MINIREVIEW:
A Reassessment of the Low Molecular Weight Phospholipase A2 Gene Family in Mammals*

Jay A. Tischfield Dagger

From the Department of Medical and Molecular Genetics and The Walther Oncology Center, Indiana University School of Medicine, Indianapolis, Indiana 46202-5251

INTRODUCTION
Classification of Mammalian Low Molecular Weight PLA2
Low Molecular Weight PLA2 Genomics and Evolution
Revised View of PLA2 Gene Expression in Cell Signaling
Perspectives
FOOTNOTES
ACKNOWLEDGEMENTS
REFERENCES


INTRODUCTION

Phospholipase activity was first described in pancreatic juice and cobra venom at about the turn of the century. Phospholipase A2s (PLA2s)1 are those phospholipases that hydrolyze the sn-2 fatty acid acyl ester bond of phosphoglycerides to free fatty acid and lysophospholipids. PLA2s have been divided into several groups based on molecular weight, amino acid sequence and homology (e.g. position of Cys residues in the low molecular weight enzymes), calcium dependence, and cellular localization (see below). Two groups of ~14-kDa snake venom PLA2s, Group I from cobras and kraits and Group II from rattlesnakes and vipers, are well known. Until 1989, however, the only well characterized mammalian PLA2 was the ~14-kDa enzyme from pancreatic juice, which was classified as a Group IB enzyme (for reviews see Refs. 1 and 2). In 1989 two groups each described the gene for a ~14-kDa enzyme from synovial fluid and platelets, which is distinct from the pancreatic enzyme and was assigned to Group IIA. These publications engendered a relatively large literature on what is thought to be Group IIA PLA2, primarily because it is believed to be elevated in serum and exudates in certain inflammatory diseases, suggesting its involvement in the production of lipid mediators of inflammation (see below). Also, despite conflicting data concerning its physiologic substrate, it was recognized that Group IIA PLA2 has the potential to release arachidonic acid from membranes, which then may serve as the precursor of prostaglandins, thromboxanes, and prostacyclins via the cyclooxygenase pathway or leukotrienes and lipoxins via the lipoxygenase pathway (for review see Ref. 3). In 1994, our group described the cloning of genes and expression of cDNAs for two new mammalian ~14-kDa PLA2s (4-6). This brought the number of well described mammalian low molecular weight PLA2 genes and enzymes to four. This review summarizes what is now known about mammalian ~14-kDa PLA2s, particularly those that have been most recently described. The focus is on possible biological functions of each of the ~14-kDa PLA2s and functional relationships to the structurally unrelated, 85-kDa group IV cytosolic PLA2. I also review new data that force a reevaluation of a significant fraction of the large literature describing tissue distribution and metabolic functions of the mammalian Group IIA PLA2.


Classification of Mammalian Low Molecular Weight PLA2

The nomenclature of PLA2 enzyme groups distinguished on the basis of structural and other criteria has been reviewed by Dennis (1, 2) and adopted here. Since the first review of the subject, however, two new ~14-kDa mammalian PLA2s have been described (see below). Whereas many novel PLA2 activities and partial amino acid sequences have been reported, we reserve group or subgroup designations for mammalian ~14-kDa PLA2s with characterized genes and demonstrated expression. Further, we have made an effort to have the gene and enzyme group nomenclature correspond with the designation of genes for both existing and newly discovered PLA2s. Therefore, for example, the mouse PLA2 group IIA, IIC, and V genes have been designated Pla2g2a, Pla2g2c, and Pla2g5, respectively (7).

All of the ~14-kDa PLA2s contain an even number of Cys at characteristic positions, each of which pairs with another specific Cys to form a disulfide bridge, thus producing a rigid three-dimensional structure. Within group I, x-ray crystallography has demonstrated that enzymes from divergent sources such as snakes and mammals have quite similar crystal structures (1). It is likely that all of the low molecular weight PLA2s utilize a specific catalytic His, assisted by an Asp, to polarize a bound H2O, which then attacks the carbonyl group of the phospholipid substrate. Ca2+ is required to stabilize the transition state and is bound within the highly evolutionarily conserved "calcium binding loop" observed in all ~14-kDa PLA2s (1, 8).

