Mechanisms of lysophosphatidic acid 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)
A family of phospholipid autacoids: occurrence
Prog. Lipid Res.
(1995)Bioactive lysophospholipids and their G protein-coupled receptors
Exp. Cell Res.
(1999)- et al.
Molecular mechanisms of lysophosphatidic acid action
Prog. Lipid Res.
(2003) - et al.
Characterization of a novel subtype of human G protein-coupled receptor for lysophosphatidic acid
J. Biol. Chem.
(1998) - et al.
Molecular cloning and characterization of a novel human G-protein-coupled receptor, EDG7, for lysophosphatidic acid [In Process Citation]
J. Biol. Chem.
(1999) - et al.
Identification of p2y9/GPR23 as a Novel G protein-coupled receptor for lysophosphatidic acid, structurally distant from the Edg family
J. Biol. Chem.
(2003) - et al.
Lysophosphatidic acid-induced mitogenesis is regulated by lipid phosphate phosphatases and is Edg-receptor independent
J. Biol. Chem.
(2001) - et al.
Lysophosphatidates bound to serum albumin activate membrane currents in Xenopus oocytes and neurite retraction in PC12 pheochromocytoma cells
J. Biol. Chem.
(1992) - et al.
Multiple mechanisms linked to platelet activation result in lysophosphatidic acid and sphingosine-1-phosphate generation in blood
J. Biol. Chem.
(2002) - et al.
Lysophosphatidic acid, a growth factor-like lipid, in the saliva
J. Lipid Res.
(2002)
Lysophosphatidic acid (LPA) receptors are activated differentially by biological fluids: possible role of LPA-binding proteins in activation of LPA receptors
FEBS Lett
Phosphatidic and lysophosphatidic acid production in phospholipase C- and thrombin-treated platelets. Possible involvement of a platelet lipase
Biochimie
Identification of the molecular species of lysophosphatidic acid produced when platelets are stimulated by thrombin
Biochim. Biophys. Acta
Lysophosphatidic acid as a phospholipid mediator: pathways of synthesis
FEBS Lett.
Secretory phospholipase A2 generates the novel lipid mediator lysophosphatidic acid in membrane microvesicles shed from activated cells
Cell
Phorbol 12-myristate 13-acetate stimulates lysophosphatidic acid secretion from ovarian and cervical cancer cells but not from breast or leukemia cells
Gynecol. Oncol.
Role for 18:1 lysophosphatidic acid as an autocrine mediator in prostate cancer cells
J. Biol. Chem.
Acyltransferases of de novo glycerophospholipid biosynthesis
Prog. Lipid Res.
Direct quantitative analysis of lysophosphatidic acid molecular species by stable isotope dilution electrospray ionization liquid chromatography-mass spectrometry
Anal. Biochem.
Lysophosphatidic acid (LPA) receptors of the EDG family are differentially activated by LPA species—structure-activity relationship of cloned LPA receptors
FEBS Lett.
Metabolic fate of platelet-activating factor in the rat enterocyte: the role of a specific lysophospholipase D
Arch Biochem Biophys
Lysophospholipase D
Methods Enzymol
Studies of lysophospholipase D of rat liver and other tissues
Arch Biochem Biophys
Physiological and pathophysiological roles of lysophosphatidic acids produced by secretory lysophospholipase D in body fluids
Biochim. Biophys. Acta
Increased formation of lysophosphatidic acids by lysophospholipase D in serum of hypercholesterolemic rabbits
J. Lipid Res.
Identification of human plasma lysophospholipase D, a lysophosphatidic acid-producing enzyme, as autotaxin, a multifunctional phosphodiesterase
J. Biol. Chem.
Identification, purification, and partial sequence analysis of autotaxin, a novel motility-stimulating protein
J Biol Chem
Autotaxin, tumor motility-stimulating exophosphodiesterase
Adv. Enzyme Regul.
Induction of in vitro tumor cell invasion of cellular monolayers by lysophosphatidic acid or phospholipase D
Biochem. Biophys. Res. Commun.
Modulation of intestinal epithelial wound healing in vitro and in vivo by lysophosphatidic acid
Gastroenterology
Autotaxin is an exoenzyme possessing 5′-nucleotide phosphodiesterase/ATP pyrophosphatase and ATPase activities
J. Biol. Chem.
Stimulation of tumor cell motility linked to phosphodiesterase catalytic site of autotaxin
J. Biol. Chem.
Rac activation by lysophosphatidic acid LPA1 receptors through the guanine nucleotide exchange factor Tiam1
J. Biol. Chem.
Exogenous phospholipase D generates lysophosphatidic acid and activates Ras, Rho and Ca2+ signaling pathways
Curr. Biol.
Lecithin cholesterol acyltransferase
Biochim. Biophys. Acta
Serine phospholipid-specific phospholipase A that is secreted from activated platelets. A new member of the lipase family
J. Biol. Chem.
Membrane sidedness of biosynthetic pathways involved in the production of lysophosphatidic acid
Adv Enzyme Regul
Diversity and regulatory functions of mammalian secretory phospholipase A2s
Adv. Immunol.
Structure and function of phosphatidylserine-specific phospholipase A1
Biochim. Biophys. Acta
Cloning of a phosphatidic acid-preferring phospholipase A1 from bovine testis
J. Biol. Chem.
A novel phospholipase A1 with sequence homology to a mammalian Sec23p-interacting protein, p125
J. Biol. Chem.
p125 is a novel mammalian Sec23p-interacting protein with structural similarity to phospholipid-modifying proteins
J. Biol. Chem.
Phospholipase A2 enzymes
Prostaglandins Other Lipid Mediat.
Phospholipase A2 activity specific for phosphatidic acid. A possible mechanism for the production of arachidonic acid in platelets
J. Biol. Chem.
Role of phospholipase D in agonist-stimulated lysophosphatidic acid synthesis by ovarian cancer cells
J. Lipid Res.
Regulation of phospholipase D
FEBS Lett.
A novel phosphatidic acid-selective phospholipase A1 that produces lysophosphatidic acid
J. Biol. Chem.
A novel arachidonic acid-selective cytosolic PLA2 contains a Ca(2+)-dependent translocation domain with homology to PKC and GAP
Cell
A novel calcium-independent phospholipase A2, cPLA2-gamma
J. Biol. Chem.
Molecular cloning of two new human paralogs of 85-kDa cytosolic phospholipase A2
J Biol Chem
Cited by (261)
Lysophospholipids and their producing enzymes: Their pathological roles and potential as pathological biomarkers
2023, Pharmacology and TherapeuticsEmerging roles of phospholipases and lysophosphatidic acid in ovarian tumorigenesis and their therapeutic targeting
2023, Phospholipases in Physiology and Pathology: Volumes 1-7Role of phospholipase A2 in cancer
2023, Phospholipases in Physiology and Pathology: Volumes 1-7An insight of molecular paradigm of phospholipase D on cervical cancer
2023, Phospholipases in Physiology and Pathology: Volumes 1-7The development of modulators for lysophosphatidic acid receptors: A comprehensive review
2021, Bioorganic ChemistryRole for CCN1 in lysophosphatidic acid response in PC-3 human prostate cancer cells
2024, Journal of Cell Communication and Signaling