Mechanisms of lysophosphatidic acid production

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Abstract

Lysophosphatidic acid is one of the most attractive phospholipid mediator with multiple biological functions and is implicated in various human diseases. In the past ten years much has been learned about the physiological roles of LPA through series of studies on LPA actions and its receptors. However, the molecular mechanisms of LPA have been poorly understood. LPA is produced in various conditions both in cells and in biological fluids, where multiple synthetic reactions occur. At least two pathways are postulated. In serum and plasma, LPA is mainly converted from lysophospholipids. By contrast, in platelets and some cancer cells, LPA is converted from phosphatidic acid. In each pathway, at least two phospholipase activities are required: phospholipase A1 (PLA1)/PLA2 plus lysophospholipase D (lysoPLD) activities are involved in the first pathway and phospholipase D (PLD) plus PLA1/PLA2 activities are involved in the second pathway. Now multiple phospholipases are identified that account for PLA1, PLA2, PLD, and lysoPLD activities. In the absence of specific inhibitors and genetically modified animals and individuals, the contribution of each phospholipase to LPA production can not be easily determined. However, apparently certain extracellular phospholipases such as secretory PLA2 (sPLA2-IIA), membrane-associated PA-selective PLA1 (mPA-PLA1), lecithin-cholesterol acyltransferase (LCAT), and lysoPLD are involved in LPA production.

Introduction

Lysophosphatidic acid (LPA) is a simple lipid with a phosphate, a glycerol, and a fatty acid in its structure [1], [2], [3]. In spite of its simple structure, it evokes various cellular responses in various cell types including cellular proliferation, prevention of apoptosis, cell migration, cytokine and chemokine secretion, platelet aggregation, smooth muscle contraction, and neurite retraction. LPA also induces transformation and cellular proliferation of smooth muscle cells. Thus, LPA has been implicated in certain human diseases such as arteriosclerosis [4], [5] and cancer cell invasion [6]. Most of these LPA actions are mediated by G protein-coupled receptors (GPCR) that are specific for LPA. At least four GPCRs have been identified so far (LPA1/EDG2, LPA2/EDG4, LPA3/EDG7, and the recently identified GPR23/p2y9/ LPA4) [7], [8], [9], [10], [11]. The former three receptors share about 50% identities with each other at the amino acid level and form part of the endothelial differentiation gene family. The physiological roles of these receptors are not fully understood. However, studies of LPA receptor-null mice suggest that the receptors are needed for normal development [12], [13]. Non-GPCR pathways have been also proposed [14], [15]. In the past ten years, much has been learned about the physiological roles of LPA through a series of studies on LPA actions and its receptors. However, the molecular mechanisms and enzymes involved in LPA production are poorly understood. Two major pathways for LPA production are shown in Fig. 1, although other pathways may be possible. This review describes the mechanisms of LPA production and summarizes recent advances in this field.

Section snippets

LPA in biological fluids

Significant amounts of LPA (∼μM level) have been detected extracellularly in biological fluids such as serum [16], [17], [18], [19], saliva [20], seminal fluid [21], follicular fluid [22], hen egg white [23] and ascites from ovarian cancer patients [24] (Table 1). Among them, serum is the best characterized source of LPA [16], [17], [19]. Interestingly, the levels in freshly prepared plasma are much lower than that in serum (see below) [16], [19]. For this reason it has been proposed that LPA

Diverse phospholipases are involved in LPA production

As described above, LPA is produced through at least two pathways. In serum and plasma, LPA is mainly converted from LPLs (Fig. 1, Fig. 2). By contrast, in platelets and some cancer cells, LPA is converted from PA (Fig. 1, Fig. 3). In each pathway, at least two phospholipase activities are required: PLA1/PLA2 plus lysoPLD activities are involved in the first pathway and phospholipase D (PLD) plus PLA1/PLA2 activities are involved in the second pathway. It should be stressed that each activity

