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Biology of Reproduction 66, 859-865 (2002)
© 2002 Society for the Study of Reproduction, Inc.

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Lysophosphatidic Acid and Its Role in Reproduction

Lygia T. Budnik1,a, and Amal K. Mukhopadhyaya

a Institute for Hormone and Fertility Research, University of Hamburg, D-22529 Hamburg, Germany


   ABSTRACT
TOP
 ABSTRACT
HISTORICAL PERSPECTIVE
 BIOCHEMISTRY OF LPA
 PRODUCTION AND RELEASE OF...
 LPA RECEPTORS
 BIOLOGICAL RESPONSES
 LPA-INDUCED SIGNAL TRANSDUCTION
 LPA DEGRADATION
 CONCLUSION AND FUTURE...
 REFERENCES
 
Lysophosphatidic acid (LPA) belongs to a new family of lipid mediators that are endogenous growth factors and that elicit diverse biological effects, usually via the activation of G protein-coupled receptors. LPA can be generated after cell activation through the hydrolysis of preexisting phospholipids in the membranes of stimulated cells. A dramatic elevation of LPA levels was found in serum of patients suffering from ovarian carcinoma. Because these high LPA amounts can be detected as early as stage I of the disease, LPA has been introduced as a new marker for ovarian cancer. Progression of the malignancy is correlated with a differential expression of various LPA receptor subtypes. The presence of LPA in the follicular fluid of healthy individuals implicates that this biological mediator may be relevant to normal ovarian physiology. LPA induces proliferation and mitogenic signaling of prostate cancer cells, and a novel LPA receptor isoform has been recognized in healthy prostate tissues. This evidence indicates multiple roles for LPA in both male and female reproductive physiology and pathology. In this review, we summarize the literature on LPA generation, the way it is degraded, and the mechanisms by which signals are transduced by various LPA receptors in reproductive tissues, and we discuss possible future research directions in these areas.

growth factors, lysolipids, ovary, signal transducers, signal transduction, testis


   HISTORICAL PERSPECTIVE
TOP
 ABSTRACT
 HISTORICAL PERSPECTIVE
BIOCHEMISTRY OF LPA
 PRODUCTION AND RELEASE OF...
 LPA RECEPTORS
 BIOLOGICAL RESPONSES
 LPA-INDUCED SIGNAL TRANSDUCTION
 LPA DEGRADATION
 CONCLUSION AND FUTURE...
 REFERENCES
 
The pioneering work of Mollenaar and coworkers established in 1989 that lysophosphatidic acid (LPA) and other lysolipids were biological mediators and not simply structural components of the cell membrane. LPA has sparked interest more recently after it was proposed as a possible marker for ovarian cancer. The subsequent discovery of the LPA receptor superfamily has endowed the growing research area with all of the major components necessary for a full understanding of its physiological and pathological relevance.


   BIOCHEMISTRY OF LPA
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 ABSTRACT
 HISTORICAL PERSPECTIVE
 BIOCHEMISTRY OF LPA
PRODUCTION AND RELEASE OF...
 LPA RECEPTORS
 BIOLOGICAL RESPONSES
 LPA-INDUCED SIGNAL TRANSDUCTION
 LPA DEGRADATION
 CONCLUSION AND FUTURE...
 REFERENCES
 
LPA and its metabolites belong to a new group of lipid-based signaling molecules with a broad range of intra- or extracellular effects [1–3]. LPA is the first intermediate in de novo phospholipid biosynthesis and one of the smallest glycerophospholipids. It consists of three structural domains; a phosphate moiety, a linker region, and a lipophilic tail [1]. Whereas the phosphate head group appears to be essential for receptor activation, the lipophilic tail is suggested to be responsible for its biological activity [1]. This long chain aliphatic group may couple to the glycerol backbone through either acyl-, alkyl-, or alkenyl linkage [3].

