Human Reproduction Update Advance Access originally published online on June 17, 2008
Human Reproduction Update 2008 14(5):519-536; doi:10.1093/humupd/dmn023
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Lysophospholipid signaling in the function and pathology of the reproductive system
1 Department of Physiology and Pharmacology, College of Veterinary Medicine, University of Georgia, Athens, GA 30602, USA 2 Interdisciplinary Toxicology Program, University of Georgia, Athens, GA, USA
3 Correspondence address. Tel:+1-706-542-6745(office)/6041(lab); Fax: +1-706-542-3015; E-mail: ye{at}uga.edu
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Abstract |
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BACKGROUND: 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.
METHODS: 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.
RESULTS: LPA and SIP are found in significant amounts in serum and other biological fluids. To date, 10 LP receptors have been identified, including LPA1–5 and S1P1–5. 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.
CONCLUSIONS: 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.
Key words: cancer / LPA / lysophospholipid receptors / reproduction / S1P
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Introduction |
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TOPAbstractIntroductionMaterials and MethodsFundingAcknowledgementsReferences |
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Lysophospholipids (LPs) were originally recognized as quantitatively minor lipid species produced during the biosynthesis of membrane phospholipids (Pieringer et al., 1967
). The signaling properties of LPs were initially noticed in the 1960s (Vogt, 1963). Later, more studies established LPs as signaling molecules (Tokumura et al., 1978, 1980; van Corven et al., 1989; Durieux et al., 1993; Hill et al., 1994a). LPs demonstrated to be involved in signaling include lysophosphatidic acid (LPA), sphingosine-1-phosphate (S1P), lysophosphatidylcholine (LPC) and sphingosylphosphorylcholine (SPC). Early studies revealed the effects of LPA on blood pressure, uterine smooth muscle contraction and platelet aggregation (Tokumura et al., 1978, 1980; Gerrard et al., 1979; Schumacher et al., 1979). Subsequently, numerous studies identified a range of physiological processes in which LPs were involved, e.g. cell proliferation (van Corven et al., 1989; Zhang et al., 1991; Olivera and Spiegel, 1993; Goodemote et al., 1995; Yoshida et al., 1996), cell survival (Cuvillier et al., 1996; Van Brocklyn et al., 1998; Goetzl et al., 1999; Weiner and Chun, 1999), cell differentiation (Piazza et al., 1995; Sato et al., 1998), cell morphological changes (Ridley and Hall, 1992; Jalink et al., 1993, 1994; Bornfeldt et al., 1995; Postma et al., 1996; Sato et al., 1997; Fukushima et al., 1998), regulation of gap junctions (Hill et al., 1994a), stimulation of the serum response element (Hill et al., 1994b), induction of inward ion currents (Durieux et al., 1993), etc. These broad biological effects have attracted increasing attention to LP signaling research in recent years. A significant portion of the recent discoveries are related to reproduction. This review will briefly introduce receptor-mediated LP signaling and comprehensively update the physiological and pathological functions of LP signaling in the reproductive system. |
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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.
Signaling LPs and LP signaling
Extracellular signaling LPs have simple chemical structures: a 3-carbon glycerol or a sphingoid backbone with a single acyl chain of varied length and saturation (Ishii et al., 2004). LPA and S1P are the most studied extracellular signaling LPs. Some LPs also have intracellular functions that are not covered here (Spiegel et al., 1994, 1996; Spiegel and Milstien, 2003; Pebay et al., 2007; Valentine et al., 2007).
LPA has been detected in significant amounts in biological fluids such as serum (up to micromolar concentration) and plasma (Tokumura et al., 1986; Baker et al., 2000; Aoki et al., 2002; Sano et al., 2002), saliva (Sugiura et al., 2002), blister fluid (Mazereeuw-Hautier et al., 2005), tear (Liliom et al., 1998), hen egg white (Nakane et al., 2001), follicular fluid (Tokumura et al., 1999), seminal plasma (Hama et al., 2002) and ascites (Xu et al., 1995b, 1998, 2003; Tokumura et al., 2007). Evidence has shown that many cell types such as activated platelets (Mauco et al., 1978; Gerrard and Robinson, 1989; Eichholtz et al., 1993; Fourcade et al., 1995), erythrocytes (Fourcade et al., 1995), postmitotic neurons (Fukushima et al., 2000), ovarian and cervical cancer cells (Shen et al., 1998; Eder et al., 2000; Luquain et al., 2003), adipocytes (Gesta et al., 2002) and mast cells (Mori et al., 2007) are able to produce LPA.
The main pathways for LPA production may differ in various cell types and the metabolism of LPA in most cell types is still unclear (Aoki, 2004). Studies on the production of extracellular LPA in the serum have suggested two main pathways involving phospholipase D (PLD), phospholipase A1 (PLA1), phospholipase A2 (PLA2) and autotaxin/lysophospholipase D (ATX/lysoPLD) (Fig. 1). One main pathway is the cleavage of phospholipids (PLs) by PLD to form phosphatidic acids (PAs). LPA is generated from hydrolysis of PAs by PLA1 and PLA2, this process can be reversed by LPA acyltransferases (Leung, 2001). The other main pathway is the cleavage of LPs such as LPC, lysophosphatidylethanolamine and lysophosphatidylserine, by ATX/lysoPLD to free LPA. PLA1 and PLA2 are involved in the production of LPs from membrane PLs in this pathway. LPA is dephosphorylated to monoacylglycerol by a family of three membrane-bound lipid phosphate phosphatases (LPP1, LPP2 and LPP3). Extracellular LPA is normally bound to molecules, such as albumin, fatty acid binding proteins, gelsolin and lipoproteins, for transportation and stability (Gaits et al., 1997; Pages et al., 2001; Mills and Moolenaar, 2003; Aoki, 2004).
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S1P also is found in significant levels in serum and plasma (Yatomi et al., 2001
). Major sources are platelets and erythrocytes (Yatomi et al., 1995; English et al., 2000; Hanel et al., 2007; Ito et al., 2007; Pappu et al., 2007). Lung endothelial cells (Zhao et al., 2007) and mast cells (Mitra et al., 2006) can also produce this molecule. S1P is the product of sphingosine phosphorylation by sphingosine kinases (SphK1 and SphK2). Sphingosine is produced from ceramide, a pro-apoptotic factor. Specific dephosphorylation of S1P by S1P phosphohydrolases or non-specific dephosphorylation of S1P by LPPs can reverse this process. S1P is metabolized by S1P lyase to form phosphoethanolamine and hexadecenal (Brindley et al., 2002; Le Stunff et al., 2004). As with LPA, extracellular S1P is also bound to molecules, such as serum albumin and lipoproteins (Okajima 2002; Kobayashi et al., 2006).
Previous debates about the mechanisms of extracellular LP signaling have been silenced by the identification of molecularly cloned receptors (Chun, 1999; Chun et al., 2000; Fukushima et al., 2001; Ishii et al., 2004). While the majority of rigorous data supported the existence of specific receptors for extracellular LPA and S1P, other data, such as the reported lack of stereo-specific effects, the detergent-like chemical structures and the use of LPs at high concentrations were consistent with actions via non-receptor mechanisms such as membrane perturbation or disruption. The cloning of the first LPA receptor in 1996 (Hecht et al., 1996) and the following identification of nine more LP receptors, as well as the establishement of receptor-specific functions, have clearly defined a receptor-mediated mechanism for the effects of extracellular LPs (Moolenaar, 2000; Spiegel and Milstien, 2003; Anliker and Chun, 2004; Ishii et al., 2004; Birgbauer and Chun, 2006; Gardell et al., 2006; Herr and Chun, 2007; Meyer zu Heringdorf and Jakobs, 2007; Watterson et al., 2007).
The 10 so far identified LP receptors include LPA1–5 and S1P1–5 (Table I). Suggested additional possible LP receptor candidates include: GPR87 and P2Y5 for LPA (Tabata et al., 2007; Pasternack et al., 2008); GPR3 and GPR12 for S1P and SPC (Uhlenbrock et al., 2002, 2003; Hinckley et al., 2005); G2A for LPC; OGR1 and GPR4 for SPC, etc (Xu 2002; Bektas et al., 2003; Ishii et al., 2004; Murakami et al., 2004; Seuwen et al., 2006). LPA1–5 and S1P1–5 are transmembrane G protein-coupled receptors (GPCRs). They can differentially couple with G12/13, Gq, Gi/o or Gs to activate the downstream signaling cascades and eventually lead to LP-induced cellular functions, such as cell proliferation, cell survival, cell differentiation and cell morphological changes (Table I) (Fig. 1) (Ye et al., 2002; Ishii et al., 2004; Gardell et al., 2006; Hannun and Obeid, 2008).
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The LP receptors have overlapping expression patterns in specific tissues and each receptor has its unique expression profile. Based on data from northern analyses, the expression of LPA1, S1P1, S1P2 and S1P3 is ubiquitous although the expression levels in different tissues vary, whereas the expression of other receptors is more confined: LPA2 is highly expressed in testis and kidney; LPA3 in testis, kidney and lung; LPA4 in heart and skin; LPA5 in small intestine and stomach, with lower levels in skin, spleen and thymus; S1P4 in lung, thymus and spleen; S1P5 in brain and skin (Contos et al., 2000b
; Ishii et al., 2001; Lee et al., 2006a, 2007). The expression of LP receptors in the reproductive tissues are summarized in Table II. Moreover, LP receptors may have preferences for different ligands. For example, LPA3 is not as responsive as LPA1 and LPA2 to LPA species with saturated acyl chains but has a relatively high affinity for 2-acyl-LPA containing unsaturated fatty acids (Bandoh et al., 1999; Fischer et al., 2001; Sonoda et al., 2002). The differential coupling to G proteins, the differential receptor expression patterns and ligand specificity may contribute to LP receptor-specific functions.
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The specific functions of LP receptors have been determined through molecular, biochemical, physiological, pharmacological and genetic approaches. Receptor-mediated LP signaling has broad implications in the nervous system. For example, LPA1 is involved in neuropathic pain, suckling behavior, psychiatric disease such as schizophrenia, Schwann cell survival and morphological change, and astrocyte proliferation (Weiner and Chun, 1999
; Contos et al., 2000a; Renback et al., 2000; Weiner et al., 2001; Harrison et al., 2003; Inoue et al., 2004, 2006; Shano et al., 2008), while LPA1 and LPA2 mediate brain formation (Kingsbury et al., 2003; Estivill-Torrus et al., 2008). S1P2 plays a role in seizure and hearing (MacLennan et al., 2001, 2006; Herr et al., 2007; Kono et al., 2007a), while S1P5 is involved in development of oligodendroglial cells (Jaillard et al., 2005) and S1P receptor(s) are implicated in multiple sclerosis (Webb et al., 2004). LPA1 and S1P1–3 have crucial roles in cardiovascular system processes, such as angiogenesis, atherosclerosis and cardiac myocyte survival (Contos et al., 2000a; Liu et al., 2000; Siess, 2002; Allende et al., 2003; Kono et al., 2004; Siess and Tigyi, 2004; Maguire and Davenport, 2005; Zhang et al., 2007). LPA1–3 and S1P1–3 have been implicated in processes of the respiratory system: proinflammatory effects, acute respiratory distress syndrome and chronic inflammatory airway diseases (Ammit et al., 2001; Jolly et al., 2002; Konishi et al., 2002; Gon et al., 2005; Saatian et al., 2006; Kono et al., 2007b). LPA1–3, S1P1, S1P3 and S1P4 can mediate LP functions in the immune system (Zheng et al., 2001; Graler and Goetzl, 2002; Bagga et al., 2004; Goetzl et al., 2004; Matsuyuki et al., 2006; Chan et al., 2007; Czeloth et al., 2007; Pappu et al., 2007; Wang et al., 2007b). In fact, FTY720, a broad-spectrum S1P receptor agonist, is in phase III studies for treating demyelinating diseases, specifically multiple sclerosis (Budde et al., 2006; Chun and Rosen, 2006; Mullershausen et al., 2007; Zhang and Schluesener, 2007). LPA1 has a specific function in craniofacial formation (Contos et al., 2000a). LPA3 plays a critical role in embryo implantation and spacing (Ye et al., 2005; Hama et al., 2007). In addition, receptor-mediated LP signaling has been implicated in stem cells and wound healing (Pebay et al., 2007; Watterson et al., 2007), as well as multiple cancers including ovarian, prostate, renal, bladder, breast, liver and other forms (Azuma et al., 2002, 2003; Mills and Moolenaar, 2003; Xu et al., 2003; Lee et al., 2005; Murph and Mills, 2007; Ng et al., 2007; Ubai et al., 2007; van Meeteren and Moolenaar, 2007). The roles of identified receptor-mediated LP signaling in reproduction are summarized in Table III.
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LP signaling in testis
It was speculated for at least three reasons that LPA signaling had potential roles in male reproduction (Budnik and Mukhopadhyay, 2002b). First, LPA biosynthetic enzymes, including PLA1 and PLA2, and autotaxin/lysoPLD are present in the testis (Higgs and Glomset, 1996; Lee et al., 1996; Ito et al., 2002; Sonoda et al., 2002; Hiramatsu et al., 2003; Aoki, 2004; Xie and Meier, 2004). Second, LPA1, LPA2 and LPA3 are highly expressed in the mouse testis (Contos et al., 2000b), while LPA4 was detected in the human testis (Noguchi et al., 2003). Third, the transgenic mice overexpressing LPP1, which degrades LPA, showed severely impaired spermatogenesis (Yue et al., 2004). In situ hybridization demonstrated that LPA1, LPA2 and LPA3 are expressed in the male germ cells. Deletion of these receptors in mice led to a testosterone-independent reduction of mating activity and sperm counts, with an increased prevalence of azoospermia in aging animals. The physiological mechanism by which the deletion of these receptors led to reduced mating activity is not readily apparent. Increased germ cell apoptosis was responsible for the consequent reduction of germ cell proliferation and the diminished sperm counts, indicating LPA signaling as a germ cell survival factor in spermatogenesis (Ye et al., 2008).
Northern analysis indicated S1P2 and S1P3 at medium expression levels, S1P1 barely detectable, and S1P4 and S1P5 undetectable in the adult mouse testis (Ishii et al., 2001). RT–PCR detected S1P1, S1P2 and S1P5 in mouse spermatozoa (Matsumoto et al., 2005). S1P1 and S1P2 were detected by immunohistochemistry in human Sertoli cells, with occasional and weak staining in the spermatogonia and early meiotic spermatocytes (Suomalainen et al., 2005).
As with LPA, S1P seemed to be a survival factor for male germ cells. S1P partially protected mouse testicular germ cells against radiation-induced cell death (Otala et al., 2004) and inhibited human germ cell apoptosis in a culture of human seminiferous tubules. Nuclear factor kappaB (NF-kappaB) and protein kinase B (Akt) phosphorylation were implicated in the effect in humans, but a receptor-independent mechanism was proposed (Suomalainen et al., 2005). Furthermore, disruption of S1P lyase, which degrades S1P and regulates the ratio of pro-apoptotic ceramide and anti-apoptotic S1P, led to reduced testis size in Drosophila caused by increased apoptosis (Phan et al., 2007). In addition, sphingolipid signaling is critical for male gametophyte development in Arabidopsis (Teng et al., 2008).
LP signaling in male sexual function
Reports have suggested that LP signaling may also participate in male sexual function. LPC is a major component of atherogenic oxidized low-density lipoproteins related to hypercholesterolemia, which can cause erectile dysfunction (Jung et al., 2007; Xie et al., 2008). It was suggested that LPC-induced intracellular calcium concentration [Ca2+]i in human corporal smooth muscle cells might be involved in hypercholesterolemia-induced erectile function (So et al., 2005). Coordinately, a tentative LPC receptor, G2A, may also provide pro-atherogenic stimulus to atherosclerotic lesions (Parks et al., 2006). Therefore, the pro-atherogenic effect of LPC signaling might have negative impact on erectile function. LPA also has atherogenic activity (Siess and Tigyi, 2004). LPA activity was detected in the seminal plasma (Hama et al., 2002). PLA2, an enzyme involved in LPA production, was down-regulated in the corpus cavernosum of hypercholesterolemic rats (Jung et al., 2007). The significance of LPA signaling in male sexual function is unclear. S1P signaling, on the other hand, may have a positive effect on penile erection, which requires the coordinated arterial endothelium-dependent vasodilation and sinusoidal endothelium-dependent corporal smooth muscle relaxation. S1P1, S1P2 and S1P3 were detected in the human penile artery and corpus cavernosum. S1P can dramatically boost the relaxation induced by acetylcholine in human corpus cavernosum strips. This effect was mediated through the Ca2+-independent Akt-endothelial nitric oxide synthase pathway that led to the production of nitric oxide, the principle peripheral pro-erectile neurotransmitter (di Villa Bianca et al., 2006).
The potential role of receptor-mediated LPA signaling in ovary was proposed before the identification of any LP receptor. Early studies demonstrated that LPA induced Ca2+-activated Cl– current in naked Xenopus laevis oocytes and a receptor-mediated Gi protein signaling mechanism was responsible for this effect (Durieux et al., 1992, 1993). Since then more potential roles of LP signaling in the ovary have been explored.
More recently LPA was detected in follicular fluid and in hens’ egg. LPA was present at significant levels in follicular fluid of the human pre-ovulatory follicle (Tokumura et al., 1999). Ovarian stimulation in women may increase LPA levels since serum ATX/lysoPLD activity from patients receiving ovarian stimulation was higher than in women with natural cycles (Chen et al., 2008). Concordantly, LPA was induced in incubated human follicular fluid by ATX/lysoPLD (Tokumura et al., 1999). High amounts of acyl LPA (micromolar range) were present in hen egg yolk, predominantly saturated LPA, and hen egg white, predominantly polyunsaturated LPA produced from LPs, suggesting that egg yolk LPA and egg white LPA may play separate physiological roles in the development, differentiation and growth of embryos (Nakane et al., 2001; Morishige et al., 2007).