Both group IA PLA2, found only in snakes, and group IB PLA2, which appears ubiquitously in mammals, have a disulfide bridge connecting Cys-11 to Cys-77 and a characteristic three-amino acid "elapid loop" composed of residues 54-56. The mammalian group IB PLA2 has 14 Cys residues and is secreted predominantly by the pancreas to function extracellularly in digestion (1, 3). Group IB PLA2 is also present in some nondigestive organs, suggesting a possible secondary role (9, 10). Group IIA PLA2, which has been described for many mammals, and group IIB PLA2, which has only been observed in the Gabon viper, also contain 14 Cys residues but, in contrast to the group I enzymes, lack the Cys-11 to Cys-77 disulfide bridge. All group II PLA2s have a C-terminal extension of 6 amino acids that terminates in a Cys joined to Cys-50 near the His-48 catalytic site. The mammalian group IIA has been reported to occur in relatively small amounts in mast cells, macrophages, and diverse tissues such as liver and spleen (3). It is also reported to occur in greater amounts in fluid from arthritic synovia and serum from patients with inflammatory diseases such as acute pancreatitis and sepsis (11). The group IIA enzyme is frequently referred to as "secreted PLA2," but this term lacks precision because the enzyme has also been localized within mitochondria (12), and other "secreted" PLA2s are now known. As described below, reports of expression of group IIA PLA2 in various cell types will require detailed reevaluation in light of new data that indicate some methods used for its detection also detect the more recently described group V PLA2.

The group IIC PLA2 gene has been characterized in rat and mouse (5, 13). It encodes a mature enzyme, with a calculated molecular mass of 14.8 kDa, which does not contain the Cys-11 to Cys-77 disulfide bridge or elapid loop characteristic of group I but does contain the 6-amino acid C-terminal extension characteristic of group II. The group IIC enzyme is distinguished from group IIA and group IIB enzymes in that it contains 16 Cys residues. Further, the group IIC enzyme from mouse and rat contains only 17 of the 18 amino acids that had been thought to be invariantly conserved in low molecular weight PLA2s (14, 15), Ile-9 being replaced by Val. Rodent group IIC PLA2 is highly expressed in adult but not prepubescent testis (5). In situ hybridization of testis tissue sections indicates that the group IIC gene is expressed mainly in pachytene spermatocytes, secondary spermatocytes, and round spermatids but not in spermatogonia, elongating spermatids, or Sertoli cells (13). The N-terminal portion of exon III is absent in the human group IIC PLA2 gene, and about 16% of alleles also exhibit a common nonsense mutation in exon II. Significantly, all other parts of the human group IIC gene appear potentially functional and highly homologous to the functional rodent genes, but there is no evidence for group IIC gene expression in human tissues. Thus, we conclude that the group IIC gene has recently evolved into a pseudogene in humans (7). It is not known whether there is compensatory activity of one of the other PLA2 genes in human testis or other tissues.

The group V PLA2 gene and its product have been characterized in human (4), rat (6), and mouse (16).2 The mature enzyme, with a calculated molecular mass of 13.6 kDa, contains neither the elapid loop of group I nor the 6-amino acid carboxyl extension of group II. Further, it contains only 12 of the Cys found in group I and II PLA2s. Thus, this second new ~14-kDa PLA2 has been placed into a new group known as group V3 (6). The group V PLA2 gene is expressed highly in heart, placenta, and, to a lesser extent, lung and liver (4, 6). Further, group V, rather than group IIA as was previously believed, appears to be the primary ~14-kDa PLA2 expressed by P388D1 macrophage-like cells and mast cells (see below). As is the case for the group IIA and IIC genes, the group V gene product is expressed initially as a prepeptide with the first 20 amino acids probably representing a signal peptide that is subsequently cleaved (4).