Although serum LPA is bound to albumin fractions, its biological effects are not critically dependent on the presence of albumin (for a detailed review see [2]). Serum contains 2–20 µM LPA and several other as yet unidentified lipids with LPA-like activity [2]. The major serum LPA band consists of a mixture of LPA species with unsaturated and saturated fatty acid chains 18:1 and 16:0 followed by the 18:2, 18:0, and 20:4 LPA [4]. The majority of LPA species in ascites from ovarian cancer patients [5] are 16:0 and 18:0, although polyunsaturated 18:2, 20:4, and 22:6 chains are also abundant [4]. LPA is more water soluble than long-chain phospholipids because of its free hydroxyl and phosphate moiety, (i.e., 1-oleoyl-sn-glycero-3-phosphate) [6]. Relatively little is known about the physical chemistry of LPA, such as phase behavior and its cation binding properties [2].


   PRODUCTION AND RELEASE OF LPA
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 ABSTRACT
 HISTORICAL PERSPECTIVE
 BIOCHEMISTRY OF LPA
 PRODUCTION AND RELEASE OF...
LPA RECEPTORS
 BIOLOGICAL RESPONSES
 LPA-INDUCED SIGNAL TRANSDUCTION
 LPA DEGRADATION
 CONCLUSION AND FUTURE...
 REFERENCES
 
LPA can be generated in an activated cell by the hydrolysis of phospholipids preexisting in the cellular membranes (Fig. 1). Although serum LPA can be generated from thrombin-activated platelets [7], its production and release appear not to be restricted to platelets [8]. Recent data indicate that LPA may also be produced locally within reproductive tissues. It has been suggested that LPA found within the ovary may be produced by the ovary itself, because LPA is present both in follicular fluid and in the ascites from ovarian cancer patients [8, 9]. Human follicular fluid contains an active lysophospholipase D, an enzyme (Fig. 2) that may be responsible for the local production of LPA [9].



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  		FIG. 1. Schematic diagram of a phospholipid (phosphatidylcholine) and the cleavage sites processed by various phospholipases. The inset shows one processed product; LPA, 1-oleoyl-sn-glycero-3-phosphate. PLA1, phospholipase A1; PLA2, phospholipase A2; PLC, phospholipase C; PLD, phospholipase D; R1/R2, variable fatty acid residues



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  		FIG. 2. Model illustrating possible events occurring within the plasma membrane that may result in LPA release and signaling. The question marks are possible ways of transducing a signal that have not been experimentally confirmed. LPA-R, receptor for LPA, GPCR; PA, phosphatidic acid; PC, phosphatididylcholine; PE, phosphatididyl-ethanolamine; LPC, lysophosphatidylcholine; LPE, lysophosphatidylethanolamine), PLA1, phospholipase A1; PLA2, phospholipase A2; PLC, phospholipase C; PLD, phospholipase D

A so-called ovarian cancer activating factor, a lipid factor found in ascites from ovarian cancers in earlier studies, has now been identified [10] as a complex of several molecular species of LPA. Elevated serum LPA levels are found in more than 90% of ovarian cancer patients at stage I or stage II [5, 11, 12]. Rough estimates suggest that LPA levels in malignant effusions are in the high micromolar range, about 10-fold higher than normally found in serum [13, 14]. Taking this into account, Xu et al. [11] suggested that the level of LPA in plasma may represent a potential biomarker for ovarian cancer. Although the precise origin of LPA in plasma and ascites fluid remains to be elucidated, it seems likely that LPA is released by the tumor cells themselves. Metabolic pathways responsible for LPA synthesis are poorly delineated though some information is available on LPA production in ovarian cancer epithelium. However, more detailed information on the biosynthetic pathways has arisen from studies employing nonreproductive tissues. In thrombin-activated blood platelets, for example, phospholipase C, phospholipase A2 (PLA2), or phospholipase A1 may contribute to LPA production [8, 15]. Based on a literature survey, Gaits et al. [8] suggested a key role for the secretory nonpancreatic phospholipase A2 type II (sPLA2 II). This enzyme accumulates in inflammatory fluid and is produced by a number of cell types in response to cytokines. Although sPLA2 II is the first reported example of a phospholipase capable of generating LPA directly from phosphatidic acid [8, 15, 16], sPLA2 II hydrolyzes phospholipid substrates only in cell membranes that have lost their phospholipid asymmetry [15]. This loss may occur under physiological or pathological conditions and results in a translocation of phospholipids (such as phosphatidic acid) from the internal leaflet to the outer leaflet of the cell membrane.