The transcripts of LPA1, LPA2 and LPA4, but not LPA3, are detectable in the mouse ovary (X. Ye and J. Chun, unpublished data) (Ye et al., 2005). LPA1, LPA2 and LPA3 mRNAs are detectable in the granulosa-lutein cells from women undergoing in vitro fertilization (IVF) (Chen et al., 2008). LPA4 has the highest mRNA expression level in the human ovary among all the human tissues that were examined (Noguchi et al., 2003). The mRNA expression of LPA5 in ovary has not been examined (Kotarsky et al., 2006; Lee et al., 2006a).
LPA signaling is involved in oocyte maturation in vitro. LPA, 10 µM, significantly increased the oocyte nuclear and cytoplasmic maturation rates in golden hamster immature oocytes via cumulus cells (Hinokio et al., 2002). LPA receptor(s) (on cumulus cells), Gi and ERK (extracellular signal-regulated kinase)/p38 signaling pathways were involved in the closure or loosening of gap junctions between cumulus cells and the oocyte, leading to an early decrease of oocyte cAMP levels that may promote nuclear maturation of mouse oocytes in vitro (Komatsu et al., 2006).
The role of LPA in granulosa-lutein cells from women undergoing IVF was recently reported. LPA enhanced the expression of angiogenic cytokines interleukin-6 (IL-6) and IL-8. LPA1, Gi, MAPK (mitogen-activated protein kinase)/p38, PI3K (phosphoinositol 3-kinase)/Akt and NF-kappaB signaling pathways were involved in the LPA-induced IL-8 expression. LPA2, Gi, MAPK/p38 and NF-kappaB signaling pathways were involved in the LPA-induced IL-6 expression. It was suggested that LPA in pre-ovulatory follicles may play a role in the angiogenesis of the corpus luteum and the excessive induction of IL-8 and IL-6 by LPA from multiple corpora luteae of stimulated ovaries may be a pathophysiological cause of ovarian hyperstimulation syndrome (Chen et al., 2008). Results from LPA2 transgenic ovaries suggested that the LPA-LPA2 circuit may regulate ovarian cells both directly and through increases in protein growth factor systems (Huang et al., 2004). A recent study demonstrated that deletion of PTEN (phosphatase and tensin homolog deleted on chromosome 10), a major negative regulator of PI3K-Akt signaling pathway, led to activation of entire primordial follicle pool and premature ovarian failure in mice (Reddy et al., 2008). LP signaling regulates PI3K-Akt signaling pathway (Fig. 1), whether or not LP signaling is involved in follicle activation remains to be determined.
LPA induced Chinese hamster ovary (CHO) cell growth, migration and lamellipodium formation through Gi. LPA1 may be the key LPA receptor in mediating these effects as LPA2 and LPA3, which also couple to Gi, are not expressed in CHO cells. LPA4, which may couple to Gi, does not seem to be expressed in CHO cells at a significant level and LPA5 does not couple to Gi (Noguchi et al., 2003; Lee et al., 2006a, 2007; Yanagida et al., 2007). However, when Gi function was blocked by pertussis toxin pretreatment, LPA inhibited, rather than induced CHO cell migration in response to insulin-like growth factor I. LPA1-G13-Rho signaling pathway relayed this inhibitory effect (Yamaji et al., 2004; Sugimoto et al., 2006).
The effects of LPA signaling in bovine ovarian theca cells and luteal cells are quite complicated. In bovine ovarian theca cells LPA signaling has the following effects: induction of transient ERK phosphorylation through LPA1-G12/13 signaling pathway (Budnik et al., 2003); redistribution of protein kinase C 
(PKC) from the cytosol to the perinuclear area; augmentation of luteinizing hormone (LH)-stimulated progesterone accumulation. LPA-induced nuclear localization of PKC might have a luteotropic function in the bovine ovary (Budnik and Mukhopadhyay, 2002a). In bovine luteal cells, LPA signaling regulated their morphology but its role in steroid synthesis was opposite to that observed in theca cells. During the development and rescue of the corpus luteum, LH induced major morphoregulatory effects such as formation of stellate processes. LPA inhibited these processes via Rho proteins (Budnik and Mukhopadhyay, 2001). LPA also dramatically inhibited LH-induced progesterone production on ovarian mid-cycle luteal cells presumably through LPA2 and possibly associated with S1P production (Budnik and Brunswig-Spickenheier, 2005).
The function of LPA signaling in ovulation has not been fully determined. Superovulation data from LPA3(–/–) females did not show any suppression of oocyte numbers released compared with the wild-type (WT) controls. This agreed with the result that LPA3 was not detectable in the mouse ovary. LPA1 and LPA2 were expressed in the ovary. Preliminary data from LPA1(–/–) LPA2(–/–) females indicated that these females had comparable numbers of implantation sites to those of WT females, suggesting that LPA1 and LPA2 are not critical for ovulation (X. Ye and J. Chun, unpublished data; Ye et al., 2005).
S1P was identified to be a heat-stable growth factor in the follicular fluid associated with follicular fluid high-density lipoproteins. The S1P concentration was 
170 nM (compared with 900 nM in serum) in the human follicular fluid obtained from women undergoing ovarian hyperstimulation. S1P induced endothelial proliferation and angiogenesis through activation of ERK1/2, PKC and Akt signaling pathways, but it is unclear (i) which cell types produce the S1P in the follicular fluid, (ii) how S1P reaches the theca to affect angiogenesis and (iii) which S1P receptors are involved in these processes (von Otte et al., 2006). Since angiogenesis plays an important role in the development of the ovarian follicle and its subsequent transition into the corpus luteum, the S1P in follicular fluid and its role in angiogenesis underscore S1P signaling as being important in ovarian function.
Indeed, the function of S1P signaling in oocytes, especially the protective role of S1P on oocytes, has been well documented. S1P at 50 µM induced Ca2+-activated Cl– inward currents in X. laevis oocytes and there was a complete cross-desensitization between LPA and S1P responses (Durieux et al., 1993). The protective role of S1P on oocytes has at least two aspects. Extracellular S1P not only could protect bovine oocytes from a physiologically relevant heat shock, but also could affect oocyte maturation in the absence of heat shock. The blastocysts that arose from S1P-treated oocytes that survived heat shock had a normal developmental potential. It was suggested that S1P may be used to improve fertility in situations where developmental competence of the oocytes was compromised (Roth and Hansen, 2004). In addition, S1P-treated oocytes can resist developmental apoptosis, in which the oocyte reserve undergoes normal apoptotic depletion throughout post-natal life. Anti-cancer treatments can lead to premature ovarian failure and infertility. Promisingly, radiation-induced oocyte loss was completely prevented by in vivo therapy with S1P in mice (Morita et al., 2000; Tilly and Kolesnick, 2002). Pre-administration of S1P into ovarian bursa had protective effects on whole-body irradiation-induced apoptosis of primordial follicles in rats (Kaya et al., 2008). Local application of S1P in mice also protected ovarian follicles from chemotherapy- induced cell death (Hancke et al., 2007). These studies provide promises to potentially preserve the fertility of female cancer patients.
S1P3 and GPR3 are expressed in both oocytes and cumulus cells in mice. GPR12 is only detectable in oocytes. Both GPR3 and GPR12 are potential receptors for S1P and SPC. Incubation of mouse oocytes with the GPR3/12 ligands SPC and S1P delayed spontaneous oocyte maturation, an effect that seemed to be opposite of LPA. It was suggested that the cAMP levels required for maintaining meiotic arrest in mouse and rat oocytes were dependent on the expression of GPR3 and/or GPR12 (Hinokio et al., 2002; Hinckley et al., 2005; Komatsu et al., 2006).
The function of S1P signaling in ovary has also been indirectly demonstrated through studies of enzymes involved in S1P metabolism in different species: mutation of SphK2, which catalyzes S1P synthesis, led to diminished ovulation in Drosophila (Herr et al., 2004); ovary degeneration was observed in Drosophila with disrupted S1P lyase, in which apoptosis was elevated (Phan et al., 2007); when S1P lyase was knocked down in Caenorhabditis elegans, oocyte production and ovulation were impaired (Mendel et al., 2003); dihydrosphingosine C4 hydroxylase (DSH) is a key enzyme for sphingolipid production in plants and yeasts and down-regulation of one of the five DSH genes, DSH1, caused sterility in rice plants (Imamura et al., 2007).
Fertilization involves the binding and fusion of sperm and oocyte cells. A main step is acrosome reaction, an exocytotic process that exposes the zona-digesting enzymes around the anterior part of the sperm head and facilitates sperm penetration of the zona pellucida. LPA could activate sperm PKC
, which is implicated in the acrosome reaction, and could promote actin polymerization, a process necessary for spermatozoa incorporation deep into the oocyte cytoplasm. Rho GTPases are involved in the later process but the LPA receptor(s) mediating this process is (are) unknown (Garbi et al., 2000; Delgado-Buenrostro et al., 2005). However, LPA did not seem to affect bovine sperm motility (Garbi et al., 2000). No change of sperm motility was observed in mice deficient of three LPA receptors, LPA1–3 (Ye et al., 2008). LPC was able to induce the acrosome reaction in capacitated bovine sperm (Parrish et al., 1988; Therien and Manjunath, 2003). LPC also accelerated and synchronized the acrosome reaction of hamster spermatozoa, as well as facilitating spermatozoa penetration of the zona pellucida, the fusion process and polyspermy (Riffo and Parraga, 1996). In addition, the detection of S1P receptors in mouse spermatozoa by RT–PCR led to a speculation that S1P might play a role in the acrosomal reaction (Matsumoto et al., 2005). Deletion of acid sphingomyelinase, an enzyme regulating sphingolipid signaling, led to impaired sperm motility (Otala et al., 2005).
LPA1, LPA2, LPA3 and LPA4 mRNAs are expressed in the mouse oviduct (X. Ye and J. Chun, unpublished data). LPA at 10 µM could facilitate ovum transport in the mouse oviducts. Although serum LPA levels can reach the concentration effective for ovum transport, the LPA levels in mouse oviduct are unknown. The receptor-mediated Gi-Ca2+ signaling pathway was involved in LPA-induced mouse ovum transport (Kunikata et al., 1999). Deletion of LPA1, LPA2 or LPA3, the three Gi-coupled LPA receptors, did not seem to affect the transport of embryos to the mouse uterus (X. Ye and J. Chun, unpublished data; Ye et al., 2005). This suggests that LPA signaling is not critical for embryo transport in the oviduct under physiological conditions, and/or other Gi-coupled LPA receptor(s) are present that compensated for the effect in the LPA receptor knockout mice.
LP signaling in early embryo development
LP signaling is involved in early stage embryo development and post-implantation embryo development processes such as vascular formation, vascular maturation and maintenance, heart development and brain formation (Kupperman et al., 2000; Liu et al., 2000; Allende and Proia, 2002; Contos et al., 2002; Kingsbury et al., 2003; Kono et al., 2004; Mizugishi et al., 2005; Tanaka et al., 2006; van Meeteren et al., 2006; Wendler and Rivkees, 2006). This section focuses on the LP signaling in early stage embryo development prior to implantation.
An early study revealed that the culture of embryos from the pronuclear stage in the presence of LPA could significantly increase the success rate of the development of 2-cell and 4-cell stage embryos to blastocysts via a Gi-protein-linked receptor mechanism (Kobayashi et al., 1994). A more recent study found mRNA expression of LPA1 in differentiating mouse blastocysts, expression of LPA2 in late blastocysts and no expression of LPA3. LPA could elevate [Ca2+]i levels, which in turn accelerated murine blastocyst differentiation. LPA could also induce the transient accumulation of heparin-binding epidermal growth factor (EGF)-like growth factor (HB-EGF) on the embryo surface. Interfering with HB-EGF signaling through EGF receptors ErbB1 or ErbB4 could attenuate LPA-stimulated blastocyst differentiation (Liu and Armant, 2004).
A study of Xenopus also supported the importance of receptor-mediated LPA signaling in early embryo development (Lloyd et al., 2005). During early embryo development, the maintenance of overall rigidity and shape of the whole embryo is required for embryogenesis to occur. A cortical actin network of filament bundles assembled in each cell is critical for maintaining embryo shape and rigidity during the egg-to-blastula stage in Xenopus. LPA could increase F-actin in the cortical actin network throughout the animal cap and in the purse-strings, leading to faster healing in the animal cap in early blastula stages in Xenopus. XLPA1 was most abundant in oocytes (Kimura et al., 2001) and expressed at lower levels throughout embryo development; the expression of XLPA2 began in the mid-blastula stage and continued to at least stage 45, the swimming tadpole. Both XLPA1 and XLPA2 were necessary and sufficient for mediating LPA signaling in the correct pattern of cortical actin assembly in Xenopus embryos. Rho and Rac were the responsible downstream signaling molecules.
A recent study in mice demonstrated an anti-apoptotic role of S1P in early embryo development. Acid ceramidase hydrolyzes the pro-apoptotic ceramide into sphingosine, the precursor for the anti-apoptotic S1P (Fig. 1) (Morales and Fernandez-Checa, 2007). Acid ceramidase knockout embryos underwent apoptotic death and could not survive beyond the 2-cell stage. S1P treatment of early 2-cell embryos from the Asah1(+/–) intercrosses not only rescued Asah1(–/–) embryos, but also enabled their progression from the 2-cell to 4–8-cell stage (Eliyahu et al., 2007).
LP signaling in embryo spacing and implantation
Embryo spacing is an event relevant to polytocous species in which embryos are implanted nearly equidistant from each other along the uterus. Implantation involves a competent embryo, a receptive uterus, and reciprocal interactions between them to achieve apposition and attachment of the embryo to the uterine luminal epithelium, invasion of the embryo into the stroma and establishment of a placenta (Carson et al., 2000; Paria et al., 2002; Genbacev et al., 2003; Wang and Dey, 2006). Published reports and recent data have revealed the roles of LP signaling in both embryo spacing and implantation.
LPA signaling influences embryo spacing and uterine receptivity in mice (Ye et al., 2005; Hama et al., 2007). Deletion of LPA3 in mice led to uneven embryo spacing, possibly contributed by defect in uterine contraction, and delayed implantation caused by defect in uterine receptivity. Embryo crowding and delayed implantation were two segregated events based on these observations: (i) restoration of on-time implantation in LPA3-null females failed to correct embryo spacing and (ii) when single embryo, which cannot be subject to embryo crowding, was transferred into LPA3-null uterus, delayed implantation persisted. Deletion of LPA3 in mice also led to delayed embryonic development, prolonged pregnancy and 50% embryonic lethality. Ovulation, fertilization, embryo transport, blastocyst development and decidualization were not adversely affected.
Prostaglandins (PGs) were identified to be at least partially responsible for the phenotypes of LPA3(–/–) females. Expression of cycloxygenase 2 (COX-2), the rate-limiting enzyme for PG synthesis, as well as PGE2 and PGI2 levels were suppressed in the preimplantation embryonic day 3.5 (E3.5) LPA3(–/–) uteri. Exogenous PGE2 and PGI2 could rescue delayed implantation in the LPA3(–/–) females. These results reinforced the importance of PGs in embryo implantation (Kennedy, 1977; Kinoshita et al., 1985; Song et al., 2002). However, PGE2 and PGI2 failed to correct embryo spacing, suggesting that different PGs that control uterine contraction or possible non-PG mechanisms may be responsible for embryo spacing (Ye et al., 2005; Hama et al., 2007). Limited studies have identified several other factors that influence embryo spacing: nicotine, phenoxybenzamine and prazosin caused crowding of implantation sites near the utero-tubal junction in rats (Yoshinaga et al., 1979; Legrand et al., 1987); estrogen (E2) and histamine increased intrauterine migration of porcine embryos (Pope et al., 1982); whereas relaxin reduced intrauterine embryo migration in rat (Pusey et al., 1980); deletion of cPLA2 (Song et al., 2002) and inhibition of Wnt/β-catenin signaling (Mohamed et al., 2005) led to aberrant embryo spacing. COX-2/PG pathways were suggested to be involved in the effects of cPLA2. It is unknown if other factors act through PG pathways and/or if LPA3-mediated LPA signaling pathways cross-talk with these factors in regulating embryo spacing.
The embryo implantation defects present in LPA3(–/–) females have not been observed in other LP receptor-null females, e.g. LPA1(–/–), LPA2(–/–), S1P2(–/–) and S1P3(–/–) mice. Among the 10 LP receptors, only LPA3 was almost exclusively expressed in the luminal endometrial epithelium, while the remaining nine LP receptors were indistinguishably expressed in the luminal endometrial epithelium, stroma and myometrium at E3.5 mouse uterus. In addition, only LPA3 was up-regulated by progesterone (P4) treatment. The data suggest that the differential expression of LPA3 in luminal endometrial epithelium and up-regulation of LPA3 by P4 may distinguish it from other LP receptors for its role in uterine receptivity (X. Ye and J. Chun, unpublished data; Ye et al., 2005; Hama et al., 2006).
The expression pattern of LPA3 in pig uterus suggests that LPA3 may play a role in pigs during early pregnancy. The highest expression level of LPA3 was detected in the uterus on Day 10–12 of gestation, when an embryo undergoes a dramatic elongation process prior to implantation (Waclawik and Ziecik, 2007). The presence of embryos also induced pig uterine LPA3 expression (Kaminska et al., 2007). This was different from the expression pattern in mice, in which LPA3 had similar expression patterns in uteri from early pregnant and pseudopregnant mice (Ye et al., 2005; Hama et al., 2006). Biomarkers for uterine receptivity have clinical applications, especially in IVF programs. It will be of great interest to examine the expression pattern of LPA3 in human endometrium to ascertain if it can serve as a potential biomarker for uterine receptivity as can some other potential biomarkers (Campbell and Rockett, 2006).
