Lysophospholipid Signaling Research Articles

Emerging Roles for Lysophospholipid Mediators in Pregnancy

Recent progress in lipid research has unveiled new biologic roles for lysophospholipids as mediators of intercellular signaling. Lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P) are representative lysophospholipids. Accumulating evidence suggests that, acting as intercellular mediators, these and other lysophospholipids may play important roles in physiological and pathological situations. This review discusses the possible involvement of LPA and S1P in reproductive processes, with a focus on the regulatory mechanisms of pregnancy maintenance. As LPA promotes prostaglandin synthesis, mediators in the LPA pathway may also play a significant role in implantation and parturition. S1P signaling is thought to be essential in vascular formation within the uteroplacental unit and in fetomaternal immunologic interactions. Derangements in either one of these lysophospholipid signaling pathways could result in pregnancy complications that may include implantation failure, preeclampsia, and preterm labor.

Bioactive lysophospholipids: role in regulation of aqueous humor outflow and intraocular pressure in the context of pathobiology and therapy of glaucoma.

Homeostasis of aqueous humor (AH) outflow and intraocular pressure (IOP) is essential for normal vision. Impaired AH outflow through the trabecular meshwork (TM) and a resultant elevation in IOP are common changes in primary open-angle glaucoma (POAG), which is the most prevalent form of glaucoma. Although elevated IOP has been recognized as a definitive risk factor for POAG and lowering elevated IOP remains a mainstay for glaucoma treatment, little is known about the molecular mechanisms, especially external cues and intracellular pathways, involved in the regulation of AH outflow in both normal and glaucomatous eyes. In addition, despite the recognition that increased resistance to AH outflow via the conventional pathway consisting of TM and Schlemm's canal is the main cause for elevated IOP, there are no clinically approved drugs that target the conventional pathway to lower IOP in glaucoma patients. The aim of this article is to briefly review published work on the importance of bioactive lysophospholipids (eg, lysophosphatidic acid and sphingosine-1-phosphate), their receptors, metabolism, signaling, and role in the regulation of AH outflow via the TM and IOP, and to discuss pharmacological targeting of key proteins in the lysophospholipid signaling pathways to lower IOP in glaucoma patients.

Rho/ROCK pathway is essential to the expansion, differentiation, and morphological rearrangements of human neural stem/progenitor cells induced by lysophosphatidic acid

We previously reported that lysophosphatidic acid (LPA) inhibits the neuronal differentiation of human embryonic stem cells (hESC). We extended these studies by analyzing LPA's effects on the expansion of neural stem/progenitor cells (NS/PC) derived from hESCs and human induced pluripotent stem cells (iPSC), and we assessed whether data obtained on the neural differentiation of hESCs were relevant to iPSCs. We showed that hESCs and iPSCs exhibited comparable mRNA expression profiles of LPA receptors and producing enzymes upon neural differentiation. We demonstrated that LPA inhibited the expansion of NS/PCs of both origins, mainly by increased apoptosis in a Rho/Rho-associated kinase (ROCK)-dependent mechanism. Furthermore, LPA inhibited the neuronal differentiation of iPSCs. Lastly, LPA induced neurite retraction of NS/PC-derived early neurons through Rho/ROCK, which was accompanied by myosin light chain (MLC) phosphorylation. Our data demonstrate the consistency of LPA effects across various sources of human NS/PCs, rendering hESCs and iPSCs valuable models for studying lysophospholipid signaling in human neural cells. Our data also highlight the importance of the Rho/ROCK pathway in human NS/PCs. As LPA levels are increased in the central nervous system (CNS) following injury, LPA-mediated effects on NS/PCs and early neurons could contribute to the poor neurogenesis observed in the CNS following injury.

PPARγNetworks in Cell Signaling: Update and Impact of Cyclic Phosphatidic Acid

Lysophospholipid (LPL) has long been recognized as a membrane phospholipid metabolite. Recently, however, the LPL has emerged as a candidate for diagnostic and pharmacological interest. LPLs include lysophosphatidic acid (LPA), alkyl glycerol phosphate (AGP), cyclic phosphatidic acid (cPA), and sphingosine-1-phosphate (S1P). These biologically active lipid mediators serve to promote a variety of responses that include cell proliferation, migration, and survival. These LPL-related responses are mediated by cell surface G-protein-coupled receptors and also intracellular receptor peroxisome proliferator-activated receptor gamma (PPARγ). In this paper, we focus mainly on the most recent findings regarding the biological function of nuclear receptor-mediated lysophospholipid signaling in mammalian systems, specifically as they relate to health and diseases. Also, we will briefly review the biology of PPARγ and then provide an update of lysophospholipids PPARγ ligands that are under investigation as a therapeutic compound and which are targets of PPARγ relevant to diseases.

