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Emerging Medicinal Roles for Lysophospholipid Signaling

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Emerging Medicinal Roles for Lysophospholipid Signaling Review TRENDS in Molecular Medicine Vol.12 No.2 February 2006 Emerging medicinal roles for lysophospholipid signaling Shannon E. Gardell, Adrienne E. Dubin and Jerold Chun Department of Molecular Biology, Helen L. Dorris Child and Adolescent Neuropsychiatric Disorder Institute, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA The two lysophospholipids (LPs) lysophosphatidic acid The recent discovery of the widespread involvement of and sphingosine 1-phosphate (S1P) regulate diverse receptor-mediated LP signaling in physiology and disease biological processes. Over the past decade, it has has sparked much interest in the potential therapeutic become clear that medically relevant LP activities are usefulness of modulating LP receptors. Indeed, entry of mediated by specific G protein-coupled receptors, the novel immunosuppressant and non-selective S1P implicating them in the etiology of a growing number receptor agonist FTY720 into clinical trials for kidney of disorders. A new class of LP agonists shows promise transplantation and multiple sclerosis (MS) has raised for drug therapy: the experimental drug FTY720 is prospects that treatment aimed at LP receptor targets phosphorylated in vivo to produce a potent S1P receptor might be therapeutically efficacious in human diseases in agonist (FTY720-P) and is currently in Phase III clinical the foreseeable future. trials for kidney transplantation and Phase II for multiple This review focuses on the regulation of LP signaling sclerosis. Recent genetic and pharmacological studies pathways at the level of the receptors; however, down- on LP signaling in animal disease models have identified stream effectors and synthetic and metabolic enzymes new areas in which interventions in LP signaling might have also been suggested as therapeutic targets [4–6].We provide novel therapeutic approaches for the treatment evaluate the pathophysiological roles of LP receptors in of human diseases. disease models, focusing on clinical data and animal models of disease using genetic and pharmacological approaches. To provide a framework for discussion on LPA and S1P involvement in disease etiology and possible Lysophospholipid receptors: G protein-coupled complicating side effects, we first briefly overview receptors with recently validated potential LP signaling. for drug targeting G protein-coupled receptors (GPCRs) have been identified Lysophospholipid synthesis, metabolism and signaling as molecular targets with proven therapeutic value. LP receptor expression, metabolism and downstream O GPCRs are the target of 30% of currently marketed signaling pathways have been extensively reviewed else- O drugs ( 200) [1]. These cell surface receptors are where [2,3]. LPA is synthesized via multiple enzymes, specifically activated by diverse extracellular stimuli, including extracellular autotaxin (ATX, also known as including classical hormones, neurotransmitters and, as lysophospholipase D or lysoPLD), phospholipase A2 discussed here, lipid mediators. Their activation initiates (PLA2) and monoacylglycerol kinase (MAG kinase) various second messenger cascades that depend on (Figure 1a). Similarly, extracellular LPA levels are effector cell identity and function. regulated by the activity of numerous enzymes including The lysophospholipids (LPs) are simple phospholipids LPA acyltransferase, at least three lipid phosphate that have been recognized for decades as components in phosphatases (LPPs) and lysophospholipases the biosynthesis of cell membranes [2]. However, the (Figure 1a). By contrast, the synthesis and degradation recent identification and cloning of GPCRs having high of extracellular S1P appear to involve relatively few affinity for lysophosphatidic acid (LPA; receptors LPA1– enzymes [7] (Figure 1b). LPA4) and sphingosine 1-phosphate (S1P; receptors S1P1– LPs are synthesized and released by diverse cell types S1P5) have enabled a greater mechanistic understanding to regulate and maintain organismal homeostasis (Box 1). of their diverse roles in biological processes [2,3]. LPA and During tissue injury in which the vascular–interstitial S1P regulate the development and function of numerous barrier is breached, LPs originate from activated platelets organ systems, including the cardiovascular, nervous, and other blood-borne cells, including mast cells, and immune, and reproductive systems. Altered LP signaling promote wound healing, inflammation and angiogenesis. has been implicated in the etiology of disorders, such as Furthermore, LPs are derived from cellular components in inflammation, autoimmune diseases, neuropathic pain, various other systems (e.g. neural, adipose and reproduc- atherosclerosis, cancer