LPA, acting on decidual cells, can increase embryo outgrowth and induce actin stress fiber formation in human decidual cells. The RhoA signaling pathway mediated the LPA effects in the decidual cells that may regulate embryo development and differentiation after attachment (Shiokawa et al., 2000).
Preliminary observations indicated comparable numbers of on-time implanted implantation sites and normal embryo spacing in S1P2(–/–) S1P3(–/–) female mice (X. Ye and J. Chun, unpublished data), suggesting no obvious defects in ovulation, fertilization, embryo transport or uterine receptivity in S1P2(–/–) S1P3(–/–) females. However, the litter sizes from S1P2(–/–) S1P3(–/–) females were significantly lower (23–33% reduction) than that from WT females mated with WT, S1P2(+/–) or S1P3(+/–) control males (Ishii et al., 2002). These results suggest maternal defects beyond implantation. S1P1, S1P2 and S1P3 had co-operative functions in mediating S1P signaling in angiogenesis during embryonic development (Liu et al., 2000; Kono et al., 2004). They were up-regulated during decidualization, suggesting that these three receptors may play co-operative roles in decidual angiogenesis as well (Skaznik-Wikiel et al., 2006). Enzymes involved in sphingolipid metabolism were also up-regulated in the uterus during decidualization (Kaneko-Tarui et al., 2007). The importance of this regulation was confirmed in SphK1(–/–)SphK2(+/–) females that showed decidualization defects. There is a link between S1P and PG signaling in early pregnancy, but PG signaling did not seem to be critical for the decidualization defects in the SphK1(–/–)SphK2(+/–) females (Mizugishi et al., 2007).
LP signaling in pregnancy and parturition
The involvement of LP signaling in pregnancy beyond implantation could be multi-faceted. First, LPA signaling has been suggested in the maintenance of human pregnancy as serum ATX/lysoPLD activity, a key enzyme for LPA production, and LPA levels were shown to increase during pregnancy (Tokumura et al., 2002). High lysophospholipase activity was present in the human placental tissues with the highest in the amnion (Jarvis et al., 1984). Although amnion has been heavily implicated in the initiation of labor presumably through the release of arachidonic acid, the high lysophospholipase activity in amnion suggests that its products, including LPs, might also involve in the regulation of labor.
Second, LP signaling has potential functions in placental and vascular tone during pregnancy. High levels of LPA2 and LPA3 expression in the placentas of patients with hypertensive disorder suggest that LPA signaling might be involved in this complication (Li et al., 2007). Hypertensive disorder can worsen with the progress of pregnancy. LPA levels increase during pregnancy. It is unknown whether even higher levels of LPA are present in the pregnant patients complicated with hypertensive disorder. LPA1, LPA3, LPA4 and LPA5 mRNAs were also detectable in mouse placenta (X. Ye and J. Chun, unpublished data; Noguchi et al., 2003; Kotarsky et al., 2006). The functions of LPA signaling in placenta await further exploration.
Several reports show the roles of S1P signaling in placental trophoblast differentiation and vascular tone. S1P inhibited the differentiation of primary human cytotrophoblasts into syncytiotrophoblasts. This inhibition of differentiation was mediated through S1P1–3, Gi, adenylate cyclase and intracellular cAMP. The study suggested that S1P signaling may play a role in pregnancy disorders, such as pre-eclampsia, that are related to improper differentiation of placental trophoblasts (Johnstone et al., 2005). S1P induced vasoconstriction in human placental arteries, a process mediated by increased Ca2+-sensitization via Rho-associated kinases and modulated by nitric oxide (Hemmings et al., 2006). S1P also induced the isometric tension of myometrial arteries isolated from normal pregnant women at term. S1P1, S1P2 and S1P3 were detected in these arteries. These results suggest that S1P may help regulate vascular tone during pregnancy (Hudson et al., 2007).
Third, the following studies suggest that LP signaling could potentially regulate uterine contractility as well as load-bearing during pregnancy and labor. An early study indicated that LPA had similar effects as PGF2 on rat smooth muscle contraction and intrauterine pressure (Tokumura et al., 1980). Although the effect of LPA signaling in parturition per se has not been established in vivo, deletion of FP, the GPCR for PGF2, led to parturition failure (Sugimoto et al., 1997). LPA stimulated myosin light chain phosphorylation through RhoA signaling in pregnant myometrial tissue (Moore et al., 2000). LPA also induced stress fiber formation that may be involved in the maintenance of uterine contractions. The G12/13-Rho kinase signaling pathway was suggested to mediate this effect (Gogarten et al., 2001). In addition, the Gi/o signaling pathway involving the regulation of [Ca2+]i was responsible for LPA-induced cell proliferation of human myometrial smooth muscle cells (Nilsson et al., 1998). A follow-up study identified the critical role of Ca2+/calmodulin-dependent protein kinase in this effect as well as the detection of LPA1, LPA2 and LPA3 in the human myometrial smooth muscle cells (Nilsson and Svensson, 2003).
LPC may play a role in infection-related preterm labor. Significant higher level of LPC was detected in human uterine endometrial cells upon exposure to extract from common anaerobes in intrauterine infection, accompanied with an elevation of arachidonic acid, a key precursor for PG synthesis in regulating labor. PLA2 activity was involved in the reported lipid metabolism (Mikamo et al., 1998a, b). Since PLA2 and LPC are important components in the LPA metabolism pathway (Fig. 1) (Aoki, 2004), it is reasonable to expect that LPA might also be involved in the infection-related preterm labor.
S1P can induce a contractile effect in rat myometrium presumably through S1P2 (Leiber et al., 2007). S1P may play a role in labor. S1P was identified as one of the components in the amniotic fluid that can modulate the synthesis of PGs, key regulators of labor (Sugimoto et al., 1997), in human amnion-derived cells (Kim et al., 2003). In addition, SphK1, a key enzyme for S1P production, was detected in rat glandular epithelium, vasculature and the myometrium, and was up-regulated by P4. A recent study also suggested that SphK1 involved growth and differentiation of uterine tissues during pregnancy (Jeng et al., 2007).
A number of articles have reviewed the roles of LP signaling in various cancers (Mills and Moolenaar, 2003; Xu et al., 2003; Brindley, 2004; Milstien and Spiegel, 2006; Sabbadini, 2006; Bandhuvula and Saba, 2007; Morales and Fernandez-Checa, 2007; Murph and Mills, 2007; Oskouian and Saba, 2007; Tokumura et al., 2007; Van Brocklyn, 2007; van Meeteren and Moolenaar, 2007). LPA levels increased in the plasma and ascites of patients with ovarian cancer, cervical cancer or endometrial cancer (Shen et al., 1998; Mills et al., 2002; Tokumura et al., 2007). LPs were suggested as potential biomarkers for these cancers (Umezu-Goto et al., 2004). This section only covers the potential roles of LP signaling in cancers in reproductive organs, such as ovary, cervix, mammary gland and prostate, as well as in related cell lines.
Ovarian cancer is the most extensively studied cancer with respect to LP signaling in carcinogenesis. Early studies demonstrated LPA, whose levels elevated in the plasma and ascites of ovarian cancer patients, promoted ovarian cancer cell proliferation. LPA, S1P and LPC were suggested as potential biomarkers for ovarian cancers and LPA-like lipids were proposed as being responsible for intraperitoneal malignancies (Xu et al., 1995a, b, 1998; Westermann et al., 1998; Sutphen et al., 2004). However, another study indicated that serum LPA could not differentiate benign from malignant ovarian tumors (Pozlep et al., 2007). LPA acyltransferase beta, which converts LPA to PA, was suggested as a specific prognostic marker (Niesporek et al., 2005; Springett et al., 2005). The increased production of LPA might be related to the down-regulation of LPP1, which degrades LPA, in ovarian cancer cells (Tanyi et al., 2003).
LPA signaling may exert its role in ovarian cancers through regulating other factors: glycodelin, an angiogenic protein with a potential immunosuppressive role in carcinogenesis (Ramachandran et al., 2002); TRIP6 (thyroid receptor interacting protein 6), a focal adhesion molecule involved in cell migration (Xu et al., 2004); telomerase, a ribonucleprotein expressed in 95% of ovarian cancers and involved in tumor progress (Bermudez et al., 2007); granulin-epithelin precursor, a growth and survival factor for ovarian cancer (Kamrava et al., 2005); internalization of Fas from the cell membrane to the cytosol, a process that would protect ovarian cancer cells from FasL-bearing immune cells (Meng et al., 2005); IL-6 and IL-8, angiogenic cytokines (Chou et al., 2005); COX-2, which potentiates aggressive cellular behavior (Symowicz et al., 2005); growth-regulated oncogene alpha (GROalpha), a chemokine with increased levels detected in the plasma and ascites of ovarian cancer patients (Lee et al., 2006b) and urokinase plasminogen activator (uPA), a critical component present at high concentration in ovarian ascites and ovarian cancers which bears an inverse correlation with cancer prognosis (Pustilnik et al., 1999; Estrella et al., 2007; Gil et al., 2008).
LPA receptors seem to play different roles in the ovarian cancers. LPA2 and LPA3 but not LPA1 were up-regulated in ovarian cancer tissues (Nakamoto et al., 2005; Wang et al., 2007a). LPA2 was a key receptor in mediating LPA-induced production of GROalpha (Lee et al., 2006b). LPA-induced uPA secretion in ovarian cancer cells was dominantly mediated through LPA2 with contribution from LPA3 (Pustilnik et al., 1999; Estrella et al., 2007). LPA3 was a key receptor for mediating the chemotactic activity of LPA (Sengupta et al., 2003). However, LPA1 seemed to be the key receptor in mediating ascitic LPA effects on other cells (Yamada et al., 2004; Sako et al., 2006).
Several LPA downstream signaling pathways have been identified in ovarian cancer cells. The up-regulation of uPA by LPA was mainly mediated through the Gi-Ras-PKC-CARMA3-NF-kappaB signaling pathway in ovarian cancer cells. CARMA3 (CARD and MAGUK domain-containing protein 3) is a scaffolding protein required for GPCR-induced NF-kappaB activation (Li et al., 2005; Grabiner et al., 2007; Mahanivong et al., 2008). Both Gi-Ras-MEKK1 (MAPK kinase kinase 1) and G12/13-RhoA-ROCK (Rho-associated kinase) signaling pathways contributed to LPA-stimulated ovarian cancer cell migration by facilitating focal adhesion kinase redistribution and autophosphorylation, respectively (Sawada et al., 2002; Bian et al., 2004, 2006). LPA signaling in ovarian cancer cells could be attenuated by RGS, a regulator of G protein signaling proteins that deactivates G proteins (Hurst et al., 2008). LPA-induced IL-6 expression was via a Gi/PI3K-Akt/NF-kappaB pathway (Chou et al., 2005), while transcription factors NF-kappaB and AP-1, which were induced by LPA, might synergistically stimulate IL-8 expression (Fang et al., 2004).
S1P was also identified in the ascites of ovarian cancer patients and as a mitogenic and cell survival factor for ovarian cancer cells (Hong et al., 1999). At low concentrations S1P had an invasive effect similar to LPA, but S1P inhibited the invasiveness at high concentrations. The dual effects on ovarian cancer invasion were probably through the regulation of LP receptors (Smicun et al., 2006, 2007). S1P induced [Ca2+]i and chemotactic migration of ovarian cancer cells. S1P1/2/3-Gi-ERK/p38 MAPK/Akt mediated these effects (Park et al., 2007). S1P and SPC had an effect similar to LPA on induction of IL-8 expression (Schwartz et al., 2001).
The cervical cancer cell line HeLa has been used to study the roles of LPs in cervical cancer. LPA induced HeLa cell migration and survival. S1P1, S1P2 and S1P3 were detectable in HeLa cells, but only over-expressed S1P2 and S1P3 seemed to mediate S1P-induced [Ca2+]i and cell survival (Rapizzi et al., 2007), whereas S1P1 seemed to mediate HeLa cell proliferation (Xu et al., 2006). A class II PI3K-activated signaling pathway was identified as mediating cell migration (Maffucci et al., 2005), while the Gi/o-PI3K-Akt signaling cascade was responsible for survival (Fang et al., 2000). Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is able to induce apoptosis in many cancer cells. Both S1P and LPA inhibited TRAIL-induced apoptosis in HeLa cells. This anti-apoptotic effect of LPs involved the activation of the PI3K-Akt signaling pathway (Kang et al., 2004).
LP signaling may also play a role in breast cancer progression. Human mammary gland expressed LPA1, LPA2 and a lower level of LPA3. The up-regulation of LPA2, but not that of LPA1 and LPA3, in the mammary gland carcinoma tissue and post-menopausal women suggest that LPA2 may be related to breast cancer, especially post-menopausal breast cancer (Kitayama et al., 2004). Studies from breast cancer cell lines indicated that both LPA1 and LPA2 could mediate LPA-induced chemotaxis in breast carcinoma cells, but LPA1 was more efficacious than LPA2 (Chen et al., 2007). LPA1 was also considered to be the culprit for LPA-promoted breast cancer cell migration (Stadler et al., 2006) and metastasis in bone (Boucharaba et al., 2004, 2006). LP signaling might be involved in breast cancer cell proliferation (Imagawa et al., 1995; Xu et al., 1995a). LPA induced stress fiber and focal adhesion formation in breast cancer cells (Dorfleutner et al., 2007). EGF receptor, whose overexpression is a prognostic indicator of a poor outcome in multiple tumor types, was identified to be in the signaling network for LPA-induced breast cancer progression (Boerner et al., 2005). The effects of LPA on breast cancer cells could be potentiated by insulin through the induction of geranylgeranylated RhoA, and consequently the augmentation of LPA-induced cyclin E expression and degradation of p27Kip1 (cyclin-dependent kinase inhibitor) and cell cycle progression (Chappell et al., 2000, 2001). LPA and S1P could promote the migration of metastatic human breast cancer cells (Sliva et al., 2000). S1P could induce [Ca2+]i and chemokinetic migration in human breast cancer cells, a process that might be mediated through S1P2 and S1P3, but not S1P1 (Dolezalova et al., 2003).
LPA1, LPA2 and LPA3 were detected in the prostate. They had significantly higher expression levels in malignant compared with the benign prostate tissues (Im et al., 2000b; Guo et al., 2006). LPA signaling plays multiple roles in prostate cancer: facilitating early prostate cancer development by inhibiting autophagy (Chang et al., 2007); inducing prostate cancer cell proliferation, survival, morphological changes, migration and invasion. LPA1 seemed to be the key receptor in mediating LPA-induced prostate cancer cell proliferation and migration (Daaka, 2002; Guo et al., 2006; Hao et al., 2007). Tyrosine kinase EGF and matrix metalloproteinases were involved in the LPA-induced ERK mitogenic signaling pathway (Kue et al., 2002). The LPA receptor-Akt-NF-kappaB signaling axis may mediate LPA-induced prostate cell survival (Raj et al., 2004). LPA may also play its roles via the involvement of other factors: phosphorylation of proline-rich tyrosine kinase 2, a potential marker in prostate epithelium for the malignancy of prostate cancer (Picascia et al., 2002); IL-6, which appeared to mediate LPA-induced prostate cancer cell growth and the cross-talk between stromal and epithelial prostate cells (Sivashanmugam et al., 2004); CYR61, an extracellular matrix signaling protein implicated as a secreted autocrine and/or paracrine mediator for LPA in prostate stromal and epithelial hyperplasia (Sakamoto et al., 2004). LPA stimulated prostate cancer cell invasion through alterations of RhoA and NF-kappaB activity (Hwang et al., 2006). RhoA also played a role in LPA-induced morphological changes of prostate cancer cells (Chen et al., 2005). LPA-induced Rho activation was dependent on PDZrhoGEF, a rho guanine nucleotide exchange factors (Wang et al., 2004). S1P signaling, on the other hand, mainly serves as an anti-apoptotic factor in prostate cancer. Sphk1 balances the ratio of ceramide/S1P. Overexpression of SphK1, which increases the production of S1P and decreases ceramide/S1P ratio, impaired the efficacy of chemotherapy; whereas inhibition of SphK1 was related to a smaller tumor volume as well as reduced occurrence and number of metastases (Pchejetski et al., 2005). Up-regulation of S1P1, S1P3 and SphK1 also accounted for prostate cancer cell escape from anti-cancer drug-induced apoptosis (Akao et al., 2006).
The abundant presence of signaling LPs in the serum and other biological fluids provides them the opportunity to reach almost every tissue. The potential functions of LP signaling in each tissue are likely determined by many local factors, such as LP metabolism, expression and regulation of LP receptors, and other factors in the LP signaling pathways. The progress on understanding LP signaling in reproduction has been exciting, yet more comprehensive studies on the factors influencing tissue-specific functions as well as receptor-specific functions are needed. The mechanisms of LP signaling in the physiological and pathological reproductive tissues await further exploration to ensure the clarification of LP signaling as a therapeutic target and for the development of modulating agents (Mills and Moolenaar, 2003; Chun and Rosen, 2006; Milstien and Spiegel, 2006; Herr and Chun, 2007).
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This work was supported by the funding from the Office of the Vice President for Research at The University of Georgia.
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I thank Drs KL Campbell, J Chun, D Herr, S Huang, O Li, and K Yoshinaga for critical reading of the manuscript and for their insightful suggestions. I thank Dr J Chun for allowing me to include the unpublished data in this review.
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Akao Y, Banno Y, Nakagawa Y, Hasegawa N, Kim TJ, Murate T, Igarashi Y, Nozawa Y. High expression of sphingosine kinase 1 and S1P receptors in chemotherapy-resistant prostate cancer PC3 cells and their camptothecin-induced up-regulation. Biochem Biophys Res Commun (2006) 342:1284–1290.[CrossRef][Web of Science][Medline]
Allende ML, Proia RL. Sphingosine-1-phosphate receptors and the development of the vascular system. Biochim Biophys Acta (2002) 1582:222–227.[Medline]
Allende ML, Yamashita T, Proia RL. G-protein-coupled receptor S1P1 acts within endothelial cells to regulate vascular maturation. Blood (2003) 102:3665–3667.