Lipid Phosphate Phosphatase 3 Negatively Regulates Smooth Muscle Cell Phenotypic Modulation to Limit Intimal Hyperplasia

The lipid phosphate phosphatase 3 (LPP3) degrades bioactive lysophospholipids, including lysophosphatidic acid and sphingosine-1-phosphate, and thereby terminates their signaling effects. Although emerging evidence links lysophosphatidic acid to atherosclerosis and vascular injury responses, little is known about the role of vascular LPP3. The goal of this study was to determine the role of LPP3 in the development of vascular neointima formation and smooth muscle cells (SMC) responses. We report that LPP3 is expressed in vascular SMC after experimental arterial injury. Using gain- and loss-of-function approaches, we establish that a major function of LPP3 in isolated SMC cells is to attenuate proliferation (extracellular signal-regulated kinases) activity, Rho activation, and migration in response to serum and lysophosphatidic acid. These effects are at least partially a consequence of LPP3-catalyzed lysophosphatidic acid hydrolysis. Mice with selective inactivation of LPP3 in SMC display an exaggerated neointimal response to injury. Our observations suggest that LPP3 serves as an intrinsic negative regulator of SMC phenotypic modulation and inflammation after vascular injury, in part, by regulating lysophospholipid signaling. These findings may provide a mechanistic link to explain the association between a PPAP2B polymorphism and coronary artery disease risk.

Novel Selective Allosteric and Bitopic Ligands for the S1P3 Receptor

Sphingosine 1-phosphate (S1P) is a lysophospholipid signaling molecule that regulates important biological functions, including lymphocyte trafficking and vascular development, by activating G protein-coupled receptors for S1P, namely, S1P(1) through S1P(5). Here, we map the S1P(3) binding pocket with a novel allosteric agonist (CYM-5541), an orthosteric agonist (S1P), and a novel bitopic antagonist (SPM-242). With a combination of site-directed mutagenesis, ligand competition assay, and molecular modeling, we concluded that S1P and CYM-5541 occupy different chemical spaces in the ligand binding pocket of S1P(3). CYM-5541 allowed us to identify an allosteric site where Phe263 is a key gate-keeper residue for its affinity and efficacy. This ligand lacks a polar moiety, and the novel allosteric hydrophobic pocket permits S1P(3) selectivity of CYM-5541 within the highly similar S1P receptor family. However, a novel S1P(3)-selective antagonist, SPM-242, in the S1P(3) pocket occupies the ligand binding spaces of both S1P and CYM-5541, showing its bitopic mode of binding. Therefore, our coordinated approach with biochemical data and molecular modeling, based on our recently published S1P(1) crystal structure data in a highly conserved set of related receptors with a shared ligand, provides a strong basis for the successful optimization of orthosteric, allosteric, and bitopic modulators of S1P(3).

International Union of Basic and Clinical Pharmacology. LXXVIII. Lysophospholipid Receptor Nomenclature: TABLE 1

Lysophospholipids are cell membrane-derived lipids that include both glycerophospholipids such as lysophosphatidic acid (LPA) and sphingoid lipids such as sphingosine 1-phosphate (S1P). These and related molecules can function in vertebrates as extracellular signals by binding and activating G protein-coupled receptors. There are currently five LPA receptors, along with a proposed sixth (LPA₁-LPA₆), and five S1P receptors (S1P₁-S1P₅). A remarkably diverse biology and pathophysiology has emerged since the last review, driven by cloned receptors and targeted gene deletion ("knockout") studies in mice, which implicate receptor-mediated lysophospholipid signaling in most organ systems and multiple disease processes. The entry of various lysophospholipid receptor modulatory compounds into humans through clinical trials is ongoing and may lead to new medicines that are based on this signaling system. This review incorporates IUPHAR Nomenclature Committee guidelines in updating the nomenclature for lysophospholipid receptors ( http://www.iuphar-db.org/DATABASE/FamilyMenuForward?familyId=36).

