Sphingosine 1-phosphate signalling in mammalian cells

Sphingosine 1-phosphate is formed in cells in response to diverse stimuli, including growth factors, cytokines, G-protein-coupled receptor agonists, a ntigen, etc. Its production is catalysed by sphingosine kinase, while degra dation is either via cleavage to produce palmitaldehyde and phosphoethanola mine or by dephosphorylation. In this review we discuss the most recent adv ances in our understanding of the role of the enzymes involved in metabolis m of this lysolipid, Sphingosine 1-phoshate 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 EDGE] to el icit biological responses. These receptors are coupled differentially via G (1), G(q), G(12/13) and Rho to multiple effector systems, including adenyla te cyclase, phospholipases C and D, extracellular-signal-regulated kinase, c-Jun N-terminal kinase, p38 mitogen-activated protein kinase and non-recep tor tyrosine kinases. These signalling pathways are linked to transcription factor activation, cytoskeletal proteins, adhesion molecule expression, ca spase activities, etc. Therefore sphingosine 1-phosphate can affect diverse biological responses, including mitogenesis, differentiation, migration an d apoptosis, via receptor-dependent mechanisms. Additionally, sphingosine 1 -phosphate has been proposed to play an intracellular role, for example in Ca2+ mobilization, activation of non-receptor tyrosine kinases, inhibition of caspases, etc. We review the evidence for both intracellular and extrace llular actions, and extensively discuss future approaches that will ultimat ely resolve the question of dual action. Certainly, sphingosine 1-phosphate will prove to be unique if it elicits both extra- and intra-cellular actio ns. Finally, we review the evidence that implicates sphingosine 1-phosphate in pathophysiological disease states, such as cancer, angiogenesis and inf lammation. Thus there is a need for the development of new therapeutic comp ounds, such as receptor antagonists. However, identification of the most su itable targets for drug intervention requires a full understanding of the s ignalling and action profile of this lysosphingolipid. This article describ es where the research field is in relation to achieving this aim.