Some distinguishing properties of the ~14-kDa PLA2s are summarized in Table I. In addition, there are common features such as pH 7-9 activity optima and a requirement for about 1-10 mM Ca2+ for maximal activity (4-6). This latter property stands in contrast with the 85-kDa group IV enzyme, which is activated by Ca2+ concentrations in the micromolar range (for review see Ref. 1). However, there is one report that under certain conditions group IIA enzyme, but not group IB, achieves 50% of maximal response with 0.5 µM Ca2+ (17). It is also important to recognize that the demonstration of substrate preferences for each of the ~14-kDa PLA2s (e.g. Refs. 4-6) was merely intended to distinguish between the various groups of PLA2s at a particular assay pH and Ca2+ concentration. Because of inherent variation in the presentation of lipid substrate (1), such assay data should not be generalized to characterize activity in vivo.

Table I. Properties of ~14-kDa mammalian PLA2s


Characteristics Group
IBHuman IIAHuman IICRat VHuman

No. of amino acids in mature protein 126 124 130 118
No. of cysteines in mature protein 14 14 16 12
Pre/propeptide +/+ +/- +/? +/-
Level of mRNA expression Pancreas >>  lung Placenta > synovia = platelets Testis Heart > placenta > lung > liver


Low Molecular Weight PLA2 Genomics and Evolution

The human group IB PLA2 gene has been shown to reside on chromosome 12 (18), and the human groups IIA and V genes and group IIC pseudogene are tightly linked on chromosome 1p34-p36.1. Consistent with the human localization, the mouse group IIA, IIC, and V genes are also tightly linked and located on the distal region of chromosome 4, which is known to be syntenic with human 1p34-36.1. The data from radiation hybrids suggest that the human group IIA and group V genes are very close whereas the group IIC pseudogene is located about 1 centimorgan toward the centromere (7). The clustering of PLA2 genes invites speculation about possible complex coordinate regulation of expression as is the case for mammalian globin genes.

The amino acid coding regions of each of the ~14-kDa PLA2s are interrupted by 3 introns, which are almost identically positioned when the enzymes are compared in homologous alignment shown in Fig. 1 (4-6, 19-21). In addition, the human and rat group V (4, 6) and the mouse group IIA (22) gene have one upstream noncoding exon, and the rat group IIC gene has three upstream noncoding exons. The first two exons in the rat group IIC gene are alternatively transcribed in testis and brain mRNA (5). This amino acid alignment clearly suggests the common evolutionary origin of these genes. We propose the evolutionary scheme of ~14-kDa PLA2 gene duplication events shown in Fig. 2, which is a modification of Davidson and Dennis (14) in light of the subsequent discovery of groups IIC and V.4 Group V PLA2s exhibit 12 Cys residues that are identical in position to the 12 of 14 Cys residues common to Groups I and II. This suggests that group V is the progenitor to groups I and II. Group III PLA2s, which are found only in bees and some lizards, have 10 Cys residues and may have diverged from the common ancestral PLA2 before the divergence of invertebrates and vertebrates (14). The divergence of groups I and II may have occurred simultaneously or at different times. Group IIC PLA2 has 16 Cys residues, 14 of which are shared with group IIA and 12 of which are identical to all 12 Cys residues of group IIB (14). Therefore, we suggest that Group IIC diverged from a common group II ancestor with 14 Cys residues and that Groups IIA and IIB diverged at a later time.


Fig. 1. Comparison of cDNA-predicted amino acid sequences of ~14-kDa PLA2s. Alignment is based on sequence homology as determined by the DNAsis (version 3.0) program. PLA2 groups IB (19), 2A (20, 21), and V (4) are from human whereas group IIC (5) is from rat. Yellow indicates four identical amino acids at a particular position, red indicates three identical amino acids, and blue indicates two identical amino acids. Boxed amino acids are specified by codons that are interrupted by introns. The entire encoded sequence including pre/propeptide regions is shown. In this alignment, the mature enzymes begin at position 29.
[View Larger Version of this Image (59K GIF file)]


