Sphingosine 1-phosphate signalling in mammalian cells

Abstract

Sphingosine 1-phosphate is formed in cells in response to diverse stimuli, including growth factors, cytokines, G-protein-coupled receptor agonists, antigen, etc. Its production is catalysed by sphingosine kinase, while degradation is either via cleavage to produce palmitaldehyde and phosphoethanolamine or by dephosphorylation. In this review we discuss the most recent advances in our understanding of the role of the enzymes involved in metabolism of this lysolipid. Sphingosine 1-phosphate can also bind to members of the endothelial differentiation gene (EDG) G-protein-coupled receptor family [namely EDG1, EDG3, EDG5 (also known as H218 or AGR16), EDG6 and EDG8] to elicit biological responses. These receptors are coupled differentially via G(i), G(q), G(12/13) and Rho to multiple effector systems, including adenylate cyclase, phospholipases C and D, extracellular-signal-regulated kinase, c-Jun N-terminal kinase, p38 mitogen-activated protein kinase and non-receptor tyrosine kinases. These signalling pathways are linked to transcription factor activation, cytoskeletal proteins, adhesion molecule expression, caspase activities, etc. Therefore sphingosine 1-phosphate can affect diverse biological responses, including mitogenesis, differentiation, migration and apoptosis, via receptor-dependent mechanisms. Additionally, sphingosine 1-phosphate has been proposed to play an intracellular role, for example in Ca(2+) mobilization, activation of non-receptor tyrosine kinases, inhibition of caspases, etc. We review the evidence for both intracellular and extracellular actions, and extensively discuss future approaches that will ultimately resolve the question of dual action. Certainly, sphingosine 1-phosphate will prove to be unique if it elicits both extra- and intra-cellular actions. Finally, we review the evidence that implicates sphingosine 1-phosphate in pathophysiological disease states, such as cancer, angiogenesis and inflammation. Thus there is a need for the development of new therapeutic compounds, such as receptor antagonists. However, identification of the most suitable targets for drug intervention requires a full understanding of the signalling and action profile of this lysosphingolipid. This article describes where the research field is in relation to achieving this aim.

Survival benefit of sphingosin‐1‐phosphate and receptors expressions in breast cancer patients

“…For anabolism, such as sphingosine kinases 1 and 2 (SPHK1, SPHK2) that are responsible for S1P synthesis. And S1P lyase1 (SGPL1) and S1P phosphatase 1 and 2 (SGPP1, SGPP2) that mediated S1P catabolism 5, 6, 7. Besides, lipid phosphate phosphatases (LPP1/2/3) regulates lipid dephosphorylation including hydrolyzing S1P.…”

Sphingosine 1-phosphate increases glucose uptake through trans-activation of insulin receptor

“…Indeed, this lysophospholipid influences a diverse range of cellular processes, including proliferation, differentiation, motility, and survival, largely through ligation to a panel of five distinct G-protein-coupled receptors (GPCRs), named S1P receptors (S1PRs) [1,2]. Intriguingly, the biological response elicited by S1P in a given cell type appears to be critically dependent on the expression pattern of S1PRs since they are differentially coupled to heterotrimeric G-proteins and downstream signaling pathways.…”

Sphingosine 1-phosphate acts as an activator for the porcine Gpr3 of constitutively active G protein-coupled receptors

“…S1P also induces a broad range of biological responses, including cell growth, differentiation, migration, apoptosis (Clemens et al, 2003), and angiogenesis (Murakami et al, 2010). Its production is catalyzed by sphingosine kinase, while degradation is either via cleavage to produce palmitaldehyde and phosphoethanolamine or by dephosphorylation (Pyne and Pyne, 2000). So far, a specific subset of the endothelial differentiation gene (Edg) family, including the S1P1 (formerly Edg-1), S1P2 (Edg-5), S1P3 (Edg-3), S1P4 (Edg-6), and S1P5 (Edg-8) receptors, has been certified to be activated by the S1P (Clemens et al, 2003).…”

“…The lysophospholipids were originally described as intracellular second messengers, but, recently, they had been recognized as extracellular mediators for GPCRs (Pyne and Pyne, 2000). S1P is an important bioactive lysophospholipid mediator generated from membrane phospholipids or in a de novo anabolic sequence of reactions.…”