Lysophospholipid signaling in human neural progenitors

Recent studies have shown that the fungal metabolite Fumonisin B1 (FB1) and the immunomodulatory drug FTY720 cause neural tube defects in mice. Both drugs inhibit ceramide synthase, resulting in an accumulation of sphingosine 1‐phosphate (S1P) and sphinganine 1‐phosphate (Sa1P) which are agonists for G‐protein coupled S1P receptors (S1PR). S1PRs are key regulators of neural development, suggesting that FB1 or FTY720 may cause developmental toxicity by altering signaling through S1PR. We have recently described S1P signaling pathways in human embryonic stem cell‐derived neuroepithelial cells (hES‐NEP). The goal of this project is to define the effects of FTY720 and FB1 on hES‐NEP cells, and establish this system as a platform in which to define the mechanism of lysophospholipid signaling in neural development. In the current study, we show that treatment of hES‐NEP with FB1 or FTY720 recapitulates the alterations in lipid profiles observed in‐vivo, resulting in marked increases in Sphinganine and Sa1P. Further, FTY720 is phosphorylated to the S1P receptor agonist FTY720‐P in hES‐NEP cells. Like S1P, both Sa1P and FTY720‐P stimulate activation of phospholipase C and inhibition of adenylyl cyclase, but with distinct rank order potencies and sensitivity to receptor and G‐protein inhibitors, suggesting these metabolites have unique signaling properties in human neural progenitors.Funding for this work is provided by the NIH and the University of Georgia.

Lysophospholipid receptors in vertebrate development, physiology, and pathology

Lysophospholipid (LP) research has experienced a period of renaissance with the discovery of the lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P) receptors in the late 1990s. Vertebrate LP receptors regulate embryogenesis, vascular development, neurogenesis, uterine development, oocyte survival, immune cell trafficking and inflammatory reactions. LP signaling is important in cancer, autoimmunity and inflammatory diseases. Research on LP biology has contributed to the development of a first-generation S1P receptor modulator that has entered phase III clinical trials for the treatment of multiple sclerosis. Further basic research on LP signaling is anticipated to lead to novel therapeutic tools to combat various human diseases.

Modulation of invasive properties of CD133(+) glioblastoma stem cells: A role for MT1‐MMP in bioactive lysophospholipid signaling

Future breakthroughs in cancer therapy must accompany targeted agents that will neutralize cancer stem cells response to circulating growth factors. Since the brain tissue microenvironmental niche is a prerequisite for expression of the stem cell marker CD133 antigen in brain tumors, we investigated the invasion mechanisms specific to CD133(+) U87 glioblastoma cells in response to lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P), two circulating bioactive lysophospholipids and potent inducers of cancer. A CD133(+) U87 glioma cell population was isolated from parental U87 glioblastoma cells using magnetic cell sorting technology. The CD133(+)-enriched cell population grew as neurospheres and showed enhanced maximal response to both LPA (approximately 5.0-fold) and S1P (approximately 2.5-fold) at 1 microM when compared to parental U87 cells. The increased response to LPA in CD133(+) cells, reflected by increased levels of phosphorylated ERK, was found independent of the cooperative functions of the membrane-type-1 matrix metalloproteinase (MT1-MMP), while this cooperativity was essential to the S1P response. Quantitative RT-PCR was performed and we found higher gene expression levels of the S1P receptors S1P1 and S1P2, and of the LPA receptor LPA1 in CD133(+) cells than in their parental U87 cells. These increased levels reflected those observed from in vivo experimental U87 tumor implants. Our data suggest that the CD133(+) cell subpopulation evokes most of the lysophospholipid response within brain tumors through a combined regulation of S1P/LPA cell surface receptors signaling and by MT1-MMP. The emergence of lead compounds targeting the stem cell niche and S1P/LPA signaling in CD133(+) cancer cells is warranted.