LysoPLD, a key enzyme of LPA production in serum

As mentioned above, serum is the main source of LPA and proposed pathways for its production [18], [19] are illustrated in Fig. 2. The main pathway for LPA production in serum or plasma can be separated into two steps: generation of LPLs and subsequent conversion of LPLs to LPA. PLA1 or PLA2 activity is involved in the first step and lysoPLD activity is involved in the second step. Among the phospholipases listed in Table 2, extracellular enzymes are the most likely candidates for LPA-producing

Phospholipases involved in generation of LPLs

LPLs are the substrate of lysoPLD. Where do LPLs come from and how are they synthesized? There are multiple pathways for LPLs generation. LPLs are generated in serum or plasma. In addition, some types of cells such as hepatoma cells and activated platelets release LPLs (mainly LPC).

Mechanisms of LPA production in cells

In contrast to the mechanism of LPA production in serum and plasma, the mechanisms of LPA production in cells are still ambiguous. LPA production in biological fluids by lysoPLD appears to be unregulated because in most cases both substrates (LPLs) and enzyme (lysoPLD) pre-exist. On the other hand, the major advantage of cellular LPA production is that it is tightly regulated. LPA is generated as a result of cellular activation induced by various stimuli (Section 2.2; Table 1). The major

Concluding remarks

We have asked where and under what conditions LPA is synthesized and made available to target cells. Now we understand there are multiple pathways for LPA synthesis and have identified possible enzymes that participate in these pathways. Our next goal is to evaluate each synthetic pathway in vivo.

References (103)

  • K Hama et al.

    Lysophosphatidic acid (LPA) receptors are activated differentially by biological fluids: possible role of LPA-binding proteins in activation of LPA receptors

    FEBS Lett

    (2002)
  • G Mauco et al.

    Phosphatidic and lysophosphatidic acid production in phospholipase C- and thrombin-treated platelets. Possible involvement of a platelet lipase

    Biochimie

    (1978)
  • J.M Gerrard et al.

    Identification of the molecular species of lysophosphatidic acid produced when platelets are stimulated by thrombin

    Biochim. Biophys. Acta

    (1989)
  • F Gaits et al.

    Lysophosphatidic acid as a phospholipid mediator: pathways of synthesis

    FEBS Lett.

    (1997)
  • O Fourcade et al.

    Secretory phospholipase A2 generates the novel lipid mediator lysophosphatidic acid in membrane microvesicles shed from activated cells

    Cell

    (1995)
  • Z Shen et al.

    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)
  • Y Xie et al.

    Role for 18:1 lysophosphatidic acid as an autocrine mediator in prostate cancer cells

    J. Biol. Chem.

    (2002)
  • L Dircks et al.

    Acyltransferases of de novo glycerophospholipid biosynthesis

    Prog. Lipid Res.

    (1999)
  • D.L Baker et al.

    Direct quantitative analysis of lysophosphatidic acid molecular species by stable isotope dilution electrospray ionization liquid chromatography-mass spectrometry

    Anal. Biochem.

    (2001)
  • K Bandoh et al.

    Lysophosphatidic acid (LPA) receptors of the EDG family are differentially activated by LPA species—structure-activity relationship of cloned LPA receptors

    FEBS Lett.

    (2000)
  • M Furukawa et al.

    Metabolic fate of platelet-activating factor in the rat enterocyte: the role of a specific lysophospholipase D

    Arch Biochem Biophys

    (1995)
  • R.L Wykle et al.

    Lysophospholipase D

    Methods Enzymol

    (1991)
  • R.L Wykle et al.

    Studies of lysophospholipase D of rat liver and other tissues

    Arch Biochem Biophys

    (1977)
  • A Tokumura

    Physiological and pathophysiological roles of lysophosphatidic acids produced by secretory lysophospholipase D in body fluids

    Biochim. Biophys. Acta

    (2002)
  • A Tokumura et al.

    Increased formation of lysophosphatidic acids by lysophospholipase D in serum of hypercholesterolemic rabbits

    J. Lipid Res.

    (2002)
  • A Tokumura et al.

    Identification of human plasma lysophospholipase D, a lysophosphatidic acid-producing enzyme, as autotaxin, a multifunctional phosphodiesterase

    J. Biol. Chem.

    (2002)
  • M.L Stracke et al.