LPA production by sPLA2 II in the LPA autoinduced ovarian cancer cell line OVCAR3 may not be seen in other ovarian carcinoma cells, which may require different stimuli [5]. For example, a significant stimulation of LPA release is observed following the treatment of ovarian and cervical cancer cells with phorbol ester [17]. Although in OVCAR3 cells LPA alone can induce LPA secretion [5, 18], cell lines such as HEY and OCC1 additionally require phorbol ester, whereas IOSE cells do not need LPA autoinduction at all [5]. An inhibitor of the cytosolic PLA2 (cPLA2) could block 75% of phorbol ester-induced LPA secretion in ovarian cancer cells, whereas autoinduction by LPA appears not to be dependent on cPLA2 [5]. Although the experiments performed with PLA2 inhibitors may predict a contribution by PLA2 to LPA secretion, direct evidence for the involvement of this enzyme has been elusive. There is no information about the expression of this enzyme in ovarian cancer tissues.

Using ovarian dispersates from healthy immature rats, Kol et al. [19] observed an induction of sPLA2 enzyme and increase in sPLA2 gene expression in response to interleukin 1 beta [19]. Although not mentioned by the authors, LPA secretion probably occurred under these experimental conditions.

Both basal and autoinduced LPA formation in ovarian cancer cells appears to require phospholipase D activity [5, 18]. Although there is copious production of LPA in ovarian cancer, phospholipase D-mediated phosphatidic acid formation in malignant ovary has not been described. However, enhanced phosphatidic acid formation in response to growth factor stimulation of ovarian luteal cells has been reported [20]. In 1986, Tokumura and his coworkers [21] described a phospholipase D responsible for the degradation of lyso derivatives of platelet activating factor to alkyl LPA. Later, the same group [9, 22] characterized a metal ion-dependent lysophospholipase D (LPLD) involved in the accumulation of LPA (both in rat plasma and in the follicular fluid collected from women undergoing treatment for in vitro fertilization [IVF]). The LPLD activity in the serum of IVF patients appears to be about 2.5-fold higher than that in unstimulated women [9].

A marked increase in serum LPLD [22] is correlated with the progress of pregnancy and immunoreactive PLA2 II increases in serum, at both preterm and term [23]. Because naturally occurring PLA2 inhibitors, annexins, decrease during the onset of labor both in amnion and chorion [24], a role for PLA2 is also possible. The expression of secretory phospholipases in gestational tissues and their contribution to LPA production is yet to be established. It is likely that several different phospholipases (and their activators or inhibitors) may work in concert.

In male reproductive tissues, there is evidence for the expression of PLA2 enzymes in various spermatogenic cells (for review see [25]). Partial purification revealed the existence of a 14- to 16-kDa sperm PLA2 showing some similarities with sPLA2 I and sPLA2 II. PLA2 activities have been reported in bull prostate, seminal vesicle, Cowper gland, and seminal plasma from both bulls and humans [26, 27]. There is compelling evidence that PLA2 plays a role in the release of fatty acids and lysophospholipids involved in sperm membrane fusion during acrosomal exocytosis [28, 29]. Recently, a new phosphatidic acid-preferring PLA1 enzyme has been purified from bovine testicular tissues [30]. This tetramer-forming phospholipase shares some properties with a 58-kDa brain PLA2, which shows an absolute preference for phosphatidic acid [31].

It is not known whether the tetrameric structure of these phospholipases is related to a functional regulatory mechanism. The family of PLA2 enzymes can be classified into several groups: high (85 kDa) and low (14 kDa) molecular mass cPLA2 enzymes and at least three so-called sPLA2 enzymes: sPLA2 I, which is produced by the pancreatic acinar cells, sPLA2 II, and sPLA2 V, which is present in several human tissues. Thus, five distinct mammalian sPLA2s and two main types of sPLA2 receptors have so far been identified (for review see [32]). The PLA2 enzymes have also been recognized as autocrine mediators [32].