Fig. 2. Scheme for evolution of PLA2 genes leading to the major present day PLA2 types, as modified from Davidson and Dennis (14). Solid vertical lines indicate ancestral lines associated with individual genes. Branch points indicate duplication of a gene. Dashed vertical lines indicate possible radiative events, i.e. evidence for a gene duplication awaits evidence that differences are not the result of speciation in the limited number of species examined. Horizontal lines denote that at the time of emergence of the indicated life forms at least as many PLA2 genes existed as are intersected by the line. Vertical scaling is not correlated with time. The Solenoglypha are movable front-fanged snakes, and the Proteroglypha are fixed front-fanged snakes.
[View Larger Version of this Image (17K GIF file)]


Revised View of PLA2 Gene Expression in Cell Signaling

Although it is well documented that individual cells of different types contain multiple PLA2s (23-25), some understanding of how these different enzymes cooperate in receptor-coupled cellular activation has only recently emerged. In certain cell types, agonist-induced PLA2 activity can be either short term, long term, or biphasic, depending on the agonist or combination of agonists. These patterns are reflected in the spatial and temporal kinetics of arachidonic acid release and the subsequent production of eicosanoids. For example, in P388D1 macrophage-like cells and mast cells arachidonic acid release in response to certain agonist combinations can be shown to be biphasic and dependent on the activities of both group IV cytosolic PLA2 and a low molecular weight PLA2 that was, until recently, believed to be group IIA. Balsinde et al. (25) showed that P388D1 mouse cells stimulated with bacterial lipopolysaccharide and platelet-activating factor release arachidonic acid in two phases, an initial rapid accumulation inside of the cell within the first few minutes and a subsequent sustained phase of accumulation in the culture medium. It was subsequently shown that group IV PLA2 acting intracellularly is responsible for the initial, rapid release of arachidonic acid whereas a ~14-kDa PLA2 acting on the outer surface of the cell was responsible for the greater, mostly extracellular, sustained release of arachidonic acid (26). The data also suggested that intracellular and extracellular arachidonic acid arise from different phospholipid pools within the cell. Most recently, Balboa et al. (16) showed that the ~14-kDa enzyme in P388D1 cells associated with the sustained release of arachidonic acid is group V and not group IIA as was previously believed. Whereas there was no detectable mRNA for PLA2 groups IIA or IIC in either resting or activated cells, the group V mRNA was abundant in both. Antisense oligonucleotides for the highly conserved Ca2+-binding domain of rat group IIA mRNA, which had previously been used in experiments that were interpreted as implicating group IIA (27), were shown to act in a nonspecific way on group V. However, more specific antisense oligonucleotides against a unique exon region of mouse group V PLA2 blocked expression by about 60-70%, whereas the control sense oligonucleotide was without effect. Interestingly, a polyclonal antiserum against human synovial fluid PLA2, presumably group IIA, was used to successfully detect expression of the P388D1 cell surface PLA2. This result indicates that this antiserum, and such antisera in general, may not be able to distinguish between PLA2 groups IIA and V (see below).

The agonist-mediated activation of mast cells includes degranulation and release of ligands such as serotonin and histamine and is similar in several key respects to the biphasic response observed in P388D1 cells. Bone marrow-derived mouse mast cells stimulated by antigen aggregation of high affinity IgE receptors on the cell surface (28) or with c-kit ligand, IL-10, and IL-1beta or by priming with c-kit ligand and IL-10 followed by IgE and antigen activation (29) exhibit an immediate phase of arachidonic acid release during the first 10-20 min followed by a delayed phase from hours 2 to 7. These phases of arachidonic acid release are reflected by early and late phases of prostaglandin D2 (PGD2) synthesis, which are mediated by the constitutive prostaglandin synthase 1 (PGS1) and the inducible prostaglandin synthase 2 (PGS2), respectively (28, 29). However, there is controversy as to which PLA2s provide the arachidonic acid for early and late PGD2 synthesis. The results from one group indicate that a ~14-kDa PLA2 coupled to PGS1 is responsible for early phase PGD2 synthesis whereas the group IV PLA2 coupled to PGS2 is responsible for late phase PGD2 synthesis (30). In contrast, a second group's data suggest the reverse, i.e. a ~14-kDa PLA2 coupled with PGS2 is responsible for late phase PGD2 production (31). These apparently contradictory conclusions may be a consequence of differences in experimental methodologies. Both groups, however, clearly demonstrate that one phase of PGD2 synthesis is a consequence of the activity of a low molecular weight PLA2 that was initially believed to be group IIA. As described below, we now know that Group IIA PLA2 is not involved in mast cell activation.