Anastellin, the Angiostatic Fibronectin Peptide, Is a Selective Inhibitor of Lysophospholipid Signaling

Angiogenesis is regulated by integrin-dependent cell adhesion and the activation of specific cell surface receptors on vascular endothelial cells by angiogenic factors. Lysophosphatidic acid (LPA) and sphingosine-1 phosphate (S1P) are bioactive lysophospholipids that activate G protein-coupled receptors that stimulate phosphatidylinositol 3-kinase (PI3K), Ras, and Rho effector pathways involved in vascular cell survival, proliferation, adhesion, and migration. Previous studies have shown that anastellin, a fragment of the first type III module of fibronectin, functions as an antiangiogenic peptide suppressing tumor growth and metastasis. We have previously shown that anastellin blocks serum-dependent proliferation of microvessel endothelial cells (MVEC) by affecting extracellular signal-regulated kinase (ERK)-dependent G(1)-S transition. However, the mechanism by which anastellin regulates endothelial cell function remains unclear. In the present study, we mapped several lysophospholipid-mediated signaling pathways in MVEC and examined the effects of anastellin on LPA- and S1P-induced MVEC proliferation, migration, and cytoskeletal organization. Both LPA and S1P activated PI3K, Ras/ERK, and Rho/Rho kinase pathways, leading to migration, G(1)-S cell cycle progression, and stress fiber formation, respectively. Stimulation of proliferation by LPA/S1P occurred through a G(i)-dependent Ras/ERK pathway, which was independent of growth factor receptors and PI3K and Rho/Rho kinase signaling. Although LPA and S1P activated both PI3K/Akt and Ras/ERK signaling through G(i), anastellin inhibited only the Ras/ERK pathway. Stress fiber formation in response to LPA was dependent on Rho/Rho kinase but independent of G(i) and unaffected by anastellin. These results suggest that lysophospholipid mediators of G(i) activation leading to PI3K/Akt and Ras/ERK signaling bifurcate downstream of G(i) and that anastellin selectively inhibits the Ras/ERK arm of the pathway.

Lysophospholipid signaling in the function and pathology of the reproductive system

Lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P) are two prominent signaling lysophospholipids (LPs) exerting their functions through a group of G protein-coupled receptors (GPCRs). This review covers current knowledge of the LP signaling in the function and pathology of the reproductive system. PubMed was searched up to May 2008 for papers on lysophospholipids/LPA/S1P/LPC/SPC in combination with each part of the reproductive system, such as testis/ovary/uterus. LPA and SIP are found in significant amounts in serum and other biological fluids. To date, 10 LP receptors have been identified, including LPA(1-5) and S1P(1-5). In vitro and in vivo studies from the past three decades have demonstrated or suggested the physiological functions of LP signaling in reproduction, such as spermatogenesis, male sexual function, ovarian function, fertilization, early embryo development, embryo spacing, implantation, decidualization, pregnancy maintenance and parturition, as well as pathological roles in ovary, cervix, mammary gland and prostate cancers. Receptor knock-out and other studies indicate tissue-specific and receptor-specific functions of LP signaling in reproduction. More comprehensive studies are required to define mechanisms of LP signaling and explore the potential use as a therapeutic target.

Potential Therapeutic Roles Of Lysophospholipid Signaling In Autoimmune-Related Disease

Autoimmune disorders are characterized by lymphocyte infiltration and destruction of affected tissues. Lysophospholipids are small, relatively simple phospholipids derived from cell membranes that have been shown over the last decade to produce a wide range of effects through cognate G protein-coupled receptors, and include sphingosine 1-phosphate (S1P), which is the focus of this review, as well as lysophosphatidic acid (LPA). S1P1, a sphingosine 1-phosphate lysophospholipid receptor, is essential for lymphocyte egress from the thymus and peripheral lymphoid tissues. Here we review how changes in S1P1-receptor expression and S1P concentration affect lymphocyte trafficking. In particular, we focus on mechanisms that involve S1P1 through its removal via genetic deletion and inhibition via pharmacological intervention, which provide a foundation for potentially useful approaches to the treatment of autoimmune disease based on lysophospholipid signaling modulation. Recent advances in our understanding of how...