and obesity [2]. tive tissues) and they appear to help maintain these Corresponding author: Chun, J. ([email protected]). systems within normal parameters [2]. LP binding to Available online 10 January 2006 cognate GPCRs activates diverse intracellular messenger www.sciencedirect.com 1471-4914/$ - see front matter Q 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.molmed.2005.12.001 66 Review TRENDS in Molecular Medicine Vol.12 No.2 February 2006 (a) (b) (c) (d) Phosphatidylcholine Ceramide Sphingosylphos- FTY720 Ki16425 phorylcholine (antagonist) PLA PLD 2 OH LCAT Sphingosine NH cholinephos- 3 Ceramidase OH N O photransferase; O PA LysoPC lysoPLD N O Sphingosine Cl LPA acyl sPLA ATX/ 2 SP transferase lysoPLD SKs S LPPs H O O - - O NH H O 3 HO H H O P O - O P O - sn-1 (R) HO O O O SKs O LPA (18:1 LPA, 1-oleoyl-LPA; OH most common form) O NH3 O P O (R) O FTY720-P S1P S1P lyases LPP-1-3 MAG kinase MAG Phosphoethanolamine + hexadecanal TRENDS in Molecular Medicine Figure 1. Synthesis and metabolism of major LPs. (a) LPA synthetic and metabolic pathways. There are multiple isoforms of LPA; which are generated depends on the backbone carbon from which the alkyl chain is hydrolyzed. The major enzymes involved in the control of 1-sn-LPA levels are shown. The synthesis of sn-2 LPA occurs when PC or PA are hydrolyzed by PLA1. Abbreviations: ATX/lysoPLD, autotaxin/lysophospholipase D; LCAT, lecithin cholesterol acyl transferase; LPP, lipid phosphate phosphatase; LysoPC, lysophosphatidylcholine; MAG, monoacylglycerol; PA, phosphatidic acid; PC, phosphatidylcholine; PLA1, phospholipase A1; PLA2, phospholipase A2; PLD, phospholipase D; sPLA2, secretory phospholipase A2. (b) Major S1P synthetic and metabolic pathways. Abbreviation: SK, sphingosine kinase. (c) Phosphorylation of FTY720 to the active S1P receptor agonist FTY720-P occurs via SKs (Table 1). Only the (R) stereoisomer of FTY720-P is active. (d) The structure of Ki16425, a specific antagonist at LPA1 and LPA3 receptors (Table 1). systems to produce a variety of biological responses (Box 1; in vivo by sphingosine kinases (SKs) makes it a potent Figure 2). agonist (Kd values in the nanomolar range) for four of the five currently known S1P receptors (S1P1 and S1P3–S1P5) FTY720: targeting lysophospholipid receptors to prevent [10,11] (Table 1). It is generally accepted that binding of transplant rejection and to treat autoimmune disorders phosphorylated FTY720 (FTY720-P; Figure 1c) to S1P1 on Transplant rejection results from an alloimmune response lymphocytes prevents their exit from secondary lymphoid of the recipient to non-self antigens expressed in donor organs, thus reversibly sequestering them from sites of tissue. Current strategies aimed at preventing acute inflammation [10,11]. However, there is controversy in the rejection ultimately target T cells, either directly or literature regarding the cellular mechanism of action of indirectly, through inhibitory actions on other immune FTY720 on S1P1 receptors. One proposed model is that cell types (e.g. antigen-presenting cells) [8]. Unfortu- FTY720 blocks lymphocyte exit via S1P1 agonist activity nately, it is not often possible to suppress the immune [10–12]. A second model suggests that FTY720 acts as a system sufficiently to prevent rejection while maintaining ‘functional antagonist’ to inactivate S1P1 receptors on defense against infections. A breakthrough in the field lymphocytes, and is equivalent to lymphocyte-specific came from the serendipitous discovery that an S1P S1P1 deficiency [13–15]. Supporting S1P1 inactivation by receptor agonist is an effective and potent immunosup- FTY720 is the finding that FTY720 itself might induce pressant with a novel mechanism of action. receptor internalization and subsequent degradation [16]. FTY720 (Figure 1c), a synthetic analog of the natural FTY720 neither overly immunocompromises the product myriocin [9], supports pharmacological interven- patient nor disrupts myelomonocyte-cell function [17]. tions involving LP signaling. Phosphorylation of FTY720 Results from clinical trials suggest that FTY720 has a www.sciencedirect.com Review TRENDS in Molecular Medicine Vol.12 No.2 February 2006 67 Box 1. Identified lysophospholipid receptor-mediated signaling mechanisms Six major cellular responses are induced by S1P- and LPA-dependent are underscored by the observation that LPA stimulates migration activation of cell-surface GPCRs, thus producing diverse downstream of ovarian cancer cells via novel recruitment of Ras–MEKK1- cellular responses dependent on cell type, developmental stage and dependent FAK to surface adhesion contact sites in ovarian cancer environment (Figure 2). cell lines [108]. S1P effects on cellular migration depend on receptors and cell context as well [109]. Survival and proliferation Stimulation of Gi,Gq and
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