The involvement of specific ~14-kDa PLA2s in mast cell activation has been clarified by the discovery of a naturally occurring mutation in the group IIA PLA2 gene of many inbred mouse strains. The "murine intestinal neoplasia" or ApcMin gene is the ortholog of the human APC gene, which has been shown to be mutated in a hereditary form of colon cancer known as familial adenomatous polyposis coli. The number of intestinal tumors is increased in mouse strains that also carry the Mom1 (modifier of Min-1) mutation that is likely a frameshift mutation in the gene for group IIA PLA2, such that Mom1 homozygotes (Pla2g2a-/- genotype) express little or no group IIA mRNA or protein (22, 32). Bingham et al. (31) demonstrated that mast cells from Mom1 homozygotes exhibit a normal biphasic response to ligand stimulation and that one phase of this response, previously attributed to group IIA PLA2, must therefore be mediated by another PLA2 that has some properties in common with the group IIA enzyme. Contemporaneously, Reddy et al. (33) demonstrated that mast cells from both Mom1 homozygotes and normal mice exhibit biphasic responses to activation and that both early and delayed PGD2 production and ~14-kDa PLA2 secretion into the medium are similar in both genotypes. Neither Mom1 homozygotes nor normal cells exhibited any group IIA or group IIC mRNA as determined by Northern blotting and the more sensitive technique of reverse transcriptase/polymerase chain reaction amplification. However, cells of both genotypes exhibited Group V mRNA, and PLA2 activity was secreted into the medium as determined by assay, binding to monoclonal antibody directed against recombinant human group IIA PLA2, and inhibition by a drug (SB203347) developed as an inhibitor of the group IIA enzyme (33). Also, it was shown that the PLA2 secreted from both Pla2g2a+/+ and Pla2g2a-/- mast cells could release arachidonic acid in distal mouse Swiss 3T3 cells, which then utilized this arachidonic acid for prostaglandin synthesis (33, 34). These data clearly implicate involvement of the group V PLA2 in one phase of mast cell immune activation.

A biphasic response implicating both the group IV and a ~14-kDa PLA2 is also observed in cytokine-stimulated rat mesangial cells (35, 36) and human endothelial cells (37). Clearly, the precise identity of the ~14-kDa PLA2 will have to be reevaluated in light of the above data from P388D1 and mast cells. High levels of ~14-kDa PLA2, believed to be group IIA, have been described in serum and tissue exudates from patients with a variety of inflammatory diseases including arthritis, pancreatitis, adult respiratory distress syndrome, and septic shock (20, 38, 39, 41-45). The identification of group IIA PLA2 in these diseases has most frequently been based on enzymatic assays, use of inhibitors developed against group IIA PLA2, or immunologic detection (cf. Ref. 46). The data of Balboa et al. (16), Bingham et al. (31), and Reddy et al. (33) clearly indicate that these criteria are inadequate for distinguishing between the group IIA and group V PLA2s. Thus, an entire literature will require reevaluation. Furthermore, existing and new PLA2 inhibitors will require evaluation with regard to their activity against both the group IIA and group V enzymes (47). A recent publication by Tseng et al. (48) suggests that it may be possible to design specific peptide inhibitors for each of the ~14-kDa PLA2s based on their individual beta -loop pentapeptide sequences.