Currently, none of the PLA1 or PLA2 enzymes can be considered as single direct effectors of LPA production; the activity of other phospholipases appears also to be relevant for the production of this biologically active phospholipid. In principle, several of the phospholipases present in various reproductive tissues should be able to generate LPA, although confirmatory evidence is still lacking. Information concerning LPA concentration in tissue and the localization of the physiological substrate remains unavailable. The most significant information on LPA production at the tissue level has been obtained from studies of ovarian cancer, where sPlA2 II appears to be a major contributor. However, under more physiological conditions, LPLD probably is the major player. Further studies are necessary to resolve this issue.


   LPA RECEPTORS
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 ABSTRACT
 HISTORICAL PERSPECTIVE
 BIOCHEMISTRY OF LPA
 PRODUCTION AND RELEASE OF...
 LPA RECEPTORS
BIOLOGICAL RESPONSES
 LPA-INDUCED SIGNAL TRANSDUCTION
 LPA DEGRADATION
 CONCLUSION AND FUTURE...
 REFERENCES
 
Because LPA does not penetrate cells, it may be metabolized in the cell membrane, and a cell-permeable metabolite may produce the observed effects. Alternatively, LPA itself may bring about its effects after binding to an extracellular receptor. The biological activity of LPA has not been definitely attributed to one of its metabolites, although this possiblilty must be considered. Based on pharmacological studies, Moolenaar and coworkers proposed that LPA may initiate its action upon binding to a G-protein-coupled seven-transmembrane receptor (GPCR) (reviewed in [2, 33]). The compelling evidence for the existence of a putative membrane receptor came from photoaffinity labeling studies, in which a 40-kDa LPA binding protein was identified [34]. A similar 40-kDa LPA binding protein has been identified using radioactively labeled LPA cross-linked to ovarian luteal cell membranes [35]. Upon binding to its receptor, LPA induces tyrosine phosphorylation of several proteins (65–125 kDa) in this cell system [35].

Although no LPA receptor protein has been purified and biochemically characterized so far, the comparative sequence and genomic structure analysis has revealed that the receptor group edg (coding orphan receptors for endothelial differentiation genes) may include such an LPA receptor [2, 36]. One such cDNA encodes a GPCR, initially designated vzg-1 and renamed edg-2 based on its high homology to the human orphan GPCR edg-1 [37]. Overexpression of the human edg-2 protein in Chinese hamster ovary cells increased specific binding of [3H]LPA [37, 38]. A sequence-based search for other GPCRs specific for LPA resulted in the discovery of genes edg-1 to edg-5 [36]. These GPCRs belong to a large edg gene superfamily encoding receptors for LPA and other lysolipids [36, 37]. Chun et al. [37] proposed a provisional nomenclature for this receptor family (Fig. 3): the LpA1/A2/A3 group (edg-2, -4, and -7) includes high-affinity LPA receptors, and the LpB1/B2 group includes receptors for sphingosine-1-phosphate [37, 38]. Analysis of edg receptors by semiquantitative reverse transcription polymerase chain reaction (RT-PCR) and Western blotting using monoclonal antibodies shows prominent expression of the edg-4 (LpA2) receptor in ovarian cancer cells as compared with nonmalignant ovarian surface epithelium [39]. In contrast, levels of edg-2, -3, and -5 appear to be higher in nonmalignant epithelium [39]. The expression of edg-2 (LpA1) is especially high in cisplatin-resistant and slowly proliferating cell lines and is almost absent from cisplatin-sensitive and rapidly proliferating ovarian cancer cell lines [40]. Because the overexpression of edg-2 in A2780 ovarian cancer cells results in a reduced cell proliferation rate without altering the cisplatin sensitivity, the Furui et al. [40] suggested that edg-2 may be a negative regulator of ovarian epithelial cell growth and metastasis.