    Identification, purification, and partial sequence analysis of autotaxin, a novel motility-stimulating protein

    J Biol Chem

    (1992)
  • M.L Stracke et al.

    Autotaxin, tumor motility-stimulating exophosphodiesterase

    Adv. Enzyme Regul.

    (1997)
  • F Imamura et al.

    Induction of in vitro tumor cell invasion of cellular monolayers by lysophosphatidic acid or phospholipase D

    Biochem. Biophys. Res. Commun.

    (1993)
  • A Sturm et al.

    Modulation of intestinal epithelial wound healing in vitro and in vivo by lysophosphatidic acid

    Gastroenterology

    (1999)
  • T Clair et al.

    Autotaxin is an exoenzyme possessing 5′-nucleotide phosphodiesterase/ATP pyrophosphatase and ATPase activities

    J. Biol. Chem.

    (1997)
  • H.Y Lee et al.

    Stimulation of tumor cell motility linked to phosphodiesterase catalytic site of autotaxin

    J. Biol. Chem.

    (1996)
  • F Van Leeuwen et al.

    Rac activation by lysophosphatidic acid LPA1 receptors through the guanine nucleotide exchange factor Tiam1

    J. Biol. Chem.

    (2003)
  • M van Dijk et al.

    Exogenous phospholipase D generates lysophosphatidic acid and activates Ras, Rho and Ca2+ signaling pathways

    Curr. Biol.

    (1998)
  • A Jonas

    Lecithin cholesterol acyltransferase

    Biochim. Biophys. Acta

    (2000)
  • T Sato et al.

    Serine phospholipid-specific phospholipase A that is secreted from activated platelets. A new member of the lipase family

    J. Biol. Chem.

    (1997)
  • F le Balle et al.

    Membrane sidedness of biosynthetic pathways involved in the production of lysophosphatidic acid

    Adv Enzyme Regul

    (1999)
  • M Murakami et al.

    Diversity and regulatory functions of mammalian secretory phospholipase A2s

    Adv. Immunol.

    (2001)
  • J Aoki et al.

    Structure and function of phosphatidylserine-specific phospholipase A1

    Biochim. Biophys. Acta

    (2002)
  • H.N Higgs et al.

    Cloning of a phosphatidic acid-preferring phospholipase A1 from bovine testis

    J. Biol. Chem.

    (1998)
  • K Nakajima et al.

    A novel phospholipase A1 with sequence homology to a mammalian Sec23p-interacting protein, p125

    J. Biol. Chem.

    (2002)
  • K Tani et al.

    p125 is a novel mammalian Sec23p-interacting protein with structural similarity to phospholipid-modifying proteins

    J. Biol. Chem.

    (1999)
  • I Kudo et al.

    Phospholipase A2 enzymes

    Prostaglandins Other Lipid Mediat.

    (2002)
  • M.M Billah et al.

    Phospholipase A2 activity specific for phosphatidic acid. A possible mechanism for the production of arachidonic acid in platelets

    J. Biol. Chem.

    (1981)
  • C Luquain et al.

    Role of phospholipase D in agonist-stimulated lysophosphatidic acid synthesis by ovarian cancer cells

    J. Lipid Res.

    (2003)
  • J.H Exton

    Regulation of phospholipase D

    FEBS Lett.

    (2002)
  • H Sonoda et al.

    A novel phosphatidic acid-selective phospholipase A1 that produces lysophosphatidic acid

    J. Biol. Chem.

    (2002)
  • J.D Clark et al.

    A novel arachidonic acid-selective cytosolic PLA2 contains a Ca(2+)-dependent translocation domain with homology to PKC and GAP

    Cell

    (1991)
  • K.W Underwood et al.

    A novel calcium-independent phospholipase A2, cPLA2-gamma

    J. Biol. Chem.

    (1998)
  • R.T Pickard et al.

    Molecular cloning of two new human paralogs of 85-kDa cytosolic phospholipase A2

    J Biol Chem

    (1999)
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