Ammit AJ, Hastie AT, Edsall LC, Hoffman RK, Amrani Y, Krymskaya VP, Kane SA, Peters SP, Penn RB, Spiegel S, et al. Sphingosine 1-phosphate modulates human airway smooth muscle cell functions that promote inflammation and airway remodeling in asthma. FASEB J (2001) 15:1212–1214.
An S, Bleu T, Hallmark OG, Goetzl EJ. Characterization of a novel subtype of human G protein-coupled receptor for lysophosphatidic acid. J Biol Chem (1998) 273:7906–7910.
Anliker B, Chun J. Lysophospholipid G protein-coupled receptors. J Biol Chem (2004) 279:20555–20558.
Aoki J. Mechanisms of lysophosphatidic acid production. Semin Cell Dev Biol (2004) 15:477–489.[CrossRef][Web of Science][Medline]
Aoki J, Taira A, Takanezawa Y, Kishi Y, Hama K, Kishimoto T, Mizuno K, Saku K, Taguchi R, Arai H. Serum lysophosphatidic acid is produced through diverse phospholipase pathways. J Biol Chem (2002) 277:48737–48744.
Azuma H, Takahara S, Ichimaru N, Wang JD, Itoh Y, Otsuki Y, Morimoto J, Fukui R, Hoshiga M, Ishihara T, et al. Marked prevention of tumor growth and metastasis by a novel immunosuppressive agent, FTY720, in mouse breast cancer models. Cancer Res (2002) 62:1410–1419.
Azuma H, Takahara S, Horie S, Muto S, Otsuki Y, Katsuoka Y. Induction of apoptosis in human bladder cancer cells in vitro and in vivo caused by FTY720 treatment. J Urol (2003) 169:2372–2377.[CrossRef][Web of Science][Medline]
Bagga S, Price KS, Lin DA, Friend DS, Austen KF, Boyce JA. Lysophosphatidic acid accelerates the development of human mast cells. Blood (2004) 104:4080–4087.
Baker DL, Umstot ES, Desiderio DM, Tigyi GJ. Quantitative analysis of lysophosphatidic acid in human blood fractions. Ann N Y Acad Sci (2000) 905:267–269.[Web of Science][Medline]
Bandhuvula P, Saba JD. Sphingosine-1-phosphate lyase in immunity and cancer: silencing the siren. Trends Mol Med (2007) 13:210–217.[CrossRef][Web of Science][Medline]
Bandoh K, Aoki J, Hosono H, Kobayashi S, Kobayashi T, Murakami-Murofushi K, Tsujimoto M, Arai H, Inoue K. Molecular cloning and characterization of a novel human G-protein-coupled receptor, EDG7, for lysophosphatidic acid. J Biol Chem (1999) 274:27776–27785.
Bektas M, Barak LS, Jolly PS, Liu H, Lynch KR, Lacana E, Suhr KB, Milstien S, Spiegel S. The G protein-coupled receptor GPR4 suppresses ERK activation in a ligand-independent manner. Biochemistry (2003) 42:12181–12191.[CrossRef][Web of Science][Medline]
Bermudez Y, Yang H, Saunders BO, Cheng JQ, Nicosia SV, Kruk PA. VEGF- and LPA-induced telomerase in human ovarian cancer cells is Sp1-dependent. Gynecol Oncol (2007) 106:526–537.[CrossRef][Web of Science][Medline]
Bian D, Su S, Mahanivong C, Cheng RK, Han Q, Pan ZK, Sun P, Huang S. Lysophosphatidic acid stimulates ovarian cancer cell migration via a Ras-MEK kinase 1 pathway. Cancer Res (2004) 64:4209–4217.
Bian D, Mahanivong C, Yu J, Frisch SM, Pan ZK, Ye RD, Huang S. The G12/13-RhoA signaling pathway contributes to efficient lysophosphatidic acid-stimulated cell migration. Oncogene (2006) 25:2234–2244.[CrossRef][Web of Science][Medline]
Birgbauer E, Chun J. New developments in the biological functions of lysophospholipids. Cell Mol Life Sci (2006) 63:2695–2701.[CrossRef][Web of Science][Medline]
Boerner JL, Biscardi JS, Silva CM, Parsons SJ. Transactivating agonists of the EGF receptor require Tyr 845 phosphorylation for induction of DNA synthesis. Mol Carcinog (2005) 44:262–273.[CrossRef][Web of Science][Medline]
Bornfeldt KE, Graves LM, Raines EW, Igarashi Y, Wayman G, Yamamura S, Yatomi Y, Sidhu JS, Krebs EG, Hakomori S, et al. Sphingosine- 1-phosphate inhibits PDGF-induced chemotaxis of human arterial smooth muscle cells: spatial and temporal modulation of PDGF chemotactic signal transduction. J Cell Biol (1995) 130:193–206.
Boucharaba A, Serre CM, Gres S, Saulnier-Blache JS, Bordet JC, Guglielmi J, Clezardin P, Peyruchaud O. Platelet-derived lysophosphatidic acid supports the progression of osteolytic bone metastases in breast cancer. J Clin Invest (2004) 114:1714–1725.[CrossRef][Web of Science][Medline]
Boucharaba A, Serre CM, Guglielmi J, Bordet JC, Clezardin P, Peyruchaud O. The type 1 lysophosphatidic acid receptor is a target for therapy in bone metastases. Proc Natl Acad Sci USA (2006) 103:9643–9648.
Brindley DN. Lipid phosphate phosphatases and related proteins: signaling functions in development, cell division, and cancer. J Cell Biochem (2004) 92:900–912.[CrossRef][Web of Science][Medline]
Brindley DN, English D, Pilquil C, Buri K, Ling ZC. Lipid phosphate phosphatases regulate signal transduction through glycerolipids and sphingolipids. Biochim Biophys Acta (2002) 1582:33–44.[Medline]
Budde K, Schutz M, Glander P, Peters H, Waiser J, Liefeldt L, Neumayer HH, Bohler T. FTY720 (fingolimod) in renal transplantation. Clin Transplant (2006) 20(Suppl 17):17–24.[CrossRef][Web of Science][Medline]
Budnik LT, Mukhopadhyay AK. Lysophosphatidic acid antagonizes the morphoregulatory effects of the luteinizing hormone on luteal cells: possible role of small Rho-G-proteins. Biol Reprod (2001) 65:180–187.
Budnik LT, Mukhopadhyay AK. Lysophosphatidic acid-induced nuclear localization of protein kinase C delta in bovine theca cells stimulated with luteinizing hormone. Biol Reprod (2002) a 67:935–944.
Budnik LT, Mukhopadhyay AK. Lysophosphatidic acid and its role in reproduction. Biol Reprod (2002) b 66:859–865.
Budnik LT, Brunswig-Spickenheier B. Differential effects of lysolipids on steroid synthesis in cells expressing endogenous LPA2 receptor. J Lipid Res (2005) 46:930–941.
Budnik LT, Brunswig-Spickenheier B, Mukhopadhyay AK. Lysophosphatidic acid signals through mitogen-activated protein kinase-extracellular signal regulated kinase in ovarian theca cells expressing the LPA1/edg2-receptor: involvement of a nonclassical pathway? Mol Endocrinol (2003) 17:1593–1606.
Campbell KL, Rockett JC. Biomarkers of ovulation, endometrial receptivity, fertilisation, implantation and early pregnancy progression. Paediatr Perinat Epidemiol (2006) 20(Suppl 1):13–25.[CrossRef][Web of Science][Medline]
Carson DD, Bagchi I, Dey SK, Enders AC, Fazleabas AT, Lessey BA, Yoshinaga K. Embryo implantation. Dev Biol (2000) 223:217–237.[CrossRef][Web of Science][Medline]
Chan LC, Peters W, Xu Y, Chun J, Farese RV Jr, Cases S. LPA3 receptor mediates chemotaxis of immature murine dendritic cells to unsaturated lysophosphatidic acid (LPA). J Leukoc Biol (2007) 82:1193–1200.
Chang CL, Liao JJ, Huang WP, Lee H. Lysophosphatidic acid inhibits serum deprivation-induced autophagy in human prostate cancer PC-3 cells. Autophagy (2007) 3:268–270.[Web of Science][Medline]
Chappell J, Golovchenko I, Wall K, Stjernholm R, Leitner JW, Goalstone M, Draznin B. Potentiation of Rho-A-mediated lysophosphatidic acid activity by hyperinsulinemia. J Biol Chem (2000) 275:31792–31797.
Chappell J, Leitner JW, Solomon S, Golovchenko I, Goalstone ML, Draznin B. Effect of insulin on cell cycle progression in MCF-7 breast cancer cells. Direct and potentiating influence. J Biol Chem (2001) 276:38023–38028.
Chen Y, Wang Y, Yu H, Wang F, Xu W. The cross talk between protein kinase A- and RhoA-mediated signaling in cancer cells. Exp Biol Med (Maywood) (2005) 230:731–741.
Chen M, Towers LN, O’Connor KL. LPA2 (EDG4) mediates Rho-dependent chemotaxis with lower efficacy than LPA1 (EDG2) in breast carcinoma cells. Am J Physiol Cell Physiol (2007) 292:C1927–C1933.
Chen SU, Chou CH, Lee H, Ho CH, Lin CW, Yang YS. Lysophosphatidic acid up-regulates expression of interleukin-8 and -6 in granulosa-lutein cells through its receptors and nuclear factor-kappaB-dependent pathways: implications for angiogenesis of corpus luteum and ovarian hyperstimulation syndrome. J Clin Endocrinol Metab (2008) 93:935–943.
Chou CH, Wei LH, Kuo ML, Huang YJ, Lai KP, Chen CA, Hsieh CY. Up-regulation of interleukin-6 in human ovarian cancer cell via a Gi/PI3K-Akt/NF-kappaB pathway by lysophosphatidic acid, an ovarian cancer-activating factor. Carcinogenesis (2005) 26:45–52.
Chun J. Lysophospholipid receptors: implications for neural signaling. Crit Rev Neurobiol (1999) 13:151–168.[Web of Science][Medline]
Chun J, Rosen H. Lysophospholipid receptors as potential drug targets in tissue transplantation and autoimmune diseases. Curr Pharm Des (2006) 12:161–171.[CrossRef][Web of Science][Medline]
Chun J, Weiner JA, Fukushima N, Contos JJ, Zhang G, Kimura Y, Dubin A, Ishii I, Hecht JH, Akita C, et al. Neurobiology of receptor-mediated lysophospholipid signaling. From the first lysophospholipid receptor to roles in nervous system function and development. Ann N Y Acad Sci (2000) 905:110–117.[CrossRef][Web of Science][Medline]
Contos JJ, Fukushima N, Weiner JA, Kaushal D, Chun J. Requirement for the lpA1 lysophosphatidic acid receptor gene in normal suckling behavior. Proc Natl Acad Sci USA (2000) a 97:13384–13389.
Contos JJ, Ishii I, Chun J. Lysophosphatidic acid receptors. Mol Pharmacol (2000) b 58:1188–1196.[Web of Science][Medline]
Contos JJ, Ishii I, Fukushima N, Kingsbury MA, Ye X, Kawamura S, Brown JH, Chun J. Characterization of lpa(2) (Edg4) and lpa(1)/lpa(2) (Edg2/Edg4) lysophosphatidic acid receptor knockout mice: signaling deficits without obvious phenotypic abnormality attributable to lpa(2). Mol Cell Biol (2002) 22:6921–6929.
Cuvillier O, Pirianov G, Kleuser B, Vanek PG, Coso OA, Gutkind S, Spiegel S. Suppression of ceramide-mediated programmed cell death by sphingosine-1-phosphate. Nature (1996) 381:800–803.[CrossRef][Web of Science][Medline]
Czeloth N, Schippers A, Wagner N, Muller W, Kuster B, Bernhardt G, Forster R. Sphingosine-1 phosphate signaling regulates positioning of dendritic cells within the spleen. J Immunol (2007) 179:5855–5863.
Daaka Y. Mitogenic action of LPA in prostate. Biochim Biophys Acta (2002) 1582:265–269.[Medline]
Delgado-Buenrostro NL, Hernandez-Gonzalez EO, Segura-Nieto M, Mujica A. Actin polymerization in the equatorial and postacrosomal regions of guinea pig spermatozoa during the acrosome reaction is regulated by G proteins. Mol Reprod Dev (2005) 70:198–210.[CrossRef][Web of Science][Medline]
di Villa Bianca R, Sorrentino R, Imbimbo C, Palmieri A, Fusco F, Maggi M, De Palma R, Cirino G, Mirone V. Sphingosine 1-phosphate induces endothelial nitric-oxide synthase activation through phosphorylation in human corpus cavernosum. J Pharmacol Exp Ther (2006) 316:703–708.
Dolezalova H, Shankar G, Huang MC, Bikle DD, Goetzl EJ. Biochemical regulation of breast cancer cell expression of S1P2 (Edg-5) and S1P3 (Edg-3) G protein-coupled receptors for sphingosine 1-phosphate. J Cell Biochem (2003) 88:732–743.[CrossRef][Web of Science][Medline]
Dorfleutner A, Stehlik C, Zhang J, Gallick GE, Flynn DC. AFAP-110 is required for actin stress fiber formation and cell adhesion in MDA-MB-231 breast cancer cells. J Cell Physiol (2007) 213:740–749.[CrossRef][Web of Science][Medline]
Durieux ME, Salafranca MN, Lynch KR, Moorman JR. Lysophosphatidic acid induces a pertussis toxin-sensitive Ca(2+)-activated Cl– current in Xenopus laevis oocytes. Am J Physiol (1992) 263:C896–C900.[Web of Science][Medline]
Durieux ME, Carlisle SJ, Salafranca MN, Lynch KR. Responses to sphingosine-1-phosphate in X. laevis oocytes: similarities with lysophosphatidic acid signaling. Am J Physiol (1993) 264:C1360–C1364.[Web of Science][Medline]
Eder AM, Sasagawa T, Mao M, Aoki J, Mills GB. Constitutive and lysophosphatidic acid (LPA)-induced LPA production: role of phospholipase D and phospholipase A2. Clin Cancer Res (2000) 6:2482–2491.
Eichholtz T, Jalink K, Fahrenfort I, Moolenaar WH. The bioactive phospholipid lysophosphatidic acid is released from activated platelets. Biochem J (1993) 291:677–680.[Web of Science][Medline]
Eliyahu E, Park JH, Shtraizent N, He X, Schuchman EH. Acid ceramidase is a novel factor required for early embryo survival. FASEB J (2007) 21:1403–1409.
English D, Welch Z, Kovala AT, Harvey K, Volpert OV, Brindley DN, Garcia JG. Sphingosine 1-phosphate released from platelets during clotting accounts for the potent endothelial cell chemotactic activity of blood serum and provides a novel link between hemostasis and angiogenesis. FASEB J (2000) 14:2255–2265.
Estivill-Torrus G, Llebrez-Zayas P, Matas-Rico E, Santin L, Pedraza C, De Diego I, Del Arco I, Fernandez-Llebrez P, Chun J, De Fonseca FR. Absence of LPA1 signaling results in defective cortical development. Cereb Cortex (2008) 18:938–950.
Estrella VC, Eder AM, Liu S, Pustilnik TB, Tabassam FH, Claret FX, Gallick GE, Mills GB, Wiener JR. Lysophosphatidic acid induction of urokinase plasminogen activator secretion requires activation of the p38MAPK pathway. Int J Oncol (2007) 31:441–449.[Web of Science][Medline]
Fang X, Yu S, LaPushin R, Lu Y, Furui T, Penn LZ, Stokoe D, Erickson JR, Bast RC Jr, Mills GB. Lysophosphatidic acid prevents apoptosis in fibroblasts via G(i)-protein-mediated activation of mitogen-activated protein kinase. Biochem J (2000) 352:135–143.[CrossRef][Web of Science][Medline]
Fang X, Yu S, Bast RC, Liu S, Xu HJ, Hu SX, LaPushin R, Claret FX, Aggarwal BB, Lu Y, et al. Mechanisms for lysophosphatidic acid-induced cytokine production in ovarian cancer cells. J Biol Chem (2004) 279:9653–9661.
Fischer DJ, Nusser N, Virag T, Yokoyama K, Wang D, Baker DL, Bautista D, Parrill AL, Tigyi G. Short-chain phosphatidates are subtype-selective antagonists of lysophosphatidic acid receptors. Mol Pharmacol (2001) 60:776–784.
Fourcade O, Simon MF, Viode C, Rugani N, Leballe F, Ragab A, Fournie B, Sarda L, Chap H. Secretory phospholipase A2 generates the novel lipid mediator lysophosphatidic acid in membrane microvesicles shed from activated cells. Cell (1995) 80:919–927.[CrossRef][Web of Science][Medline]
Fukushima N, Kimura Y, Chun J. A single receptor encoded by vzg-1/lpA1/edg-2 couples to G proteins and mediates multiple cellular responses to lysophosphatidic acid. Proc Natl Acad Sci USA (1998) 95:6151–6156.
Fukushima N, Weiner JA, Chun J. Lysophosphatidic acid (LPA) is a novel extracellular regulator of cortical neuroblast morphology. Dev Biol (2000) 228:6–18.[CrossRef][Web of Science][Medline]
Fukushima N, Ishii I, Contos JJ, Weiner JA, Chun J. Lysophospholipid receptors. Annu Rev Pharmacol Toxicol (2001) 41:507–534.[CrossRef][Web of Science][Medline]
Gaits F, Fourcade O, Le Balle F, Gueguen G, Gaige B, Gassama-Diagne A, Fauvel J, Salles JP, Mauco G, Simon MF, et al. Lysophosphatidic acid as a phospholipid mediator: pathways of synthesis. FEBS Lett (1997) 410:54–58.[CrossRef][Web of Science][Medline]
Garbi M, Rubinstein S, Lax Y, Breitbart H. Activation of protein kinase calpha in the lysophosphatidic acid-induced bovine sperm acrosome reaction and phospholipase D1 regulation. Biol Reprod (2000) 63:1271–1277.