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  		FIG. 3. The relationship of LPA receptors to other close family members. This new nomenclature was proposed by Chun et al. [37]. The receptors for lysolipids such as LPA (LpA1, LpA2) and for sphingosine 1-phosphate (LpB) are related to other lipid receptors and to canabinoid and cholecystokinin receptors.The recently discovered edg-7 gene belongs to a new subgroup, LpA3

Contos and Chun [41] looked at the regulation and genetics of the edg-4 receptor, the prominently expressed subtype in ovarian cancer cells. These authors analyzed several splice variants of the edg-4 receptor and determined that one such variant arises from a frame shift mutation near the 3' end of the coding region [41]. This G-deletion variant is derived from an ovarian tumor. In addition to increasing our understanding of the mechanisms underlying LPA signaling and lysophospholipid receptor gene evolution, these results have important implications regarding the genomic targeting and oncogenic potential of LpA2. A newly identified member of the LPA receptor family, edg-7 (LpA3) [42], has properties distinct from the known cloned LPA receptors and is prominently expressed in prostate [43].

To address the possibility of a isoform-specific signaling mechanism, receptor subtype-specific antagonists are necessary. In addition to the pharmacological approaches, the molecular biological approach should bring more light in this issue. RT-PCR, RNase protection assays, and molecular cloning strategies can be used to identify and characterize various LPA receptor isoforms in reproductive tissues under physiological conditions, which will be an important area for future investigation. Little is known about the expression of various receptor isoforms in nonmalignant reproductive tissues. Furthermore, the potential physiological modulation of LPA receptor expression has not been reported thus far.


   BIOLOGICAL RESPONSES
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 ABSTRACT
 HISTORICAL PERSPECTIVE
 BIOCHEMISTRY OF LPA
 PRODUCTION AND RELEASE OF...
 LPA RECEPTORS
 BIOLOGICAL RESPONSES
LPA-INDUCED SIGNAL TRANSDUCTION
 LPA DEGRADATION
 CONCLUSION AND FUTURE...
 REFERENCES
 
Because it is a growth factor, LPA may function as an autocrine or juxtacrine mediator, thereby evoking many mitogenic and nonmitogenic cellular responses [33, 36, 44]. Several of the biological activities of LPA were originally identified as responses to whole serum [2]. Proliferation-stimulating and survival-enhancing activities of LPA are mediated mainly by serum response elements and the recruitment of immediate early genes coupled to growth [36]. LPA may also cause some cells to proliferate by inducing the production or secretion of one or more polypeptide growth factors [33, 36, 44]. LPA also directly stimulates the proliferation of primary ovarian carcinoma cells (OV202) but has no mitogenic effect on normal ovarian epithelium [39]. LPA may promote ovarian tumor growth by inducing the stimulation of angiogenic factors such as vascular endothelial growth factor or polypeptide growth factors such as insulin-like growth factor II and urokinase plasminogen activator [45, 46]. LPA stimulates the proliferation of several prostate cancer cell lines [47]; its most prominent mitogenic effect is seen in androgen-insensitive cells [48]. Although LPA may seem to increase DNA synthesis only in cancer cells systems, its mitogenic effects have also been implicated in follicular growth in chickens [49].

In addition to its mitogenic effects, LPA also produces dramatic effects on the actin cytoskeleton [44]. In particular, the cells of neuronal origin appear to show clearly the morphoregulatory effects of LPA (for review see [44]). LPA may also be one of the factors regulating tissue remodeling processes taking place during the growth, differentiation, and regression of the corpus luteum [50]. Luteal cells are known to be mainly regulated by LH (during the ovarian cycle) or chorionic gonadotropins (during pregnancy). The action of the gonadotropins appear to be under modulatory regulation of LPA in the ovary. Several important functions of the ovary, such as steroid production, can only be modulated by LPA at particular stages of the cycle (unpublished results).

Other parts of the female reproductive tract may also be affected by this locally produced bioactive lipid. Kunikata et al. [51] reported that the addition of LPA significantly enhanced ovum transport in the mouse oviduct. The outgrowth of embryos on decidual cells similarly increases in response to LPA [52].

