These hydrolytic steps occur in the acidic organelles as well as in several other subcellular compartments. Ceramide is deacylated by Ceramidase to release sphingosine, which is then phosphorylated by SphK1 (Sphingosine Kinase-1) (Ref.1).

The bioactive S-1P (Sphingosine 1-Phosphate), a sphingolipid metabolite found in organisms as diverse as plants, yeast, worms, flies, and mammals, has been linked to a wide spectrum of biological processes, among which cell growth, survival, and motility are prominent . The cellular levels of S1P are controlled by its formation from sphingosine through the activity of SphK, and by its degradation by S-1P lyase and S-1P phosphatases. In the basal state, this balance between S-1P generation and degradation results in low cellular levels of S-1P (Ref.2). SphK is a highly conserved enzyme that is activated by numerous stimuli. S-1P elicits a variety of biological responses, such as fibroblast proliferation, neurite retraction, calcium signaling, regulation of apoptosis, morphogenetic differentiation, inhibition of cell motility, induction of Activator Protein-1 transcription factor activity, regulation of G-protein-dependent cAMP (cyclic Adenosine-3’, 5’-Monophosphate) levels, and MAPK (Mitogen-Activated Protein Kinase) activity. The most well known actions of S-1P are mediated by plasma membrane receptors that are coupled to G-proteins (Ref.3). 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 GPCRs (G Protein-Coupled Receptors). S-1P is thus the ligand for specific GPCRs that were originally known as the EDG1 (Endothelial Differentiation Gene-1) family of proteins but were recently renamed S1PRs (S-1P Receptors). To date, five members of the S1PR family have been cloned including EDG1/S1P1, EDG5/S1P2, EDG3/S1P3, EDG6/S1P4, and EDG8/S1P5 all of which bind and are activated specifically by S-1P and dihydro-S-1P (also known as Sphinganine 1-Phosphate). S1P1 and S1P5 are coupled mainly to GN-AlphaI, S1P2 can be coupled to all G-proteins, S1P3 is coupled to GN-AlphaI, G-AlphaQ and G-Alpha12/13 and S1P4 activates GN-AlphaI and GN-Alpha12 but not GN-AlphaS or GN-AlphaQ/11 in response to S-1P. As a consequence, S-1P influences distinct biological processes depending on the relative expression of S1PRs as well as G-Proteins (Ref.4).

Stimulation of these receptors results in either activation or inhibition of members of the Rho family of small GTPases, most prominently Rho and Rac. Members of the Rho family act downstream of the heterotrimeric G-Proteins and play important role in reorganization of the cytoskeleton. Activated Rho thus induces the formation of stress fibers, and activated Rac induces formation of the cortical actin network. Activation of S1PR1 promotes this latter function of Rac, whereas activation of S1PR2 inhibits it and thereby prevents Rac-induced chemotaxis and membrane ruffling. However, the binding of S-1P to S1PR2 or S1PR3 triggers Rho-mediated stress fiber assembly. The differential expression of S1PRs is thus able to determine the chemotactic responses of cells to extracellular gradients of S-1P (Ref.5). Downstream of heterotrimeric G-proteins, the S1PRs regulate tyrosine kinases such as FAK (Focal Adhesion Kinase) and c-Src, which reside in focal adhesions and the small GTPases of the Rho family, that are important for cadherin stimulation and cytoskeletal rearrangements. Whereas binding of S-1P to S1P1 mediates cortical actin assembly and Rac activation, binding to S1P2 and S1P3 induces stress fiber formation and activation of Rho, and S1P2 negatively regulates Rac activity, thereby inhibiting cell migration. Moreover, S-1P also has second messenger functions important for calcium homeostasis, cell growth, and suppression of apoptosis. S-1P can activate a number of non-receptor tyrosine kinases in order to transmit signals to well defined effector systems. For example, S-1P activates PYK2, which has been identified as a Ca2+ and PKC (Protein Kinase-C)-regulated effector of GPCRs, resulting in the activation of ERK (Extracellular-Signal-Regulated Kinase) (Ref.6). Conversely, binding of the PDGF (Platelet-Derived Growth Factor) to the PDGFR (PDGF Receptor) activates and recruits SphK1 to the cells leading edge, producing S-1P, which spatially and temporally stimulates S1P1 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 (Phosphatidylinositol 3-Kinase), Akt1, and Rac important for cell migration or other downstream signaling, such as PLC (Phospholipase-C) and AC (Adenylyl Cyclase) that regulates calcium levels. Some specific effects of intracellular S-1P include mobilization of intracellular calcium, activation of ERK1/2, stimulation of DNA binding activity of NF-KappaB, and inhibition of Caspases. S-1P is also an obligatory signaling intermediate in adhesion molecule expression of vascular endothelial cells, indicating a role for this lipid in the inflammatory response. Of all of these GPCRs, S1P5, which is expressed predominantly by oligodendrocytes and/or fibrous astrocytes, is the only one that mediates anti-proliferative effects, and it has the most unusual signaling properties. Surprisingly, ligand-activated S1P5 inhibited serum-induced activation of ERK1/2, most probably because of activation of a tyrosine phosphatase (Ref.4).

Several sphingolipids are now recognised as second messengers and they play an important role in the regulation of cell proliferation, survival, and cell death. Ceramide and Sphingosine usually inhibit proliferation and promote apoptosis, while the further metabolite S-1P stimulates growth and suppresses apoptosis. 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. To conclude, SphK not only protects tumors from apoptosis, it may also increase their vascularization, further enhancing growth. The cytoprotective effects of SphK/S-1P may also be important for clinical benefit, as S-1P protects oocytes from radiation-induced cell death (Ref.4).