Diversity of cellular receptors and functions for the lysophospholipid growth factors lysophosphatidic acid and sphingosine 1‐phosphate

Abstract

The lysophospholipid (LPL) mediators lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P) are generated by enzymatic cleavage of stores of glycerophospholipids and sphingomyelin, respectively, in membranes of stimulated cells. LPLs are albumin bound, distributed widely in mammalian tissues, and increased in concentration by physiological activation of platelets and some other cells, tissue injury, inflammation, and neoplasia. The principal effects of LPA and S1P are growth related, including induction of cellular proliferation, alterations in differentiation and survival, and suppression of apoptosis. LPA and S1P also evoke cellular effector functions, which are dependent on cytoskeletal responses such as contraction, secretion, adhesion, and chemotaxis. The extracellular mediator activities of LPLs are transduced by subfamilies of G-protein-coupled receptors (GPCRs), of which the most completely characterized are those encoded by the endothelial differentiation genes (edgs). One homology cluster composed of Edg-1, -3, and -5 recognizes and responds to S1P, and the other cluster of Edg-2 and -4 is dedicated to LPA. Edg proteins are developmentally regulated and differ in tissue distribution, but couple similarly to multiple types of G-proteins to signal through ras and mitogen-activated protein kinase, rho, phospholipase C, and several protein tyrosine kinases. Numerous interactions between glycerophospholipids and sphingolipids are observed in their biosynthetic and signaling pathways. Many of the cellular effects of LPA and S1P are attributable to modifications in the content and/or activity of a major functional protein. Examples are increases in nuclear levels of transcription factors that regulate the serum response element, suppression of death caspase activities in apoptosis, and elevation of membrane content of heparin binding-epidermal growth factor-like growth factor, which serves as an autocrine and juxtacrine stimulus of proliferation. These ubiquitous LPL mediators of cellular growth, differentiation, and activities thus act directly through complex subfamilies of GPCRs and by regulating expression of biologically critical proteins.

Serum bioactive lysophospholipids prevent TRAIL-induced apoptosis via PI3K/Akt-dependent cFLIP expression and Bad phosphorylation

“…*Po0.01 versus TRAIL alone LPA and S1P are bioactive molecules responsible for serum antiapoptotic factors Albumin transports multiple substances within the bloodstream to and from tissues, including phospholipids such as LPA and S1P. 19,20 LPA and S1P are thought to be involved in many biological activities including mitogenesis and proliferation of cells. 21 We thus determined whether LPA and S1P act as antiapoptotic factors that accounted for the cytoprotective activity of serum and albumin.…”

The immunomodulator FTY720 interferes with effector functions of human monocyte‐derived dendritic cells

“…This mechanism of action has been shown to be highly effective in suppressing allograft rejection and autoimmune diseases in a variety of animal models [4,5] and in initial clinical trials [6,7]. As a synthetic analog of the lysophospholipid sphingosine 1-phosphate (S1P), phosphorylated FTY720 (FTY720-P) targets and activates G protein-coupled S1P receptors (S1PR), which are well characterized for their prominent functions in regulating growth-related and cytoskeleton-dependent cellular activities [8][9][10]. The current concept of FTY720-induced lymphopenia is that FTY720 modulates lymphocyte trafficking in a dual manner: acceleration of migration into secondary lymphoid organs and blocking the egress into efferent lymphatics.…”

Lysosphingolipid receptor‐mediated diuresis and natriuresis in anaesthetized rats

“…Lysosphingolipids such as sphingosine-1-phosphate (SPP) and sphingosylphosphorylcholine (SPPC) have long been known as intracellular bioactive molecules, but recently they have also emerged as representatives of a novel class of intercellular messengers (Goetzl & An, 1998;Meyer zu Heringdorf et al, 1997;Spiegel & Milstien, 2000). In that function lysosphingolipids may act mainly in an auto-or paracrine manner, but considerable SPP concentrations have also been detected in human serum and plasma, i.e.…”

“…Serum and plasma SPP may result at least partly from platelets which can release it upon activation (Yatomi et al, 1995). As intercellular messengers lysosphingolipids act on speci®c receptors, some of which couple to pertussis toxin (PTX) sensitive G-proteins (Goetzl & An, 1998;Meyer zu Heringdorf et al, 1997). While some members of the Edg receptor family are preferentially activated by lysophosphatidic acid, Edg1, Edg3, Edg5, Edg6 and Edg 8 are preferentially activated by SPP (Im et al, 2000; renal function.…”