In the male reproductive system, a local role for LPA may exist. Garbi et al. [53] demonstrated the presence of phospholipase D1 in bovine sperm, and it is known that exogenous phospholipase D is capable of generating LPA [9, 54]. At the time of fertilization, the spermatozoon undergoes a process of regulated exocytosis, the acrosomal reaction. Many agonists may initiate this reaction, and others have been reported as modulators or cofactors [25]. Some of these factors are present in oviductal fluid. Earlier studies suggested that phospholipases and unidentified lysolipids are involved in sperm membrane fusion during acrosomal exocytosis [25]. Recent studies have revealed that LPA can activate the acrosomal reaction [53], suggesting that LPA, which is both locally produced and biologically active, could be the unidentified lysolipid.

Most reproductive tissues can be considered possible LPA targets. The biological effects of LPA may differ among the various organs and may depend on the particular physiological status of the target tissue. In the ovary, the effects of LPA may vary depending upon the various stages of the cycle. LPA may also have different functions within a given tissue. Although the available evidence is preliminary, the published data suggest that LPA may play an important role in various processes of the oviduct such as ovum transport and facilitation of the acrosomal reaction.


   LPA-INDUCED SIGNAL TRANSDUCTION
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 ABSTRACT
 HISTORICAL PERSPECTIVE
 BIOCHEMISTRY OF LPA
 PRODUCTION AND RELEASE OF...
 LPA RECEPTORS
 BIOLOGICAL RESPONSES
 LPA-INDUCED SIGNAL TRANSDUCTION
LPA DEGRADATION
 CONCLUSION AND FUTURE...
 REFERENCES
 
There is no consistent picture as to how LPA signals are transduced in a cell. Multiple LPA receptors and various G-protein-coupled pathways can be used within the same cell [44]. These receptors can then mediate responses as diverse as cellular proliferation, the regulation of cell shape, or even protection from apoptosis [44]. The array of biochemical pathways that link an LPA receptor to its biological response is very complex. Only very recently were the first LPA receptor knockout mice reported [55]. The targeted deletion of the LpA1 receptor results in approximately 50% neonatal lethality, impaired suckling in neonatal pups, and increased apoptosis in sciatic nerve Schwann cells [55]. Unfortunately, there is no published information on the reproductive tissues in these knockout animals.

In studies performed with cell lines expressing a single LpA1 receptor, this receptor activated distinct signaling pathways, i.e., the phospholipase C/MAP kinase pathway, arachidonic acid release, and the inhibition of adenylyl cyclase [56]. Heterologous expression of LpA2 in the same cell system produces LPA-dependent cell rounding in addition to the other effects [55, 56]. The stimulation of the LPA-induced proliferation of ovarian cancer cells is correlated with an increase in [Ca2+]i and the activation of p125 FAK and MAP kinases [57]. Whether these pathways are responsible for the mitogenic effects of LPA remains to be determined. Ovarian cancer cells show high expression levels of LpA2 receptors (edg-4) but low expression of LpA1 receptors [56]. This difference may indicate that the LpA2-induced (rather than LpA1-induced) activation of the MAP kinase pathway contributes to the transmission of LPA-induced proliferative signals in ovarian carcinoma cells. A similar activation of the MAP kinases Erk1/2 is also observed in prostate cancer cells in response to LPA [58]. However, because the type of LPA receptor expressed in this prostate cancer cell line is unknown, these results are difficult to compare with those observed in the ovarian cells. Results obtained by others [43] have indicated that prostate tissues express a novel LPA receptor form, edg-7. It is not known whether the observed mitogenic effect of LPA in prostate cancer cells is a consequence of an activation of the edg-7 receptor.

LPA receptors can couple to several classes of heterotrimeric G proteins, i.e., G12/13, Gi/o, Gq, and probably other G proteins except GS [44, 56]. In the case of PC-3 prostate cancer cells [58], pretreatment with pertussis toxin inhibits the mitogenic response by 70%–80% indicating coupling to Gi/o. The expression of the G beta-gamma sequestrant peptides results in an inhibition of LPA-mediated Erk1/2 activation [58]. LPA-induced mitogenic stimulation in the prostate requires the participation of epidermal growth factor-mediated responses and c-Src protein kinases. In tissues outside the reproductive system, crosstalk to growth factor receptor kinase, a novel c-Src-effector kinase, is involved in the LPA-induced signal transduction cascade [2].