Lysophospholipid Receptors as Potential Drug Targets in Tissue Transplantation and Autoimmune Diseases

New therapies directed at ameliorating or altering autoimmune diseases represent an area of significant medical need. Included amongst autoimmune diseases are problems related to transplantation rejection, as well as a number of neurological diseases such as Multiple Sclerosis (MS). A new group of molecular targets that may lead to novel therapies are lysophospholipid (LP) receptors. A large range of biological activities has been attributed to the actions of these simple phospholipids that include well-studied members lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P). Documented cellular effects of these lipid molecules encompass growth-factor-like influences on cells, including but not limited to survival, migration, adhesion differentiation, as well as pathophysiological actions associated with cancer. In turn, these cellular effects have roles in developing and adult organ systems such as the nervous system, cardiovascular system, reproductive system and, of relevance here, the immune system. The mechanisms for these actions can be attributed to a growing family of cognate, 7-transmembrane G protein-coupled receptors (GPCRs), with documented validation through studies utilizing pharmacology, molecular genetics and an enlarging repertoire of chemical tools having agonist or antagonist properties. The growing literature on immunological effects of LP receptors, particularly those mediating the effects of S1P, has suggested possible therapeutic roles for this class of receptors. In particular, entry into humans of a non-selective S1P receptor agonist, FTY720, for kidney transplantation and possibly other indications (e.g., Multiple Sclerosis), has raised prospects for efficacious treatment of human diseases based on LP receptor targets. Here we provide a brief introduction to receptor-mediated lysophospholipid signaling and discuss its basic and potential therapeutic roles in autoimmune-related diseases.

Cell surface receptors in lysophospholipid signaling.

The lysophospholipids, lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P), regulate various signaling pathways within cells by binding to multiple G protein-coupled receptors. Receptor-mediated LPA and S1P signaling induces diverse cellular responses including proliferation, adhesion, migration, morphogenesis, differentiation and survival. This review will focus on major components of lysophospholipid signaling: metabolism, identification and expression of LPA and S1P receptors, general signaling pathways and specific signaling mechanisms in mouse embryonic fibroblasts. Finally, in vivo effects of LP receptor gene deletion in mice will be discussed.

Lysophospholipids in development: Miles apart and edging in.

Sphingosine-1-phosphate (S1P) and lysophosphatidic acid (LPA) are endogenous bioactive lipids that participate in the regulation of mammalian cell proliferation, apoptosis, migration, and angiogenesis. These processes are each critical for successful embryogenesis, raising the possibility that lysophospholipid signaling may contribute to normal animal development. In fact, recent studies in developmental model systems have established that S1P and LPA are necessary for diverse developmental programs including those required for morphogenesis of vertebrate reproductive, cardiovascular and central and peripheral nervous systems (PNS), as well as the establishment of maternal-fetal circulation and the immune system. Genetic, morphological, and biochemical characterization of developmental model systems offer powerful approaches to elucidating the molecular mechanisms of lysophospholipid signaling and its contributions to animal development and postnatal physiology. In this review, the routes of S1P and LPA metabolism and our current understanding of lysophospholipid-mediated signal transduction in mammalian cells will be summarized. The evidence implicating lysophospholipid signaling in the development of specific vertebrate systems will then be reviewed, with an emphasis on signals mediated through G protein-coupled receptors of the Edg family. Lastly, recent insights derived from the study of simple metazoan models and implications regarding lysophospholipid signaling in organisms in which Edg receptors are not conserved will be explored.

Lipid Phosphate Phosphatases Regulate Lysophosphatidic Acid Production and Signaling in Platelets: STUDIES USING CHEMICAL INHIBITORS OF LIPID PHOSPHATE PHOSPHATASE ACTIVITY

Blood platelets play an essential role in ischemic heart disease and stroke contributing to acute thrombotic events by release of potent inflammatory agents within the vasculature. Lysophosphatidic acid (LPA) is a bioactive lipid mediator produced by platelets and found in the blood and atherosclerotic plaques. LPA receptors on platelets, leukocytes, endothelial cells, and smooth muscle cells regulate growth, differentiation, survival, motility, and contractile activity. Definition of the opposing pathways of synthesis and degradation that control extracellular LPA levels is critical to understanding how LPA bioactivity is regulated. We show that intact platelets and platelet membranes actively dephosphorylate LPA and identify the major enzyme responsible as lipid phosphate phosphatase 1 (LPP1). Localization of LPP1 to the platelet surface is increased by exposure to LPA. A novel receptor-inactive sn-3-substituted difluoromethylenephosphonate analog of phosphatidic acid that is a potent competitive inhibitor of LPP1 activity potentiates platelet aggregation and shape change responses to LPA and amplifies LPA production by agonist-stimulated platelets. Our results identify LPP1 as a pivotal regulator of LPA signaling in the cardiovascular system. These findings are consistent with genetic and cell biological evidence implicating LPPs as negative regulators of lysophospholipid signaling and suggest that the mechanisms involve both attenuation of lysophospholipid actions at cell surface receptors and opposition of lysophospholipid production.

