Dual Actions of Sphingosine-1-Phosphate: Extracellular through the Gi-coupled Receptor Edg-1 and Intracellular to Regulate Proliferation and Survival

Abstract

Sphingosine-1-phosphate (SPP), a bioactive lipid, acts both intracellularly and extracellularly to cause pleiotropic biological responses. Recently, we identified SPP as a ligand for the G protein–coupled receptor Edg-1 (Lee, M.-J., J.R. Van Brocklyn, S. Thangada, C.H. Liu, A.R. Hand, R. Menzeleev, S. Spiegel, and T. Hla. 1998. Science. 279:1552–1555). Edg-1 binds SPP with remarkable specificity as only sphinganine-1-phosphate displaced radiolabeled SPP, while other sphingolipids did not. Binding of SPP to Edg-1 resulted in inhibition of forskolin-stimulated cAMP accumulation, in a pertussis toxin–sensitive manner. In contrast, two well-characterized biological responses of SPP, mitogenesis and prevention of apoptosis, were clearly unrelated to binding to Edg-1 and correlated with intracellular uptake. SPP also stimulated signal transduction pathways, including calcium mobilization, activation of phospholipase D, and tyrosine phosphorylation of p125FAK, independently of edg-1 expression. Moreover, DNA synthesis in Swiss 3T3 fibroblasts was significantly and specifically increased by microinjection of SPP. Finally, SPP suppresses apoptosis of HL-60 and pheochromocytoma PC12 cells, which do not have specific SPP binding or expression of Edg-1 mRNA. Conversely, sphinganine-1-phosphate, which binds to and signals via Edg-1, does not have any significant cytoprotective effect. Thus, SPP is a prototype for a novel class of lipid mediators that act both extracellularly as ligands for cell surface receptors and intracellularly as second messengers.

CXCL4‐induced monocyte survival, cytokine expression, and oxygen radical formation is regulated by sphingosine kinase 1

“…Similar results were published by Van Brocklyn et al [24], who could demonstrate that S1P at high concentrations acts not necessarily through binding to S1P receptors, but rather following cellular uptake of the phospho-lipid. Mononuclear phagocytes mainly express two S1P receptors, S1P 1 and S1P 2 [12].…”

“…3 and 6). S1P is a unique signaling molecule in that it can act both as an extracellular ligand for G protein-coupled receptors and as an intracellular second messenger [11,[24][25][26]. A few studies have suggested that suppression of apoptosis by S1P is mediated via its intracellular action, many others have argued in favor of the involvement of S1P membrane receptors, making this a controversial area (for review, see Hla et al [27]).…”

Sphingosine 1-phosphate stimulates proliferation and migration of human endothelial cells possibly through the lipid receptors, Edg-1 and Edg-3

“…In previous studies, in fibroblasts [6,31], the intracellular mechanisms have been proposed for S1P action on cell proliferation. Our results, however, favour the extracellular mechanism, through S1P receptors, for the S1P-induced actions on the proliferation and migration of endothelial cells.…”

“…100 nM), although the magnitude of the activity without FBS, regardless of the presence of S1P, was about one-third of the activity with FBS (results not shown). We also examined the effects of dihydrosphingosine 1-phosphate, which is thought to be an agonist for S1P receptors [31]. We found that the S1P derivative mimicked the S1P-induced actions…”

Sphingolipids and membrane biology as determined from genetic models

“…Subsequent studies established that at least in chordates and mammals, S1P act as extracellular ligands for a family of G-protein coupled receptors called S1P receptors [152][153][154]. In mammals, S1P executes most of its extracellular functions by engaging these receptors.…”