Morphological responses to LPA are often manifested through its dramatic effects on the actin-based cytoskeleton [2, 36, 44]. In nonreproductive tissues such as motile fibroblasts, a depletion of LPA triggers a loss of detyrosinated microtubules, whereas the addition of LPA to astrocytes inhibits the cAMP-dependent stellation process [59, 60]. In cultured luteal cells, LPA influences the actin cytoskeleton by modulating the morphological changes induced by LH [50]. These morphoregulatory effects of LPA could be mimicked by CNF1, a bacterial toxin known to activate small G-proteins from the Rho family. However, botulinum-C3-exotransferase, which acts mainly through the inhibition of RhoA, mimics the effects of LH. Therefore, we suggested that the morphomodulatory effects of LPA in the ovary are mediated primarily through the activation of RhoGTPases [50]. In astrocytes [60] and melanoma cells [61], the overexpression of RhoA protein leads to an inhibition of the stellation process induced by either cAMP or C3-exotransferase. Although these mechanisms appear to be physiologically far removed from the developing corpus luteum, the underlying biochemical pathways may not be too different.

A pathway involving Rho kinase has also been recently implicated in LPA- and oxytocin-induced uterine contractions [62]. Stimulation of cultured myometrial cells with LPA plus oxytocin resulted in an increase in stress fiber formation, a process that contributes to the initiation and maintenance of smooth muscle contraction [62]. Although the molecular mechanism of the LPA-induced stress fiber formation differs from that involved in stellation, both processes converge at the level of RhoGTPases. Further downstream of the RhoGTPases, LPA activates a series of kinases, including various protein kinase C (PKC) isoforms. LPA-induced activation of sperm PKC{alpha} has been implicated in the sperm acrosomal reaction [53], and the activation of protein kinase C{delta} by LPA has been reported in ovarian theca lutein cells [63].

The substrates for the PKC-induced phosphorylation in sperm have not been identified. PKC{alpha} in the sperm coimmunoprecipitates with phospholipase D1 in cells stimulated with either LPA or phorbol ester [53]. Although the function of phospholipase D1 in the PKC signal transduction is as yet unknown, it is tempting to speculate that intracellular production of phosphatidic acid may contribute to LPA receptor-mediated effects on the sperm.

Although these results add another piece to the LPA signal transduction puzzle, a clear picture is yet to emerge. We are still in the process of learning how bioactive lipids transmit signals within a single cell, and we are only beginning to understand the heterogeneity of the LPA receptors, the variability of G-protein coupling, and the multitude of downstream effector proteins (for review see [44, 56]. Although the vast majority of LPA effects appear to be receptor mediated, the relative importance of non-receptor-mediated mechanisms for the action of LPA remains to be elucidated. Because LPA can signal without recourse to its receptor, LPA may use both classical and nonclassical pathways to mediate the signal.


   LPA DEGRADATION
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 ABSTRACT
 HISTORICAL PERSPECTIVE
 BIOCHEMISTRY OF LPA
 PRODUCTION AND RELEASE OF...
 LPA RECEPTORS
 BIOLOGICAL RESPONSES
 LPA-INDUCED SIGNAL TRANSDUCTION
 LPA DEGRADATION
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 REFERENCES
 
In addition to binding to its cell surface receptors, LPA can also be subject to degradation in a living cell, curtailing the duration of LPA effects. There are two possible degradation pathways; deacylation (lysophospholipase) and dephosphorylation (lysophosphatase). Both pathways can modulate the LPA signal in the cell membrane. When radioactively labeled LPA was added to cultured luteal cells, only 26%–28% of the radioactivity was associated with LPA after 60 min [35]. Less than 9% was metabolized to phosphatidic acid, and 10%–14% was metabolized to free fatty acid. A significant quantity of radioactive LPA (45%–50%) was converted to monoacylglycerol [35]. These data may indicate the presence of LPA-degrading phosphatase activity in the plasma membrane. Existence of a phosphatase superfamily that can attenuate phospholipid signaling has been previously proposed [64]. Recently, a phosphatase that metabolizes LPA has been demonstrated in ovarian cancers [65]. Incubation of membranes from GnRH-sensitive ovarian cancers with the GnRH agonist buselerin induces a dose-dependent increase in the activity of the LPA-degrading phosphatase [65]. An LPA phosphatase has been purified from bovine brain cytosol [66]. It is not known whether this 44-kDa enzyme is the same enzyme responsible for dephosphorylation of LPA in the ovary.