Perspectives

Knowledge of at least three (humans) or four (rodents) related genes encoding distinct ~14-kDa PLA2s that are expressed in a tissue-specific manner begs the question of whether or not there are differences among the PLA2s that relate to function in vivo. A first step toward answering this question will be determination of the expression of each PLA2 in a wide variety of cell types and under different circumstances (e.g. activation). This, in turn, may require technical innovations such as more specific inhibitors or antibodies for immunocytochemistry. Naturally occurring (e.g. Mom1) or targeted gene knockouts could also be useful to this end, especially if, as has been the case to date (33), there is no compensatory activation of another PLA2 gene. One should be cautious, however, in postulating a molecular basis for a phenotype in knockout mice. For example, cyclooxygenase-2 gene knockout mice or mice treated with specific cyclooxygenase-2 inhibitors exhibit a reduced level of ApcMin-related intestinal polyposis (49). One might have anticipated the opposite result from what is known about Mom1 mice, given that arachidonic acid is the substrate for cyclooxygenase-2. Mom1 mice, which exhibit increased intestinal polyposis, may have reduced levels of arachidonic acid release in intestinal cells, which clearly express the group IIA enzyme in wild-type mice (16). Also, our consideration of phospholipid metabolism should include possible functions of newly discovered PLA2-like genes, such as PLA2L mapped to human chromosome 8q24 (50).

Finally, the gene encoding a receptor for PLA2 has been cloned from cow (51), rabbit (52), and human (53). These homologous receptors are composed of about 1460 amino acids and are structurally related to the macrophage mannose receptor (51). Whereas the cow and rabbit receptors bind porcine group IB PLA2 with high affinity and the rabbit receptor binds group IIA PLA2 with high but somewhat lesser affinity, the human kidney receptor has only weak affinity for group IB and little affinity for group IIA (53). The human PLA2 receptor is highly expressed in diverse tissues such as kidney, lung, placenta, and skeletal muscle, a pattern that is different from rabbit. Humans also exhibit a soluble form of the receptor not reported for the other species (53), in addition to the membrane-bound form. The initial view based on the research in cow was that the PLA2 receptor mediated extrapancreatic group IB PLA2-induced DNA synthesis, contraction, eicosanoid production, and chemokinetic cell migration (see Ref. 51), but the lack of receptor affinity for group IB PLA2 in humans does not support this idea (53). The critical region(s) in PLA2 for binding to the receptor appears to reside within the Ca2+-binding domain (40), which exhibits relatively high homology among all ~14-kDa PLA2s (1, 15). There are, as yet, no reports of experiments testing the binding of group IIC or group V PLA2 to this receptor. It is possible that either one or both of these enzymes will prove to be a natural ligand for the PLA2 receptor in a particular species, suggesting novel functions for these enzymes. The PLA2 receptor has also been implicated in the induction of group IIA PLA2 mRNA transcription by the group IB pancreatic enzyme in rat mesangial cells (36). Perhaps the PLA2 receptor also mediates cross-talk between additional ~14-kDa PLA2s in a cell type- or species-specific manner.


FOOTNOTES

*   This minireview will be reprinted in the 1997 Minireview Compendium, which will be available in December, 1997. This is the fifth article of six in "A Thematic Series on Phospholipases." This work was supported by National Institutes of Health Grants R01 GM 38185 and P01 ES05652-06.
Dagger    To whom correspondence should be addressed: Dept. of Medical and Molecular Genetics, Indiana University School of Medicine, 975 West Walnut St., IB-130, Indianapolis, IN 46202-5251. Tel.: 317-274-5738; Fax: 317-274-1069; E-mail: jay{at}medgen.iupui.edu.
1   The abbreviations used are: PLA2, phospholipase A2; IL, interleukin; PGS, prostaglandin synthase; PGD2, prostaglandin D2.
2   M. V. Winstead and J. A. Tischfield, unpublished results.
3   Dennis (1) numbered the well characterized PLA2s in the order of their discovery and clear characterization. Thus, the 85-kDa cytosolic PLA2 is group IV according to his nomenclature.
4   J. Chen and J. A. Tischfield, unpublished data.

ACKNOWLEDGEMENTS

I thank Michelle V. Winstead for Fig. 1 and helpful comments, and Drs. E. A. Dennis and H. R. Herschman for critically reading the manuscript.


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