Gardell SE, Dubin AE, Chun J. Emerging medicinal roles for lysophospholipid signaling. Trends Mol Med (2006) 12:65–75.[CrossRef][Web of Science][Medline]
Genbacev OD, Prakobphol A, Foulk RA, Krtolica AR, Ilic D, Singer MS, Yang ZQ, Kiessling LL, Rosen SD, Fisher SJ. Trophoblast L-selectin-mediated adhesion at the maternal-fetal interface. Science (2003) 299:405–408.
Gerrard JM, Robinson P. Identification of the molecular species of lysophosphatidic acid produced when platelets are stimulated by thrombin. Biochim Biophys Acta (1989) 1001:282–285.[Medline]
Gerrard JM, Kindom SE, Peterson DA, Peller J, Krantz KE, White JG. Lysophosphatidic acids. Influence on platelet aggregation and intracellular calcium flux. Am J Pathol (1979) 96:423–438.[Abstract]
Gesta S, Simon MF, Rey A, Sibrac D, Girard A, Lafontan M, Valet P, Saulnier-Blache JS. Secretion of a lysophospholipase D activity by adipocytes: involvement in lysophosphatidic acid synthesis. J Lipid Res (2002) 43:904–910.
Gil OD, Lee C, Ariztia EV, Wang FQ, Smith PJ, Hope JM, Fishman DA. Lysophosphatidic acid (LPA) promotes E-cadherin ectodomain shedding and OVCA429 cell invasion in an uPA-dependent manner. Gynecol Oncol (2008) 108:361–369.[CrossRef][Web of Science][Medline]
Goetzl EJ, Kong Y, Mei B. Lysophosphatidic acid and sphingosine 1-phosphate protection of T cells from apoptosis in association with suppression of Bax. J Immunol (1999) 162:2049–2056.
Goetzl EJ, Wang W, McGiffert C, Huang MC, Graler MH. Sphingosine 1-phosphate and its G protein-coupled receptors constitute a multifunctional immunoregulatory system. J Cell Biochem (2004) 92:1104–1114.[CrossRef][Web of Science][Medline]
Gogarten W, Emala CW, Lindeman KS, Hirshman CA. Oxytocin and lysophosphatidic acid induce stress fiber formation in human myometrial cells via a pathway involving Rho-kinase. Biol Reprod (2001) 65:401–406.
Gon Y, Wood MR, Kiosses WB, Jo E, Sanna MG, Chun J, Rosen H. S1P3 receptor-induced reorganization of epithelial tight junctions compromises lung barrier integrity and is potentiated by TNF. Proc Natl Acad Sci USA (2005) 102:9270–9275.
Gonda K, Okamoto H, Takuwa N, Yatomi Y, Okazaki H, Sakurai T, Kimura S, Sillard R, Harii K, Takuwa Y. The novel sphingosine 1-phosphate receptor AGR16 is coupled via pertussis toxin-sensitive and -insensitive G-proteins to multiple signalling pathways. Biochem J (1999) 337:67–75.[CrossRef][Web of Science][Medline]
Goodemote KA, Mattie ME, Berger A, Spiegel S. Involvement of a pertussis toxin-sensitive G protein in the mitogenic signaling pathways of sphingosine 1-phosphate. J Biol Chem (1995) 270:10272–10277.
Grabiner BC, Blonska M, Lin PC, You Y, Wang D, Sun J, Darnay BG, Dong C, Lin X. CARMA3 deficiency abrogates G protein-coupled receptor-induced NF-{kappa}B activation. Genes Dev (2007) 21:984–996.
Graler MH, Goetzl EJ. Lysophospholipids and their G protein-coupled receptors in inflammation and immunity. Biochim Biophys Acta (2002) 1582:168–174.[Medline]
Guo R, Kasbohm EA, Arora P, Sample CJ, Baban B, Sud N, Sivashanmugam P, Moniri NH, Daaka Y. Expression and function of lysophosphatidic acid LPA1 receptor in prostate cancer cells. Endocrinology (2006) 147:4883–4892.[CrossRef][Web of Science][Medline]
Hama K, Bandoh K, Kakehi Y, Aoki J, Arai H. Lysophosphatidic acid (LPA) receptors are activated differentially by biological fluids: possible role of LPA-binding proteins in activation of LPA receptors. FEBS Lett (2002) 523:187–192.[CrossRef][Web of Science][Medline]
Hama K, Aoki J, Bandoh K, Inoue A, Endo T, Amano T, Suzuki H, Arai H. Lysophosphatidic receptor, LPA3, is positively and negatively regulated by progesterone and estrogen in the mouse uterus. Life Sci (2006) 79:1736–1740.[CrossRef][Web of Science][Medline]
Hama K, Aoki J, Inoue A, Endo T, Amano T, Motoki R, Kanai M, Ye X, Chun J, Matsuki N, et al. Embryo spacing and implantation timing are differentially regulated by LPA3-mediated lysophosphatidic acid signaling in mice. Biol Reprod (2007) 77:954–959.
Hancke K, Strauch O, Kissel C, Gobel H, Schafer W, Denschlag D. Sphingosine 1-phosphate protects ovaries from chemotherapy-induced damage in vivo. Fertil Steril (2007) 87:172–177.[CrossRef][Medline]
Hanel P, Andreani P, Graler MH. Erythrocytes store and release sphingosine 1-phosphate in blood. FASEB J (2007) 21:1202–1209.
Hannun YA, Obeid LM. Principles of bioactive lipid signalling: lessons from sphingolipids. Nat Rev Mol Cell Biol (2008) 9:139–150.[CrossRef][Web of Science][Medline]
Hao F, Tan M, Xu X, Han J, Miller DD, Tigyi G, Cui MZ. Lysophosphatidic acid induces prostate cancer PC3 cell migration via activation of LPA(1), p42 and p38alpha. Biochim Biophys Acta (2007) 1771:883–892.[Medline]
Harrison SM, Reavill C, Brown G, Brown JT, Cluderay JE, Crook B, Davies CH, Dawson LA, Grau E, Heidbreder C, et al. LPA1 receptor-deficient mice have phenotypic changes observed in psychiatric disease. Mol Cell Neurosci (2003) 24:1170–1179.[CrossRef][Web of Science][Medline]
Hecht JH, Weiner JA, Post SR, Chun J. Ventricular zone gene-1 (vzg-1) encodes a lysophosphatidic acid receptor expressed in neurogenic regions of the developing cerebral cortex. J Cell Biol (1996) 135:1071–1083.
Hemmings DG, Hudson NK, Halliday D, O’Hara M, Baker PN, Davidge ST, Taggart MJ. Sphingosine-1-phosphate acts via rho-associated kinase and nitric oxide to regulate human placental vascular tone. Biol Reprod (2006) 74:88–94.
Herr DR, Chun J. Effects of LPA and S1P on the nervous system and implications for their involvement in disease. Curr Drug Targets (2007) 8:155–167.[CrossRef][Web of Science][Medline]
Herr DR, Fyrst H, Creason MB, Phan VH, Saba JD, Harris GL. Characterization of the Drosophila sphingosine kinases and requirement for Sk2 in normal reproductive function. J Biol Chem (2004) 279:12685–12694.
Herr DR, Grillet N, Schwander M, Rivera R, Muller U, Chun J. Sphingosine 1-phosphate (S1P) signaling is required for maintenance of hair cells mainly via activation of S1P2. J Neurosci (2007) 27:1474–1478.
Higgs HN, Glomset JA. Purification and properties of a phosphatidic acid-preferring phospholipase A1 from bovine testis. Examination of the molecular basis of its activation. J Biol Chem (1996) 271:10874–10883.
Hill CS, Oh SY, Schmidt SA, Clark KJ, Murray AW. Lysophosphatidic acid inhibits gap-junctional communication and stimulates phosphorylation of connexin-43 in WB cells: possible involvement of the mitogen-activated protein kinase cascade. Biochem J (1994) a 303:475–479.[Web of Science][Medline]
Hill CS, Wynne J, Treisman R. Serum-regulated transcription by serum response factor (SRF): a novel role for the DNA binding domain. Embo J (1994) b 13:5421–5432.[Web of Science][Medline]
Hinckley M, Vaccari S, Horner K, Chen R, Conti M. The G-protein-coupled receptors GPR3 and GPR12 are involved in cAMP signaling and maintenance of meiotic arrest in rodent oocytes. Dev Biol (2005) 287:249–261.[CrossRef][Web of Science][Medline]
Hinokio K, Yamano S, Nakagawa K, Iraharaa M, Kamada M, Tokumura A, Aono T. Lysophosphatidic acid stimulates nuclear and cytoplasmic maturation of golden hamster immature oocytes in vitro via cumulus cells. Life Sci (2002) 70:759–767.[CrossRef][Web of Science][Medline]
Hiramatsu T, Sonoda H, Takanezawa Y, Morikawa R, Ishida M, Kasahara K, Sanai Y, Taguchi R, Aoki J, Arai H. Biochemical and molecular characterization of two phosphatidic acid-selective phospholipase A1s, mPA-PLA1alpha and mPA-PLA1beta. J Biol Chem (2003) 278:49438–49447.
Hla T, Lee MJ, Ancellin N, Paik JH, Kluk MJ. Lysophospholipids–receptor revelations. Science (2001) 294:1875–1878.
Hong G, Baudhuin LM, Xu Y. Sphingosine-1-phosphate modulates growth and adhesion of ovarian cancer cells. FEBS Lett (1999) 460:513–518.[CrossRef][Web of Science][Medline]
Huang MC, Lee HY, Yeh CC, Kong Y, Zaloudek CJ, Goetzl EJ. Induction of protein growth factor systems in the ovaries of transgenic mice overexpressing human type 2 lysophosphatidic acid G protein-coupled receptor (LPA2). Oncogene (2004) 23:122–129.[CrossRef][Web of Science][Medline]
Hudson NK, O’Hara M, Lacey HA, Corcoran J, Hemmings DG, Wareing M, Baker P, Taggart MJ. Modulation of human arterial tone during pregnancy: the effect of the bioactive metabolite sphingosine-1-phosphate. Biol Reprod (2007) 77:45–52.
Hurst JH, Henkel PA, Brown AL, Hooks SB. Endogenous RGS proteins attenuate Galpha(i)-mediated lysophosphatidic acid signaling pathways in ovarian cancer cells. Cell Signal (2008) 20:381–389.[CrossRef][Web of Science][Medline]
Hwang YS, Hodge JC, Sivapurapu N, Lindholm PF. Lysophosphatidic acid stimulates PC-3 prostate cancer cell Matrigel invasion through activation of RhoA and NF-kappaB activity. Mol Carcinog (2006) 45:518–529.[CrossRef][Web of Science][Medline]
Im DS, Heise CE, Ancellin N, O’Dowd BF, Shei GJ, Heavens RP, Rigby MR, Hla T, Mandala S, McAllister G, et al. Characterization of a novel sphingosine 1-phosphate receptor, Edg-8. J Biol Chem (2000) a 275:14281–14286.
Im DS, Heise CE, Harding MA, George SR, O’Dowd BF, Theodorescu D, Lynch KR. Molecular cloning and characterization of a lysophosphatidic acid receptor, Edg-7, expressed in prostate. Mol Pharmacol (2000) b 57:753–759.
Imagawa W, Bandyopadhyay GK, Nandi S. Analysis of the proliferative response to lysophosphatidic acid in primary cultures of mammary epithelium: differences between normal and tumor cells. Exp Cell Res (1995) 216:178–186.[CrossRef][Web of Science][Medline]
Imamura T, Kusano H, Kajigaya Y, Ichikawa M, Shimada H. A rice dihydrosphingosine C4 hydroxylase (DSH1) gene, which is abundantly expressed in the stigmas, vascular cells and apical meristem, may be involved in fertility. Plant Cell Physiol (2007) 48:1108–1120.
Inoue M, Rashid MH, Fujita R, Contos JJ, Chun J, Ueda H. Initiation of neuropathic pain requires lysophosphatidic acid receptor signaling. Nat Med (2004) 10:712–718.[CrossRef][Web of Science][Medline]
Inoue M, Yamaguchi A, Kawakami M, Chun J, Ueda H. Loss of spinal substance P pain transmission under the condition of LPA1 receptor-mediated neuropathic pain. Mol Pain (2006) 2:25.[CrossRef][Medline]
Ishii I, Friedman B, Ye X, Kawamura S, McGiffert C, Contos JJ, Kingsbury MA, Zhang G, Brown JH, Chun J. Selective loss of sphingosine 1-phosphate signaling with no obvious phenotypic abnormality in mice lacking its G protein-coupled receptor, LP(B3)/EDG-3. J Biol Chem (2001) 276:33697–33704.
Ishii I, Ye X, Friedman B, Kawamura S, Contos JJ, Kingsbury MA, Yang AH, Zhang G, Brown JH, Chun J. Marked perinatal lethality and cellular signaling deficits in mice null for the two sphingosine 1-phosphate (S1P) receptors, S1P(2)/LP(B2)/EDG-5 and S1P(3)/LP(B3)/EDG-3. J Biol Chem (2002) 277:25152–25159.
Ishii I, Fukushima N, Ye X, Chun J. Lysophospholipid receptors: signaling and biology. Annu Rev Biochem (2004) 73:321–354.[CrossRef][Web of Science][Medline]
Ito M, Tchoua U, Okamoto M, Tojo H. Purification and properties of a phospholipase A2/lipase preferring phosphatidic acid, bis(monoacylglycerol) phosphate, and monoacylglycerol from rat testis. J Biol Chem (2002) 277:43674–43681.
Ito K, Anada Y, Tani M, Ikeda M, Sano T, Kihara A, Igarashi Y. Lack of sphingosine 1-phosphate-degrading enzymes in erythrocytes. Biochem Biophys Res Commun (2007) 357:212–217.[CrossRef][Web of Science][Medline]
Jaillard C, Harrison S, Stankoff B, Aigrot MS, Calver AR, Duddy G, Walsh FS, Pangalos MN, Arimura N, Kaibuchi K, et al. Edg8/S1P5: an oligodendroglial receptor with dual function on process retraction and cell survival. J Neurosci (2005) 25:1459–1469.
Jalink K, Eichholtz T, Postma FR, van Corven EJ, Moolenaar WH. Lysophosphatidic acid induces neuronal shape changes via a novel, receptor-mediated signaling pathway: similarity to thrombin action. Cell Growth Differ (1993) 4:247–255.[Abstract]
Jalink K, van Corven EJ, Hengeveld T, Morii N, Narumiya S, Moolenaar WH. Inhibition of lysophosphatidate- and thrombin-induced neurite retraction and neuronal cell rounding by ADP ribosylation of the small GTP-binding protein Rho. J Cell Biol (1994) 126:801–810.
Jarvis AA, Cain C, Dennis EA. Purification and characterization of a lysophospholipase from human amnionic membranes. J Biol Chem (1984) 259:15188–15195.
Jeng YJ, Suarez VR, Izban MG, Wang HQ, Soloff MS. Progesterone-induced sphingosine kinase-1 expression in the rat uterus during pregnancy and signaling consequences. Am J Physiol Endocrinol Metab (2007) 292:E1110–E1121.
Johnstone ED, Chan G, Sibley CP, Davidge ST, Lowen B, Guilbert LJ. Sphingosine-1-phosphate inhibition of placental trophoblast differentiation through a G(i)-coupled receptor response. J Lipid Res (2005) 46:1833–1839.
Jolly PS, Rosenfeldt HM, Milstien S, Spiegel S. The roles of sphingosine- 1-phosphate in asthma. Mol Immunol (2002) 38:1239–1245.[CrossRef][Web of Science][Medline]
Jung HG, Shin JH, Kim KW, Yu JY, Kang KK, Ahn BO, Kwon JW, Yoo M. Microarray analysis of gene expression profile in the corpus cavernosum of hypercholesterolemic rats after chronic treatment with PDE5 inhibitor. Life Sci (2007) 80:699–708.[CrossRef][Web of Science][Medline]
Kaminska K, Wasielak M, Bogacka I, Blitek M, Bogacki M. Quantitative expression of lysophosphatidic acid receptor 3 gene in porcine endometrium during the periimplantation period and estrous cycle. Prostaglandins Other Lipid Mediat (2008) 85:26–32.[CrossRef][Web of Science][Medline]
Kamrava M, Simpkins F, Alejandro E, Michener C, Meltzer E, Kohn EC. Lysophosphatidic acid and endothelin-induced proliferation of ovarian cancer cell lines is mitigated by neutralization of granulin-epithelin precursor (GEP), a prosurvival factor for ovarian cancer. Oncogene (2005) 24:7084–7093.[CrossRef][Web of Science][Medline]
Kaneko-Tarui T, Zhang L, Austin KJ, Henkes LE, Johnson J, Hansen TR, Pru JK. Maternal and embryonic control of uterine sphingolipid-metabolizing enzymes during murine embryo implantation. Biol Reprod (2007) 77:658–665.