Lipids such as LPA cannot move rapidly in an uncontrolled manner within the plasma membrane unless they are helped by an enzyme such as flipase, scramblase, or translocase. Therefore, a possible colocalization (intra- or extracellular) of both the lipid substrate and these enzymes must be considered [64]. The LPA-metabolizing enzymes are potentially important regulators of LPA signaling. In particular, the ecto-lipid-phosphatase (acting extracellularly) has been implicated as a possible negative regulator of LPA-induced mitogenic signals [67]. The LPA-degrading enzymes (LPA phospholipases, LPA phosphatases) are probably also actively involved in modulation of LPA signaling. These enzymes may influence the duration of the lipid signal and may also generate new potential signaling molecules, such as phoshatidic acid, diacylglycerol, or monoacylglycerol.


   CONCLUSION AND FUTURE PERSPECTIVES
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 ABSTRACT
 HISTORICAL PERSPECTIVE
 BIOCHEMISTRY OF LPA
 PRODUCTION AND RELEASE OF...
 LPA RECEPTORS
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 LPA-INDUCED SIGNAL TRANSDUCTION
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Although a clear picture is yet to emerge, the local importance of LPA in reproductive organs under both physiological and pathological conditions is well supported by published data. There is compelling evidence that LPA may be produced locally within the reproductive tissues; however, the metabolic pathways responsible for LPA synthesis remain obscure. Because most of the relevant enzymes have yet to be purified and characterized, it is not possible currently to define how LPA is synthesized. Further work is needed to clarify whether a single enzyme is responsible for LPA production or whether there is sequential activation of several phospholipases. Although, several prominent LPA receptors have been recognized or at least partially characterized in various reproductive tissues, we are just beginning to understand the variability of this receptor family. Detailed structure-activity relationships of various LPA receptor isoforms, distinctive expression patterns, and functional analysis are necessary to reveal the role of the various LPA receptors in the reproductive system. Because we are dealing with a novel receptor system, novelty in the transduction of LPA signal(s) can also be expected.

The mode of LPA action is a function of its local concentration, the differentiation status of the target cell, and its receptor status. Each of these aspects must be studied in detail because LPA may play more than one role within a particular tissue. Elucidation of these roles will significantly advances our understanding of the biological and pathological effects of this fascinating lipid.

Of special interest is the molecular mechanism responsible for the functional transition of a potential survival factor into an aggressive carcinogen. This identification of this mechanism will be both challenging and rewarding, will extend our knowledge of the biology of LPA, and will lead to identification of new and clinically useful pathological markers and development of possible therapeutic applications. Studies designed to determine the synthesis and degradation pathways and the mechanism of LPA action have already begun in many laboratories, and those being planned currently will soon throw more light on the physiological and pathological actions of this fascinating small phospholipid in reproductive tissues.


   ACKNOWLEDGMENTS
 
We thank our colleague Dr. Kevan Willey for a critical reading of the manuscript.


   FOOTNOTES
 
First decision: 20 August 2001.

1 Correspondence: L.T. Budnik, Institute for Hormone and Fertility Research, University of Hamburg, Grandweg 64, D-22529 Hamburg, Germany. FAX: 4940 56190864; budnik{at}ihf.de Back

Accepted: October 3, 2001.

Received: July 26, 2001.


   REFERENCES
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 ABSTRACT
 HISTORICAL PERSPECTIVE
 BIOCHEMISTRY OF LPA
 PRODUCTION AND RELEASE OF...
 LPA RECEPTORS
 BIOLOGICAL RESPONSES
 LPA-INDUCED SIGNAL TRANSDUCTION
 LPA DEGRADATION
 CONCLUSION AND FUTURE...
 REFERENCES
 

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