The Edg family G protein-coupled receptors for lysophospholipids: their signaling properties and biological activities.

Sphingosine-1-phosphate (S1P) and lysophosphatidic acid (LPA) are blood-borne lysophospholipids with a wide spectrum of biological activities, which include stimulation of cell growth, prevention of apoptosis, regulation of actin cytoskeleton, and modulation of cell shape, cell migration, and invasion. Activated platelets appear to be a major source of both S1P and LPA in blood. Despite the diversity of their biosynthetic origins, they are considered to share substantial structural similarity. Indeed, recent investigation has revealed that S1P and LPA act via a single family of G protein-coupled receptors designated as Edg. Thus, the Edg isoforms, Edg1 (also called S1P(1)), Edg5 (S1P(2)), Edg3 (S1P(3)), Edg6 (S1P(4)), and Edg8 (S1P(5)), are specific receptors for S1P (and SPC with a lower affinity), whereas Edg2 (LPA(1)), Edg4 (LPA(2)), and Edg7 (LPA(3)) serve as receptors specific for LPA. Each receptor isoform displays a unique tissue expression pattern and coupling to a distinct set of heterotrimeric G proteins, leading to the activation of an isoform-specific panel of multiple intracellular signaling pathways. Recent studies on knockout mice have unveiled non-redundant Edg receptor functions that are essential for normal development and vascular maturation. In addition, the Edg lysophospholipid signaling system may play a role in modulating cell motility under such pathological conditions as inflammation, tumor cell dissemination and vascular remodeling.

Neurobiology of Receptor‐Mediated Lysophospholipid Signaling: From the First Lysophospholipid Receptor to Roles in Nervous System Function and Development

Identification of the first lysophospholipid receptor, LPA1/Vzg-1, cloned by way of neurobiological analyses on the embryonic cerebral cortex, has led to the realization and demonstration that there exist multiple, homologous LP receptors, including those encoded by a number of orphan receptor genes known as "Edg," all of which are members of the G-protein-coupled receptor (GPCR) superfamily. These receptors interact with apparent high affinity for lysophosphatidic acid (LPA) or sphingosine-1-phosphate (S1P or SPP), and are referred to based upon their functional identity as lysophospholipid receptors: LPA and LPB receptors, respectively, with the expectation that additional subgroups will be identified (i.e., LPC, etc.). Here an update is provided on insights gained from analyses of these receptor genes as they relate to the nervous system, particularly the cerebral cortex, and myelinating cells (oligodendrocytes and Schwann cells).

Schwann cell survival mediated by the signaling phospholipid lysophosphatidic acid.

Lysophosphatidic acid (LPA) is a bioactive phospholipid with properties of an extracellular growth factor for many cell lines, including those derived from neuroblastomas. However, the relevance of LPA signaling to the normal, developing nervous system is unknown, in part reflecting the previous unavailability of cloned receptor genes. Recent studies of the first such gene, encoding the G protein-coupled receptor LPA1/VZG-1 (lysophospholipid receptor A1/ventricular zone gene-1), revealed a major locus of expression in oligodendrocytes and Schwann cells (SCs) during development, suggesting an influence of LPA on these myelinating cells. Here we report that LPA (>/=10 nM) is a potent survival factor for cultured neonatal SCs, with survival activity equaling the maximal effect of neuregulin, the major peptide SC survival factor. LPA activates a pharmacologically defined signaling pathway in SCs, involving Gi and phosphoinositide 3-kinase. Moreover, LPA's effect depends on Akt, a downstream kinase that can mediate phosphoinositide 3-kinase-dependent survival, as demonstrated by both Western blot and transfection analyses. Overexpression of functional epitope-tagged LPA1/VZG-1 protein decreases SC apoptosis in response to serum withdrawal. These data demonstrate a role for extracellular LPA and its receptor LPA1/VZG-1 in SC survival and, more broadly, implicate G protein-coupled receptor-mediated lysophospholipid signaling as a significant mechanism in neural development.