Kang YC, Kim KM, Lee KS, Namkoong S, Lee SJ, Han JA, Jeoung D, Ha KS, Kwon YG, Kim YM. Serum bioactive lysophospholipids prevent TRAIL-induced apoptosis via PI3K/Akt-dependent cFLIP expression and Bad phosphorylation. Cell Death Differ (2004) 11:1287–1298.[CrossRef][Web of Science][Medline]
Kaya H, Desdicioglu R, Sezik M, Ulukaya E, Ozkaya O, Yilmaztepe A, Demirci M. Does sphingosine-1-phosphate have a protective effect on cyclophosphamide- and irradiation-induced ovarian damage in the rat model? Fertil Steril (2008) 89:732–735.[CrossRef][Web of Science][Medline]
Kennedy TG. Evidence for a role for prosaglandins in the initiation of blastocyst implantation in the rat. Biol Reprod (1977) 16:286–291.[Abstract]
Kim JI, Jo EJ, Lee HY, Cha MS, Min JK, Choi CH, Lee YM, Choi YA, Baek SH, Ryu SH, et al. Sphingosine 1-phosphate in amniotic fluid modulates cyclooxygenase-2 expression in human amnion-derived WISH cells. J Biol Chem (2003) 278:31731–31736.
Kimura Y, Schmitt A, Fukushima N, Ishii I, Kimura H, Nebreda AR, Chun J. Two novel Xenopus homologs of mammalian LP(A1)/EDG-2 function as lysophosphatidic acid receptors in Xenopus oocytes and mammalian cells. J Biol Chem (2001) 276:15208–15215.
Kingsbury MA, Rehen SK, Contos JJ, Higgins CM, Chun J. Non-proliferative effects of lysophosphatidic acid enhance cortical growth and folding. Nat Neurosci (2003) 6:1292–1299.[CrossRef][Web of Science][Medline]
Kinoshita K, Satoh K, Ishihara O, Tsutsumi O, Nakayama M, Kashimura F, Mizuno M. Involvement of prostaglandins in implantation in the pregnant mouse. Adv Prostaglandin Thromboxane Leukot Res (1985) 15:605–607.[Medline]
Kitayama J, Shida D, Sako A, Ishikawa M, Hama K, Aoki J, Arai H, Nagawa H. Over-expression of lysophosphatidic acid receptor-2 in human invasive ductal carcinoma. Breast Cancer Res (2004) 6:R640–R646.[CrossRef][Web of Science][Medline]
Kobayashi T, Yamano S, Murayama S, Ishikawa H, Tokumura A, Aono T. Effect of lysophosphatidic acid on the preimplantation development of mouse embryos. FEBS Lett (1994) 351:38–40.[CrossRef][Web of Science][Medline]
Kobayashi N, Nishi T, Hirata T, Kihara A, Sano T, Igarashi Y, Yamaguchi A. Sphingosine 1-phosphate is released from the cytosol of rat platelets in a carrier-mediated manner. J Lipid Res (2006) 47:614–621.
Komatsu J, Yamano S, Kuwahara A, Tokumura A, Irahara M. The signaling pathways linking to lysophosphatidic acid-promoted meiotic maturation in mice. Life Sci (2006) 79:506–511.[CrossRef][Web of Science][Medline]
Konishi K, Inobe M, Yamada A, Murakami M, Todo S, Uede T. Combination treatment with FTY720 and CTLA4IgG preserves the respiratory epithelium and prevents obliterative disease in a murine airway model. J Heart Lung Transplant (2002) 21:692–700.[CrossRef][Web of Science][Medline]
Kono M, Mi Y, Liu Y, Sasaki T, Allende ML, Wu YP, Yamashita T, Proia RL. The sphingosine-1-phosphate receptors S1P1, S1P2, and S1P3 function coordinately during embryonic angiogenesis. J Biol Chem (2004) 279:29367–29373.
Kono M, Belyantseva IA, Skoura A, Frolenkov GI, Starost MF, Dreier JL, Lidington D, Bolz SS, Friedman TB, Hla T, et al. Deafness and stria vascularis defects in S1P2 receptor-null mice. J Biol Chem (2007) a 282:10690–10696.
Kono Y, Nishiuma T, Nishimura Y, Kotani Y, Okada T, Nakamura S, Yokoyama M. Sphingosine kinase 1 regulates differentiation of human and mouse lung fibroblasts mediated by TGF-beta1. Am J Respir Cell Mol Biol (2007) b 37:395–404.
Kotarsky K, Boketoft A, Bristulf J, Nilsson NE, Norberg A, Hansson S, Owman C, Sillard R, Leeb-Lundberg LM, Olde B. Lysophosphatidic acid binds to and activates GPR92, a G protein-coupled receptor highly expressed in gastrointestinal lymphocytes. J Pharmacol Exp Ther (2006) 318:619–628.
Kue PF, Taub JS, Harrington LB, Polakiewicz RD, Ullrich A, Daaka Y. Lysophosphatidic acid-regulated mitogenic ERK signaling in androgen-insensitive prostate cancer PC-3 cells. Int J Cancer (2002) 102:572–579.[CrossRef][Web of Science][Medline]
Kunikata K, Yamano S, Tokumura A, Aono T. Effect of lysophosphatidic acid on the ovum transport in mouse oviducts. Life Sci (1999) 65:833–840.[CrossRef][Web of Science][Medline]
Kupperman E, An S, Osborne N, Waldron S, Stainier DY. A sphingosine-1-phosphate receptor regulates cell migration during vertebrate heart development. Nature (2000) 406:192–195.[CrossRef][Web of Science][Medline]
Le Stunff H, Milstien S, Spiegel S. Generation and metabolism of bioactive sphingosine-1-phosphate. J Cell Biochem (2004) 92:882–899.[CrossRef][Web of Science][Medline]
Lee HY, Murata J, Clair T, Polymeropoulos MH, Torres R, Manrow RE, Liotta LA, Stracke ML. Cloning, chromosomal localization, and tissue expression of autotaxin from human teratocarcinoma cells. Biochem Biophys Res Commun (1996) 218:714–719.[CrossRef][Web of Science][Medline]
Lee MJ, Van Brocklyn JR, Thangada S, Liu CH, Hand AR, Menzeleev R, Spiegel S, Hla T. Sphingosine-1-phosphate as a ligand for the G protein-coupled receptor EDG-1. Science (1998) 279:1552–1555.
Lee TK, Man K, Ho JW, Wang XH, Poon RT, Xu Y, Ng KT, Chu AC, Sun CK, Ng IO, et al. FTY720: a promising agent for treatment of metastatic hepatocellular carcinoma. Clin Cancer Res (2005) 11:8458–8466.
Lee CW, Rivera R, Gardell S, Dubin AE, Chun J. GPR92 as a new G(12/13)- and G(q)-coupled lysophosphatidic acid receptor that increases cAMP, LPA5. J Biol Chem (2006) a 281:23589–23597.
Lee Z, Swaby RF, Liang Y, Yu S, Liu S, Lu KH, Bast RC Jr, Mills GB, Fang X. Lysophosphatidic acid is a major regulator of growth-regulated oncogene alpha in ovarian cancer. Cancer Res (2006) b 66:2740–2748.
Lee CW, Rivera R, Dubin AE, Chun J. LPA(4)/GPR23 is a lysophosphatidic acid (LPA) receptor utilizing G(s)-, G(q)/G(i)-mediated calcium signaling and G(12/13)-mediated Rho activation. J Biol Chem (2007) 282:4310–4317.
Legrand C, Banuelos-Nevarez A, Rigolot C, Maltier JP. Comparative effects of 6-hydroxydopamine and alpha-adrenoceptor antagonists on intrauterine migration and spacing of blastocysts in the rat. J Reprod Fertil (1987) 81:51–58.
Leiber D, Banno Y, Tanfin Z. Exogenous sphingosine 1-phosphate and sphingosine kinase activated by endothelin-1 induced myometrial contraction through differential mechanisms. Am J Physiol Cell Physiol (2007) 292:C240–C250.
Leung DW. The structure and functions of human lysophosphatidic acid acyltransferases. Front Biosci (2001) 6:D944–D953.[Web of Science][Medline]
Li H, Ye X, Mahanivong C, Bian D, Chun J, Huang S. Signaling mechanisms responsible for lysophosphatidic acid-induced urokinase plasminogen activator expression in ovarian cancer cells. J Biol Chem (2005) 280:10564–10571.
Li LX, Zhou W, Qiao YH, Wang M, Zhang JH. Expression and significance of Edg4 and Edg7 in the placentas of patients with hypertensive disorder complicating pregnancy. Zhonghua Fu Chan Ke Za Zhi (2007) 42:386–389.[Medline]
Liliom K, Guan Z, Tseng JL, Desiderio DM, Tigyi G, Watsky MA. Growth factor-like phospholipids generated after corneal injury. Am J Physiol (1998) 274:C1065–C1074.[Web of Science][Medline]
Liu Z, Armant DR. Lysophosphatidic acid regulates murine blastocyst development by transactivation of receptors for heparin-binding EGF-like growth factor. Exp Cell Res (2004) 296:317–326.[CrossRef][Web of Science][Medline]
Liu Y, Wada R, Yamashita T, Mi Y, Deng CX, Hobson JP, Rosenfeldt HM, Nava VE, Chae SS, Lee MJ, et al. Edg-1, the G protein-coupled receptor for sphingosine-1-phosphate, is essential for vascular maturation. J Clin Invest (2000) 106:951–961.[Web of Science][Medline]
Lloyd B, Tao Q, Lang S, Wylie C. Lysophosphatidic acid signaling controls cortical actin assembly and cytoarchitecture in Xenopus embryos. Development (2005) 132:805–816.
Luquain C, Singh A, Wang L, Natarajan V, Morris AJ. Role of phospholipase D in agonist-stimulated lysophosphatidic acid synthesis by ovarian cancer cells. J Lipid Res (2003) 44:1963–1975.
MacLennan AJ, Carney PR, Zhu WJ, Chaves AH, Garcia J, Grimes JR, Anderson KJ, Roper SN, Lee N. An essential role for the H218/AGR16/Edg-5/LP(B2) sphingosine 1-phosphate receptor in neuronal excitability. Eur J Neurosci (2001) 14:203–209.[CrossRef][Web of Science][Medline]
MacLennan AJ, Benner SJ, Andringa A, Chaves AH, Rosing JL, Vesey R, Karpman AM, Cronier SA, Lee N, Erway LC, et al. The S1P2 sphingosine 1-phosphate receptor is essential for auditory and vestibular function. Hear Res (2006) 220:38–48.[CrossRef][Web of Science][Medline]
Maffucci T, Cooke FT, Foster FM, Traer CJ, Fry MJ, Falasca M. Class II phosphoinositide 3-kinase defines a novel signaling pathway in cell migration. J Cell Biol (2005) 169:789–799.
Maguire JJ, Davenport AP. Regulation of vascular reactivity by established and emerging GPCRs. Trends Pharmacol Sci (2005) 26:448–454.[Medline]
Mahanivong C, Chen HM, Yee SW, Pan ZK, Dong Z, Huang S. Protein kinase Calpha-CARMA3 signaling axis links Ras to NF-kappa B for lysophosphatidic acid-induced urokinase plasminogen activator expression in ovarian cancer cells. Oncogene (2008) 27:1273–1280.[CrossRef][Web of Science][Medline]
Matsumoto K, Banno Y, Murate T, Akao Y, Nozawa Y. Localization of sphingosine kinase-1 in mouse sperm acrosomes. J Histochem Cytochem (2005) 53:243–247.
Matsuyuki H, Maeda Y, Yano K, Sugahara K, Chiba K, Kohno T, Igarashi Y. Involvement of sphingosine 1-phosphate (S1P) receptor type 1 and type 4 in migratory response of mouse T cells toward S1P. Cell Mol Immunol (2006) 3:429–437.[Medline]
Mauco G, Chap H, Simon MF, Douste-Blazy L. Phosphatidic and lysophosphatidic acid production in phospholipase C-and thrombin- treated platelets. Possible involvement of a platelet lipase. Biochimie (1978) 60:653–661.[CrossRef][Web of Science][Medline]
Mazereeuw-Hautier J, Gres S, Fanguin M, Cariven C, Fauvel J, Perret B, Chap H, Salles JP, Saulnier-Blache JS. Production of lysophosphatidic acid in blister fluid: involvement of a lysophospholipase D activity. J Invest Dermatol (2005) 125:421–427.[CrossRef][Web of Science][Medline]
Mendel J, Heinecke K, Fyrst H, Saba JD. Sphingosine phosphate lyase expression is essential for normal development in Caenorhabditis elegans. J Biol Chem (2003) 278:22341–22349.
Meng Y, Kang S, So J, Reierstad S, Fishman DA. Translocation of Fas by LPA prevents ovarian cancer cells from anti-Fas-induced apoptosis. Gynecol Oncol (2005) 96:462–469.[CrossRef][Web of Science][Medline]
Meyer zu Heringdorf D, Jakobs KH. Lysophospholipid receptors: signalling, pharmacology and regulation by lysophospholipid metabolism. Biochim Biophys Acta (2007) 1768:923–940.[Medline]
Mikamo H, Kawazoe K, Sato Y, Imai A, Tamaya T. Preterm labor and bacterial intra-amniotic infection: arachidonic acid liberation by phospholipase A2 of Prevotella bivia. Anaerobe (1998) a 4:209–212.[CrossRef][Web of Science][Medline]
Mikamo H, Kawazoe K, Sato Y, Imai A, Tamaya T. Preterm labor and bacterial intraamniotic infection: arachidonic acid liberation by phospholipase A2 of Fusobacterium nucleatum. Am J Obstet Gynecol (1998) b 179:1579–1582.[CrossRef][Web of Science][Medline]
Mills GB, Moolenaar WH. The emerging role of lysophosphatidic acid in cancer. Nat Rev Cancer (2003) 3:582–591.[CrossRef][Web of Science][Medline]
Mills GB, Eder A, Fang X, Hasegawa Y, Mao M, Lu Y, Tanyi J, Tabassam FH, Wiener J, Lapushin R, et al. Critical role of lysophospholipids in the pathophysiology, diagnosis, and management of ovarian cancer. Cancer Treat Res (2002) 107:259–283.[Medline]
Milstien S, Spiegel S. Targeting sphingosine-1-phosphate: a novel avenue for cancer therapeutics. Cancer Cell (2006) 9:148–150.[CrossRef][Web of Science][Medline]
Mitra P, Oskeritzian CA, Payne SG, Beaven MA, Milstien S, Spiegel S. Role of ABCC1 in export of sphingosine-1-phosphate from mast cells. Proc Natl Acad Sci USA (2006) 103:16394–16399.
Mizugishi K, Yamashita T, Olivera A, Miller GF, Spiegel S, Proia RL. Essential role for sphingosine kinases in neural and vascular development. Mol Cell Biol (2005) 25:11113–11121.
Mizugishi K, Li C, Olivera A, Bielawski J, Bielawska A, Deng CX, Proia RL. Maternal disturbance in activated sphingolipid metabolism causes pregnancy loss in mice. J Clin Invest (2007) 117:2993–3006.[CrossRef][Web of Science][Medline]
Mohamed OA, Jonnaert M, Labelle-Dumais C, Kuroda K, Clarke HJ, Dufort D. Uterine Wnt/{beta}-catenin signaling is required for implantation. Proc Natl Acad Sci USA (2005) 102:8579–8584.
Moolenaar WH. Development of our current understanding of bioactive lysophospholipids. Ann N Y Acad Sci (2000) 905:1–10.[CrossRef][Web of Science][Medline]
Moore F, Da Silva C, Wilde JI, Smarason A, Watson SP, Lopez Bernal A. Up-regulation of p21- and RhoA-activated protein kinases in human pregnant myometrium. Biochem Biophys Res Commun (2000) 269:322–326.[CrossRef][Web of Science][Medline]
Morales A, Fernandez-Checa JC. Pharmacological modulation of sphingolipids and role in disease and cancer cell biology. Mini Rev Med Chem (2007) 7:371–382.[CrossRef][Web of Science][Medline]
Mori K, Kitayama J, Aoki J, Kishi Y, Shida D, Yamashita H, Arai H, Nagawa H. Submucosal connective tissue-type mast cells contribute to the production of lysophosphatidic acid (LPA) in the gastrointestinal tract through the secretion of autotaxin (ATX)/lysophospholipase D (lysoPLD). Virchows Arch (2007) 451:47–56.[Web of Science][Medline]
Morishige J, Touchika K, Tanaka T, Satouchi K, Fukuzawa K, Tokumura A. Production of bioactive lysophosphatidic acid by lysophospholipase D in hen egg white. Biochim Biophys Acta (2007) 1771:491–499.[Medline]
Morita Y, Perez GI, Paris F, Miranda SR, Ehleiter D, Haimovitz-Friedman A, Fuks Z, Xie Z, Reed JC, Schuchman EH, et al. Oocyte apoptosis is suppressed by disruption of the acid sphingomyelinase gene or by sphingosine-1-phosphate therapy. Nat Med (2000) 6:1109–1114.[CrossRef][Web of Science][Medline]
Mullershausen F, Craveiro LM, Shin Y, Cortes-Cros M, Bassilana F, Osinde M, Wishart WL, Guerini D, Thallmair M, Schwab ME, et al. Phosphorylated FTY720 promotes astrocyte migration through sphingosine-1-phosphate receptors. J Neurochem (2007) 102:1151–1161.[CrossRef][Web of Science][Medline]
Murakami N, Yokomizo T, Okuno T, Shimizu T. G2A is a proton-sensing G-protein-coupled receptor antagonized by lysophosphatidylcholine. J Biol Chem (2004) 279:42484–42491.
Murph M, Mills GB. Targeting the lipids LPA and S1P and their signalling pathways to inhibit tumour progression. Expert Rev Mol Med (2007) 9:1–18.[Medline]
Nakamoto T, Yasuda K, Yasuhara M, Yoshimura T, Kinoshita T, Nakajima T, Okada H, Ikuta A, Kanzaki H. Expression of the endothelial cell differentiation gene 7 (EDG-7), a lysophosphatidic acid receptor, in ovarian tumor. J Obstet Gynaecol Res (2005) 31:344–351.[CrossRef][Web of Science][Medline]
Nakane S, Tokumura A, Waku K, Sugiura T. Hen egg yolk and white contain high amounts of lysophosphatidic acids, growth factor-like lipids: distinct molecular species compositions. Lipids (2001) 36:413–419.[Web of Science][Medline]
Ng KT, Man K, Ho JW, Sun CK, Lee TK, Zhao Y, Lo CM, Poon RT, Fan ST. Marked suppression of tumor growth by FTY720 in a rat liver tumor model: the significance of down-regulation of cell survival Akt pathway. Int J Oncol (2007) 30:375–380.[Web of Science][Medline]
Niesporek S, Denkert C, Weichert W, Kobel M, Noske A, Sehouli J, Singer JW, Dietel M, Hauptmann S. Expression of lysophosphatidic acid acyltransferase beta (LPAAT-beta) in ovarian carcinoma: correlation with tumour grading and prognosis. Br J Cancer (2005) 92:1729–1736.[CrossRef][Web of Science][Medline]
Nilsson UK, Svensson SP. Inhibition of Ca2+/calmodulin-dependent protein kinase or epidermal growth factor receptor tyrosine kinase abolishes lysophosphatidic acid-mediated DNA-synthesis in human myometrial smooth muscle cells. Cell Biol Int (2003) 27:341–347.[CrossRef][Web of Science][Medline]
Nilsson UK, Grenegard M, Berg G, Svensson SP. Different proliferative responses of Gi/o-protein-coupled receptors in human myometrial smooth muscle cells. A possible role of calcium. J Mol Neurosci (1998) 11:11–21.[CrossRef][Web of Science][Medline]
Noguchi K, Ishii S, Shimizu T. Identification of p2y9/GPR23 as a novel G protein-coupled receptor for lysophosphatidic acid, structurally distant from the Edg family. J Biol Chem (2003) 278:25600–25606.
Okajima F. Plasma lipoproteins behave as carriers of extracellular sphingosine 1-phosphate: is this an atherogenic mediator or an anti-atherogenic mediator? Biochim Biophys Acta (2002) 1582:132–137.[Medline]
Okamoto H, Takuwa N, Yatomi Y, Gonda K, Shigematsu H, Takuwa Y. EDG3 is a functional receptor specific for sphingosine 1-phosphate and sphingosylphosphorylcholine with signaling characteristics distinct from EDG1 and AGR16. Biochem Biophys Res Commun (1999) 260:203–208.[CrossRef][Web of Science][Medline]
Olivera A, Spiegel S. Sphingosine-1-phosphate as second messenger in cell proliferation induced by PDGF and FCS mitogens. Nature (1993) 365:557–560.[CrossRef][Web of Science][Medline]
Oskouian B, Saba J. Sphingosine-1-phosphate metabolism and intestinal tumorigenesis: lipid signaling strikes again. Cell Cycle (2007) 6:522–527.[Web of Science][Medline]
Otala M, Suomalainen L, Pentikainen MO, Kovanen P, Tenhunen M, Erkkila K, Toppari J, Dunkel L. Protection from radiation-induced male germ cell loss by sphingosine-1-phosphate. Biol Reprod (2004) 70:759–767.
Otala M, Pentikainen MO, Matikainen T, Suomalainen L, Hakala JK, Perez GI, Tenhunen M, Erkkila K, Kovanen P, Parvinen M, et al. Effects of acid sphingomyelinase deficiency on male germ cell development and programmed cell death. Biol Reprod (2005) 72:86–96.
Pages C, Simon M, Valet P, Saulnier-Blache JS. Lysophosphatidic acid synthesis and release(1). Prostaglandins (2001) 64:1–10.[Medline]
Pappu R, Schwab SR, Cornelissen I, Pereira JP, Regard JB, Xu Y, Camerer E, Zheng YW, Huang Y, Cyster JG, et al. Promotion of lymphocyte egress into blood and lymph by distinct sources of sphingosine-1-phosphate. Science (2007) 316:295–298.
Paria BC, Reese J, Das SK, Dey SK. Deciphering the cross-talk of implantation: advances and challenges. Science (2002) 296:2185–2188.
Park KS, Kim MK, Lee HY, Kim SD, Lee SY, Kim JM, Ryu SH, Bae YS. S1P stimulates chemotactic migration and invasion in OVCAR3 ovarian cancer cells. Biochem Biophys Res Commun (2007) 356:239–244.[CrossRef][Web of Science][Medline]
Parks BW, Lusis AJ, Kabarowski JH. Loss of the lysophosphatidylcholine effector, G2A, ameliorates aortic atherosclerosis in low-density lipoprotein receptor knockout mice. Arterioscler Thromb Vasc Biol (2006) 26:2703–2709.
Parrish JJ, Susko-Parrish J, Winer MA, First NL. Capacitation of bovine sperm by heparin. Biol Reprod (1988) 38:1171–1180.[Abstract]
Pasternack SM, von Kugelgen I, Aboud KA, Lee YA, Ruschendorf F, Voss K, Hillmer AM, Molderings GJ, Franz T, Ramirez A, et al. G protein-coupled receptor P2Y5 and its ligand LPA are involved in maintenance of human hair growth. Nat Genet (2008) 40:329–334.[CrossRef][Web of Science][Medline]
Pchejetski D, Golzio M, Bonhoure E, Calvet C, Doumerc N, Garcia V, Mazerolles C, Rischmann P, Teissie J, Malavaud B, et al. Sphingosine kinase-1 as a chemotherapy sensor in prostate adenocarcinoma cell and mouse models. Cancer Res (2005) 65:11667–11675.
Pebay A, Bonder CS, Pitson SM. Stem cell regulation by lysophospholipids. Prostaglandins Other Lipid Mediat (2007) 84:83–97.[CrossRef][Web of Science][Medline]
Phan VH, Herr DR, Panton D, Fyrst H, Saba JD, Harris GL. Disruption of sphingolipid metabolism elicits apoptosis-associated reproductive defects in Drosophila. Dev Biol (2007) 309:329–341.[CrossRef][Web of Science][Medline]
Piazza GA, Ritter JL, Baracka CA. Lysophosphatidic acid induction of transforming growth factors alpha and beta: modulation of proliferation and differentiation in cultured human keratinocytes and mouse skin. Exp Cell Res (1995) 216:51–64.[CrossRef][Web of Science][Medline]
Picascia A, Stanzione R, Chieffi P, Kisslinger A, Dikic I, Tramontano D. Proline-rich tyrosine kinase 2 regulates proliferation and differentiation of prostate cells. Mol Cell Endocrinol (2002) 186:81–87.[CrossRef][Web of Science][Medline]
Pieringer RA, Bonner H Jr, Kunnes RS. Biosynthesis of phosphatidic acid, lysophosphatidic acid, diglyceride, and triglyceride by fatty acyltransferase pathways in Escherichia coli. J Biol Chem (1967) 242:2719–2724.
Pope WF, Maurer RR, Stormshak F. Intrauterine migration of the porcine embryo: influence of estradiol-17 beta and histamine. Biol Reprod (1982) 27:575–579.[Abstract]
Postma FR, Jalink K, Hengeveld T, Moolenaar WH. Sphingosine-1-phosphate rapidly induces Rho-dependent neurite retraction: action through a specific cell surface receptor. EMBO J (1996) 15:2388–2392.[Web of Science][Medline]
Pozlep B, Meleh M, Kobal B, Verdenik I, Osredkar J, Kralj LZ, Meden-Vrtovec H. Use of lysophosphatidic acid in the management of benign and malignant ovarian tumors. Eur J Gynaecol Oncol (2007) 28:394–399.[Web of Science][Medline]
Pusey J, Kelly WA, Bradshaw JM, Porter DG. Myometrial activity and the distribution of blastocysts in the uterus of the rat: interference by relaxin. Biol Reprod (1980) 23:394–397.[Abstract]
Pustilnik TB, Estrella V, Wiener JR, Mao M, Eder A, Watt MA, Bast RC Jr, Mills GB. Lysophosphatidic acid induces urokinase secretion by ovarian cancer cells. Clin Cancer Res (1999) 5:3704–3710.
Raj GV, Sekula JA, Guo R, Madden JF, Daaka Y. Lysophosphatidic acid promotes survival of androgen-insensitive prostate cancer PC3 cells via activation of NF-kappaB. Prostate (2004) 61:105–113.[CrossRef][Web of Science][Medline]
Ramachandran S, Ramaswamy S, Cho C, Parthasarathy S. Lysophosphatidic acid induces glycodelin gene expression in cancer cells. Cancer Lett (2002) 177:197–202.[CrossRef][Web of Science][Medline]
Rapizzi E, Donati C, Cencetti F, Pinton P, Rizzuto R, Bruni P. Sphingosine 1-phosphate receptors modulate intracellular Ca2+ homeostasis. Biochem Biophys Res Commun (2007) 353:268–274.[CrossRef][Web of Science][Medline]
Reddy P, Liu L, Adhikari D, Jagarlamudi K, Rajareddy S, Shen Y, Du C, Tang W, Hamalainen T, Peng SL, et al. Oocyte-specific deletion of Pten causes premature activation of the primordial follicle pool. Science (2008) 319:611–613.
Renback K, Inoue M, Yoshida A, Nyberg F, Ueda H. Vzg-1/lysophosphatidic acid-receptor involved in peripheral pain transmission. Brain Res Mol Brain Res (2000) 75:350–354.[CrossRef][Medline]
Ridley AJ, Hall A. The small GTP-binding protein rho regulates the assembly of focal adhesions and actin stress fibers in response to growth factors. Cell (1992) 70:389–399.[CrossRef][Web of Science][Medline]
Riffo MS, Parraga M. Study of the acrosome reaction and the fertilizing ability of hamster epididymal cauda spermatozoa treated with antibodies against phospholipase A2 and/or lysophosphatidylcholine. J Exp Zool (1996) 275:459–468.[CrossRef][Web of Science][Medline]
Roth Z, Hansen PJ. Sphingosine 1-phosphate protects bovine oocytes from heat shock during maturation. Biol Reprod (2004) 71:2072–2078.
Saatian B, Zhao Y, He D, Georas SN, Watkins T, Spannhake EW, Natarajan V. Transcriptional regulation of lysophosphatidic acid-induced interleukin-8 expression and secretion by p38 MAPK and JNK in human bronchial epithelial cells. Biochem J (2006) 393:657–668.[CrossRef][Web of Science][Medline]
Sabbadini RA. Targeting sphingosine-1-phosphate for cancer therapy. Br J Cancer (2006) 95:1131–1135.[CrossRef][Web of Science][Medline]
Sakamoto S, Yokoyama M, Zhang X, Prakash K, Nagao K, Hatanaka T, Getzenberg RH, Kakehi Y. Increased expression of CYR61, an extracellular matrix signaling protein, in human benign prostatic hyperplasia and its regulation by lysophosphatidic acid. Endocrinology (2004) 145:2929–2940.
Sako A, Kitayama J, Shida D, Suzuki R, Sakai T, Ohta H, Nagawa H. Lysophosphatidic acid (LPA)-induced vascular endothelial growth factor (VEGF) by mesothelial cells and quantification of host-derived VEGF in malignant ascites. J Surg Res (2006) 130:94–101.[CrossRef][Web of Science][Medline]
Sano T, Baker D, Virag T, Wada A, Yatomi Y, Kobayashi T, Igarashi Y, Tigyi G. Multiple mechanisms linked to platelet activation result in lysophosphatidic acid and sphingosine 1-phosphate generation in blood. J Biol Chem (2002) 277:21197–21206.
Sato K, Tomura H, Igarashi Y, Ui M, Okajima F. Exogenous sphingosine 1-phosphate induces neurite retraction possibly through a cell surface receptor in PC12 cells. Biochem Biophys Res Commun (1997) 240:329–334.[CrossRef][Web of Science][Medline]
Sato K, Murata N, Kon J, Tomura H, Nochi H, Tamoto K, Osada M, Ohta H, Tokumitsu Y, Ui M, et al. Downregulation of mRNA expression of Edg-3, a putative sphingosine 1-phosphate receptor coupled to Ca2+ signaling, during differentiation of HL-60 leukemia cells. Biochem Biophys Res Commun (1998) 253:253–256.[CrossRef][Web of Science][Medline]
Sawada K, Morishige K, Tahara M, Ikebuchi Y, Kawagishi R, Tasaka K, Murata Y. Lysophosphatidic acid induces focal adhesion assembly through Rho/Rho-associated kinase pathway in human ovarian cancer cells. Gynecol Oncol (2002) 87:252–259.[CrossRef][Web of Science][Medline]
Schumacher KA, Classen HG, Spath M. Platelet aggregation evoked in vitro and in vivo by phosphatidic acids and lysoderivatives: identity with substances in aged serum (DAS). Thromb Haemost (1979) 42:631–640.[Web of Science][Medline]
Schwartz BM, Hong G, Morrison BH, Wu W, Baudhuin LM, Xiao YJ, Mok SC, Xu Y. Lysophospholipids increase interleukin-8 expression in ovarian cancer cells. Gynecol Oncol (2001) 81:291–300.[CrossRef][Web of Science][Medline]
Sengupta S, Xiao YJ, Xu Y. A novel laminin-induced LPA autocrine loop in the migration of ovarian cancer cells. Faseb J (2003) 17:1570–1572.
Seuwen K, Ludwig MG, Wolf RM. Receptors for protons or lipid messengers or both? J Recept Signal Transduct Res (2006) 26:599–610.[CrossRef][Medline]
Shano S, Moriyama R, Chun J, Fukushima N. Lysophosphatidic acid stimulates astrocyte proliferation through LPA(1). Neurochem Int (2008) 52:216–220.[CrossRef][Web of Science][Medline]
Shen Z, Belinson J, Morton RE, Xu Y. Phorbol 12-myristate 13-acetate stimulates lysophosphatidic acid secretion from ovarian and cervical cancer cells but not from breast or leukemia cells. Gynecol Oncol (1998) 71:364–368.[CrossRef][Web of Science][Medline]
Shiokawa S, Sakai K, Akimoto Y, Suzuki N, Hanashi H, Nagamatsu S, Iwashita M, Nakamura Y, Hirano H, Yoshimura Y. Function of the small guanosine triphosphate-binding protein RhoA in the process of implantation. J Clin Endocrinol Metab (2000) 85:4742–4749.
Siess W. Athero- and thrombogenic actions of lysophosphatidic acid and sphingosine-1-phosphate. Biochim Biophys Acta (2002) 1582:204–215.[Medline]
Siess W, Tigyi G. Thrombogenic and atherogenic activities of lysophosphatidic acid. J Cell Biochem (2004) 92:1086–1094.[CrossRef][Web of Science][Medline]
Sivashanmugam P, Tang L, Daaka Y. Interleukin 6 mediates the lysophosphatidic acid-regulated cross-talk between stromal and epithelial prostate cancer cells. J Biol Chem (2004) 279:21154–21159.
Skaznik-Wikiel ME, Kaneko-Tarui T, Kashiwagi A, Pru JK. Sphingosine-1-phosphate receptor expression and signaling correlate with uterine prostaglandin-endoperoxide synthase 2 expression and angiogenesis during early pregnancy. Biol Reprod (2006) 74:569–576.
Sliva D, Mason R, Xiao H, English D. Enhancement of the migration of metastatic human breast cancer cells by phosphatidic acid. Biochem Biophys Res Commun (2000) 268:471–479.[CrossRef][Web of Science][Medline]
Smicun Y, Reierstad S, Wang FQ, Lee C, Fishman DA. S1P regulation of ovarian carcinoma invasiveness. Gynecol Oncol (2006) 103:952–959.[CrossRef][Web of Science][Medline]
Smicun Y, Gil O, Devine K, Fishman DA. S1P and LPA have an attachment-dependent regulatory effect on invasion of epithelial ovarian cancer cells. Gynecol Oncol (2007) 107:298–309.[CrossRef][Web of Science][Medline]
So I, Chae MR, Kim SJ, Lee SW. Lysophosphatidylcholine, a component of atherogenic lipoproteins, induces the change of calcium mobilization via TRPC ion channels in cultured human corporal smooth muscle cells. Int J Impot Res (2005) 17:475–483.[CrossRef][Web of Science][Medline]
Song H, Lim H, Paria BC, Matsumoto H, Swift LL, Morrow J, Bonventre JV, Dey SK. Cytosolic phospholipase A2alpha is crucial [correction of A2alpha deficiency is crucial] for ‘on-time’ embryo implantation that directs subsequent development. Development (2002) 129:2879–2889.[Web of Science][Medline]
Sonoda H, Aoki J, Hiramatsu T, Ishida M, Bandoh K, Nagai Y, Taguchi R, Inoue K, Arai H. A novel phosphatidic acid-selective phospholipase A1 that produces lysophosphatidic acid. J Biol Chem (2002) 277:34254–34263.
Spiegel S, Milstien S. Sphingosine-1-phosphate: an enigmatic signalling lipid. Nat Rev Mol Cell Biol (2003) 4:397–407.[CrossRef][Web of Science][Medline]
Spiegel S, Olivera A, Zhang H, Thompson EW, Su Y, Berger A. Sphingosine-1-phosphate, a novel second messenger involved in cell growth regulation and signal transduction, affects growth and invasiveness of human breast cancer cells. Breast Cancer Res Treat (1994) 31:337–348.[CrossRef][Web of Science][Medline]
Spiegel S, Foster D, Kolesnick R. Signal transduction through lipid second messengers. Curr Opin Cell Biol (1996) 8:159–167.[CrossRef][Web of Science][Medline]
Springett GM, Bonham L, Hummer A, Linkov I, Misra D, Ma C, Pezzoni G, Di Giovine S, Singer J, Kawasaki H, et al. Lysophosphatidic acid acyltransferase-beta is a prognostic marker and therapeutic target in gynecologic malignancies. Cancer Res (2005) 65:9415–9425.
Stadler CR, Knyazev P, Bange J, Ullrich A. FGFR4 GLY388 isotype suppresses motility of MDA-MB-231 breast cancer cells by EDG-2 gene repression. Cell Signal (2006) 18:783–794.[CrossRef][Web of Science][Medline]
Sugimoto Y, Yamasaki A, Segi E, Tsuboi K, Aze Y, Nishimura T, Oida H, Yoshida N, Tanaka T, Katsuyama M, et al. Failure of parturition in mice lacking the prostaglandin F receptor. Science (1997) 277:681–683.
Sugimoto N, Takuwa N, Yoshioka K, Takuwa Y. Rho-dependent, Rho kinase-independent inhibitory regulation of Rac and cell migration by LPA1 receptor in Gi-inactivated CHO cells. Exp Cell Res (2006) 312:1899–1908.[CrossRef][Web of Science][Medline]
Sugiura T, Nakane S, Kishimoto S, Waku K, Yoshioka Y, Tokumura A. Lysophosphatidic acid, a growth factor-like lipid, in the saliva. J Lipid Res (2002) 43:2049–2055.
Suomalainen L, Pentikainen V, Dunkel L. Sphingosine-1-phosphate inhibits nuclear factor kappaB activation and germ cell apoptosis in the human testis independently of its receptors. Am J Pathol (2005) 166:773–781.
Sutphen R, Xu Y, Wilbanks GD, Fiorica J, Grendys EC Jr, LaPolla JP, Arango H, Hoffman MS, Martino M, Wakeley K, et al. Lysophospholipids are potential biomarkers of ovarian cancer. Cancer Epidemiol Biomarkers Prev (2004) 13:1185–1191.
Symowicz J, Adley BP, Woo MM, Auersperg N, Hudson LG, Stack MS. Cyclooxygenase-2 functions as a downstream mediator of lysophosphatidic acid to promote aggressive behavior in ovarian carcinoma cells. Cancer Res (2005) 65:2234–2242.
Tabata K, Baba K, Shiraishi A, Ito M, Fujita N. The orphan GPCR GPR87 was deorphanized and shown to be a lysophosphatidic acid receptor. Biochem Biophys Res Commun (2007) 363:861–866.[CrossRef][Web of Science][Medline]
Tanaka M, Okudaira S, Kishi Y, Ohkawa R, Iseki S, Ota M, Noji S, Yatomi Y, Aoki J, Arai H. Autotaxin stabilizes blood vessels and is required for embryonic vasculature by producing lysophosphatidic acid. J Biol Chem (2006) 281:25822–25830.
Tanyi JL, Hasegawa Y, Lapushin R, Morris AJ, Wolf JK, Berchuck A, Lu K, Smith DI, Kalli K, Hartmann LC, et al. Role of decreased levels of lipid phosphate phosphatase-1 in accumulation of lysophosphatidic acid in ovarian cancer. Clin Cancer Res (2003) 9:3534–3545.
Teng C, Dong H, Shi L, Deng Y, Mu J, Zhang J, Yang X, Zuo J. Serine palmitoyltransferase, a key enzyme for de novo synthesis of sphingolipids, is essential for male gametophyte development in Arabidopsis. Plant Physiol (2008) 146:1322–1332.
Therien I, Manjunath P. Effect of progesterone on bovine sperm capacitation and acrosome reaction. Biol Reprod (2003) 69:1408–1415.
Tilly JL, Kolesnick RN. Sphingolipids, apoptosis, cancer treatments and the ovary: investigating a crime against female fertility. Biochim Biophys Acta (2002) 1585:135–138.[Medline]
Tokumura A, Fukuzawa K, Tsukatani H. Effects of synthetic and natural lysophosphatidic acids on the arterial blood pressure of different animal species. Lipids (1978) 13:572–574.[Web of Science][Medline]
Tokumura A, Fukuzawa K, Yamada S, Tsukatani H. Stimulatory effect of lysophosphatidic acids on uterine smooth muscles of non-pregant rats. Arch Int Pharmacodyn Ther (1980) 245:74–83.[Web of Science][Medline]
Tokumura A, Harada K, Fukuzawa K, Tsukatani H. Involvement of lysophospholipase D in the production of lysophosphatidic acid in rat plasma. Biochim Biophys Acta (1986) 875:31–38.[Medline]
Tokumura A, Miyake M, Nishioka Y, Yamano S, Aono T, Fukuzawa K. Production of lysophosphatidic acids by lysophospholipase D in human follicular fluids of In vitro fertilization patients. Biol Reprod (1999) 61:195–199.
Tokumura A, Kanaya Y, Miyake M, Yamano S, Irahara M, Fukuzawa K. Increased production of bioactive lysophosphatidic acid by serum lysophospholipase D in human pregnancy. Biol Reprod (2002) 67:1386–1392.
Tokumura A, Kume T, Fukuzawa K, Tahara M, Tasaka K, Aoki J, Arai H, Yasuda K, Kanzaki H. Peritoneal fluids from patients with certain gynecologic tumor contain elevated levels of bioactive lysophospholipase D activity. Life Sci (2007) 80:1641–1649.[CrossRef][Web of Science][Medline]
Ubai T, Azuma H, Kotake Y, Inamoto T, Takahara K, Ito Y, Kiyama S, Sakamoto T, Horie S, Muto S, et al. FTY720 induced Bcl-associated and Fas-independent apoptosis in human renal cancer cells in vitro and significantly reduced in vivo tumor growth in mouse xenograft. Anticancer Res (2007) 27:75–88.
Uhlenbrock K, Gassenhuber H, Kostenis E. Sphingosine 1-phosphate is a ligand of the human gpr3, gpr6 and gpr12 family of constitutively active G protein-coupled receptors. Cell Signal (2002) 14:941–953.[CrossRef][Web of Science][Medline]
Uhlenbrock K, Huber J, Ardati A, Busch AE, Kostenis E. Fluid shear stress differentially regulates gpr3, gpr6, and gpr12 expression in human umbilical vein endothelial cells. Cell Physiol Biochem (2003) 13:75–84.[CrossRef][Web of Science][Medline]
Umezu-Goto M, Tanyi J, Lahad J, Liu S, Yu S, Lapushin R, Hasegawa Y, Lu Y, Trost R, Bevers T, et al. Lysophosphatidic acid production and action: validated targets in cancer? J Cell Biochem (2004) 92:1115–1140.[CrossRef][Web of Science][Medline]
Valentine WJ, Fujiwara Y, Tsukahara R, Tigyi G. Lysophospholipid signaling: beyond the EDGs. Biochim Biophys Acta (2008) 1780:597–605.[Medline]
Van Brocklyn JR. Sphingolipid signaling pathways as potential therapeutic targets in gliomas. Mini Rev Med Chem (2007) 7:984–990.[CrossRef][Web of Science][Medline]
Van Brocklyn JR, Lee MJ, Menzeleev R, Olivera A, Edsall L, Cuvillier O, Thomas DM, Coopman PJ, Thangada S, Liu CH, et al. Dual actions of sphingosine-1-phosphate: extracellular through the Gi-coupled receptor Edg-1 and intracellular to regulate proliferation and survival. J Cell Biol (1998) 142:229–240.
Van Brocklyn JR, Graler MH, Bernhardt G, Hobson JP, Lipp M, Spiegel S. Sphingosine-1-phosphate is a ligand for the G protein-coupled receptor EDG-6. Blood (2000) 95:2624–2629.
van Corven EJ, Groenink A, Jalink K, Eichholtz T, Moolenaar WH. Lysophosphatidate-induced cell proliferation: identification and dissection of signaling pathways mediated by G proteins. Cell (1989) 59:45–54.[CrossRef][Web of Science][Medline]
van Meeteren LA, Moolenaar WH. Regulation and biological activities of the autotaxin-LPA axis. Prog Lipid Res (2007) 46:145–160.[CrossRef][Web of Science][Medline]
van Meeteren LA, Ruurs P, Stortelers C, Bouwman P, van Rooijen MA, Pradere JP, Pettit TR, Wakelam MJ, Saulnier-Blache JS, Mummery CL, et al. Autotaxin, a secreted lysophospholipase D, is essential for blood vessel formation during development. Mol Cell Biol (2006) 26:5015–5022.
Vogt W. Pharamacologically active acidic phospholipids and glycolipids. Biochem Pharmacol (1963) 12:415–420.[CrossRef][Web of Science][Medline]
von Otte S, Paletta JR, Becker S, Konig S, Fobker M, Greb RR, Kiesel L, Assmann G, Diedrich K, Nofer JR. Follicular fluid high density lipoprotein-associated sphingosine 1-phosphate is a novel mediator of ovarian angiogenesis. J Biol Chem (2006) 281:5398–5405.
Waclawik A, Ziecik AJ. Differential expression of prostaglandin (PG) synthesis enzymes in conceptus during peri-implantation period and endometrial expression of carbonyl reductase/PG 9-ketoreductase in the pig. J Endocrinol (2007) 194:499–510.
Wang H, Dey SK. Roadmap to embryo implantation: clues from mouse models. Nat Rev Genet (2006) 7:185–199.[CrossRef][Web of Science][Medline]
Wang Q, Liu M, Kozasa T, Rothstein JD, Sternweis PC, Neubig RR. Thrombin and lysophosphatidic acid receptors utilize distinct rhoGEFs in prostate cancer cells. J Biol Chem (2004) 279:28831–28834.
Wang P, Wu X, Chen W, Liu J, Wang X. The lysophosphatidic acid (LPA) receptors their expression and significance in epithelial ovarian neoplasms. Gynecol Oncol (2007) a 104:714–720.[CrossRef][Web of Science][Medline]
Wang W, Huang MC, Goetzl EJ. Type 1 sphingosine 1-phosphate G protein-coupled receptor (S1P1) mediation of enhanced IL-4 generation by CD4 T cells from S1P1 transgenic mice. J Immunol (2007) b 178:4885–4890.
Watterson KR, Lanning DA, Diegelmann RF, Spiegel S. Regulation of fibroblast functions by lysophospholipid mediators: potential roles in wound healing. Wound Repair Regen (2007) 15:607–616.[CrossRef][Web of Science][Medline]
Webb M, Tham CS, Lin FF, Lariosa-Willingham K, Yu N, Hale J, Mandala S, Chun J, Rao TS. Sphingosine 1-phosphate receptor agonists attenuate relapsing-remitting experimental autoimmune encephalitis in SJL mice. J Neuroimmunol (2004) 153:108–121.[CrossRef][Web of Science][Medline]
Weiner JA, Chun J. Schwann cell survival mediated by the signaling phospholipid lysophosphatidic acid. Proc Natl Acad Sci USA (1999) 96:5233–5238.
Weiner JA, Fukushima N, Contos JJ, Scherer SS, Chun J. Regulation of Schwann cell morphology and adhesion by receptor-mediated lysophosphatidic acid signaling. J Neurosci (2001) 21:7069–7078.
Wendler CC, Rivkees SA. Sphingosine-1-phosphate inhibits cell migration and endothelial to mesenchymal cell transformation during cardiac development. Dev Biol (2006) 291:264–277.[CrossRef][Web of Science][Medline]
Westermann AM, Havik E, Postma FR, Beijnen JH, Dalesio O, Moolenaar WH, Rodenhuis S. Malignant effusions contain lysophosphatidic acid (LPA)-like activity. Ann Oncol (1998) 9:437–442.
Xie Y, Meier KE. Lysophospholipase D and its role in LPA production. Cell Signal (2004) 16:975–981.[Web of Science][Medline]
Xie D, Annex BH, Donatucci CF. Growth factors for therapeutic angiogenesis in hypercholesterolemic erectile dysfunction. Asian J Androl (2008) 10:23–27.[CrossRef][Web of Science][Medline]
Xu Y. Sphingosylphosphorylcholine and lysophosphatidylcholine: G protein-coupled receptors and receptor-mediated signal transduction. Biochim Biophys Acta (2002) 1582:81–88.[Medline]
Xu Y, Fang XJ, Casey G, Mills GB. Lysophospholipids activate ovarian and breast cancer cells. Biochem J (1995) a 309:933–940.[Web of Science][Medline]
Xu Y, Gaudette DC, Boynton JD, Frankel A, Fang XJ, Sharma A, Hurteau J, Casey G, Goodbody A, Mellors A, et al. Characterization of an ovarian cancer activating factor in ascites from ovarian cancer patients. Clin Cancer Res (1995) b 1:1223–1232.[Abstract]
Xu Y, Shen Z, Wiper DW, Wu M, Morton RE, Elson P, Kennedy AW, Belinson J, Markman M, Casey G. Lysophosphatidic acid as a potential biomarker for ovarian and other gynecologic cancers [see comments]. Jama (1998) 280:719–723.
Xu Y, Xiao YJ, Zhu K, Baudhuin LM, Lu J, Hong G, Kim KS, Cristina KL, Song L, F SW, et al. Unfolding the pathophysiological role of bioactive lysophospholipids. Curr Drug Targets Immune Endocr Metabol Disord (2003) 3:23–32.[CrossRef][Medline]
Xu J, Lai YJ, Lin WC, Lin FT. TRIP6 enhances lysophosphatidic acid-induced cell migration by interacting with the lysophosphatidic acid 2 receptor. J Biol Chem (2004) 279:10459–10468.
Xu R, Jin J, Hu W, Sun W, Bielawski J, Szulc Z, Taha T, Obeid LM, Mao C. Golgi alkaline ceramidase regulates cell proliferation and survival by controlling levels of sphingosine and S1P. FASEB J (2006) 20:1813–1825.
Yamada T, Sato K, Komachi M, Malchinkhuu E, Tobo M, Kimura T, Kuwabara A, Yanagita Y, Ikeya T, Tanahashi Y, et al. Lysophosphatidic acid (LPA) in malignant ascites stimulates motility of human pancreatic cancer cells through LPA1. J Biol Chem (2004) 279:6595–6605.
Yamaji H, Sakai K, Joho T, Izumoto E, Fukuda H. Cell cycle analysis of Chinese hamster ovary cells stimulated by phosphatidic acid in serum-free culture. J Biosci Bioeng (2004) 98:487–489.[Web of Science][Medline]
Yamazaki Y, Kon J, Sato K, Tomura H, Sato M, Yoneya T, Okazaki H, Okajima F, Ohta H. Edg-6 as a putative sphingosine 1-phosphate receptor coupling to Ca(2+) signaling pathway. Biochem Biophys Res Commun (2000) 268:583–589.[CrossRef][Web of Science][Medline]
Yanagida K, Ishii S, Hamano F, Noguchi K, Shimizu T. LPA4/p2y9/GPR23 mediates rho-dependent morphological changes in a rat neuronal cell line. J Biol Chem (2007) 282:5814–5824.
Yatomi Y, Ruan F, Hakomori S, Igarashi Y. Sphingosine-1-phosphate: a platelet-activating sphingolipid released from agonist-stimulated human platelets. Blood (1995) 86:193–202.
Yatomi Y, Ozaki Y, Ohmori T, Igarashi Y. Sphingosine 1-phosphate: synthesis and release. Prostaglandins (2001) 64:107–122.[Web of Science][Medline]
Ye X, Ishii I, Kingsbury MA, Chun J. Lysophosphatidic acid as a novel cell survival/apoptotic factor. Biochim Biophys Acta (2002) 1585:108–113.[Medline]
Ye X, Hama K, Contos JJ, Anliker B, Inoue A, Skinner MK, Suzuki H, Amano T, Kennedy G, Arai H, et al. LPA3-mediated lysophosphatidic acid signalling in embryo implantation and spacing. Nature (2005) 435:104–108.[CrossRef][Web of Science][Medline]
Ye X, Skinner MK, Kennedy G, Chun J. Age-dependent loss of sperm production in mice via impaired lysophosphatidic acid signaling. Biol Reprod (2008) (in press).
Yoshida S, Fujisawa-Sehara A, Taki T, Arai K, Nabeshima Y. Lysophosphatidic acid and bFGF control different modes in proliferating myoblasts. J Cell Biol (1996) 132:181–193.
Yoshinaga K, Rice C, Krenn J, Pilot RL. Effects of nicotine on early pregnancy in the rat. Biol Reprod (1979) 20:294–303.[Abstract]
Yue J, Yokoyama K, Balazs L, Baker DL, Smalley D, Pilquil C, Brindley DN, Tigyi G. Mice with transgenic overexpression of lipid phosphate phosphatase-1 display multiple organotypic deficits without alteration in circulating lysophosphatidate level. Cell Signal (2004) 16:385–399.[CrossRef][Web of Science][Medline]
Zhang Z, Schluesener HJ. FTY720: a most promising immunosuppressant modulating immune cell functions. Mini Rev Med Chem (2007) 7:845–850.[CrossRef][Web of Science][Medline]
Zhang H, Desai NN, Olivera A, Seki T, Brooker G, Spiegel S. Sphingosine-1-phosphate, a novel lipid, involved in cellular proliferation. J Cell Biol (1991) 114:155–167.
Zhang J, Honbo N, Goetzl EJ, Chatterjee K, Karliner JS, Gray MO. Signals from type 1 sphingosine 1-phosphate receptors enhance adult mouse cardiac myocyte survival during hypoxia. Am J Physiol Heart Circ Physiol (2007) 293:H3150–H3158.
Zhao Y, Kalari SK, Usatyuk PV, Gorshkova I, He D, Watkins T, Brindley DN, Sun C, Bittman R, Garcia JG, et al. Intracellular generation of sphingosine 1-phosphate in human lung endothelial cells: role of lipid phosphate phosphatase-1 and sphingosine kinase 1. J Biol Chem (2007) 282:14165–14177.
Zheng Y, Kong Y, Goetzl EJ. Lysophosphatidic acid receptor-selective effects on Jurkat T cell migration through a Matrigel model basement membrane. J Immunol (2001) 166:2317–2322.
Zondag GC, Postma FR, Etten IV, Verlaan I, Moolenaar WH. Sphingosine 1-phosphate signalling through the G-protein-coupled receptor Edg-1. Biochem J (1998) 330:605–609.[Web of Science][Medline]
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