A Reassessment of the Low Molecular Weight Phospholipase A2 Gene Family in Mammals (1997)

Phospholipase activity was first described in pancreatic juice and cobra venom at about the turn of the century. Phospholipase A2s (PLA2s) 1The abbreviations used are: PLA2, phospholipase A2; IL, interleukin; PGS, prostaglandin synthase; PGD2, prostaglandin D2. 1The abbreviations used are: PLA2, phospholipase A2; IL, interleukin; PGS, prostaglandin synthase; PGD2, prostaglandin D2. 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. 1Dennis E.A. J. Biol. Chem. 1994; 269: 13057-13060Abstract Full Text PDF PubMed Google Scholar and 2Dennis E.A. Trends Biochem. Sci. 1997; 22: 1-2Abstract Full Text PDF PubMed Scopus (756) Google Scholar). 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. 3Kudo I. Murakami M. Hara S. Inoue K. Biochim. Biophys. Acta. 1993; 117: 217-231Crossref Scopus (371) Google Scholar). In 1994, our group described the cloning of genes and expression of cDNAs for two new mammalian ∼14-kDa PLA2s (4Chen J. Engle S.J. Seilhamer J.J. Tischfield J.A. J. Biol. Chem. 1994; 269: 2365-2368Abstract Full Text PDF PubMed Google Scholar, 5Chen J. Engle S.J. Seilhamer J.J. Tischfield J.A. J. Biol. Chem. 1994; 269: 23018-23024Abstract Full Text PDF PubMed Google Scholar, 6Chen J. Engle S.J. Seilhamer J.J. Tischfield J.A. Biochim. Biophys. Acta. 1994; 1215: 115-120Crossref PubMed Scopus (50) Google Scholar). 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 PLA2The nomenclature of PLA2 enzyme groups distinguished on the basis of structural and other criteria has been reviewed by Dennis (1Dennis E.A. J. Biol. Chem. 1994; 269: 13057-13060Abstract Full Text PDF PubMed Google Scholar, 2Dennis E.A. Trends Biochem. Sci. 1997; 22: 1-2Abstract Full Text PDF PubMed Scopus (756) Google Scholar) 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 PLA2group IIA, IIC, and V genes have been designated Pla2g2a,Pla2g2c, and Pla2g5, respectively (7Tischfield J.A. Xia Y-R. Shih D.M. Klisak I. Chen J. Engle S.J. Siakotos A.N. Winstead M.V. Seilhamer J.J. Allamand V. Gyapay G. Lusis A.J. Genomics. 1996; 32: 328-333Crossref PubMed Scopus (91) Google Scholar).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 (1Dennis E.A. J. Biol. Chem. 1994; 269: 13057-13060Abstract Full Text PDF PubMed Google Scholar). 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 (1Dennis E.A. J. Biol. Chem. 1994; 269: 13057-13060Abstract Full Text PDF PubMed Google Scholar, 8Wery L-P. Schevitz R.W. Clawson D.K. Bobbitt J.L. Dow E.R. Gamboa G. Goodson Jr., T. Hermann R.B. Kramer R.M. McClure D.B. Mihelich E.D. Putnam J.E. Sharp J.D. Stark D.H. Teater C. Warrick M.W. Jones N.D. Nature. 1991; 352: 79-82Crossref PubMed Scopus (198) Google Scholar).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 (1Dennis E.A. J. Biol. Chem. 1994; 269: 13057-13060Abstract Full Text PDF PubMed Google Scholar, 3Kudo I. Murakami M. Hara S. Inoue K. Biochim. Biophys. Acta. 1993; 117: 217-231Crossref Scopus (371) Google Scholar). Group IB PLA2 is also present in some nondigestive organs, suggesting a possible secondary role (9Sakata T. Nakamura E. Tsuruta Y. Tamaki M. Teraoka H. Tojo H. Ono T. Okamoto M. Biochim. Biophys. Acta. 1989; 1007: 124-126Crossref PubMed Scopus (101) Google Scholar, 10Kortesuo P.T. Hietaranta A.J. Jämiä M. Hirsimäki P. Nevalainen T.J. Int. J. Pancreatol. 1993; 13: 113-118Google Scholar). 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 (3Kudo I. Murakami M. Hara S. Inoue K. Biochim. Biophys. Acta. 1993; 117: 217-231Crossref Scopus (371) Google Scholar). 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 (11Nevalainen T.J. Clin. Chem. 1993; 39: 2453-2459Crossref PubMed Scopus (191) Google Scholar). 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 (12Van den Bosch H. Aarsman A.J. de Jong J.G.N. Arnoldussen E. Neys F.W. Wassenaar P.D. J. Biol. Chem. 1989; 364: 10008-10014Google Scholar), 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 (5Chen J. Engle S.J. Seilhamer J.J. Tischfield J.A. J. Biol. Chem. 1994; 269: 23018-23024Abstract Full Text PDF PubMed Google Scholar, 13Chen J. Shao C. Lazar V. Srivastava C.H. Lee W-H. Tischfield J.A. J. Cell. Biochem. 1997; 64: 369-375Crossref PubMed Scopus (35) Google Scholar). 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 (14Davidson F.F. Dennis E.A. J. Mol. Evol. 1990; 31: 228-238Crossref PubMed Scopus (292) Google Scholar, 15Heinrikson R.L. Methods Enzymol. 1991; 197: 201-214Crossref PubMed Scopus (65) Google Scholar), Ile-9 being replaced by Val. Rodent group IIC PLA2 is highly expressed in adult but not prepubescent testis (5Chen J. Engle S.J. Seilhamer J.J. Tischfield J.A. J. Biol. Chem. 1994; 269: 23018-23024Abstract Full Text PDF PubMed Google Scholar). 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 (13Chen J. Shao C. Lazar V. Srivastava C.H. Lee W-H. Tischfield J.A. J. Cell. Biochem. 1997; 64: 369-375Crossref PubMed Scopus (35) Google Scholar). 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 (7Tischfield J.A. Xia Y-R. Shih D.M. Klisak I. Chen J. Engle S.J. Siakotos A.N. Winstead M.V. Seilhamer J.J. Allamand V. Gyapay G. Lusis A.J. Genomics. 1996; 32: 328-333Crossref PubMed Scopus (91) Google Scholar). 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 (4Chen J. Engle S.J. Seilhamer J.J. Tischfield J.A. J. Biol. Chem. 1994; 269: 2365-2368Abstract Full Text PDF PubMed Google Scholar), rat (6Chen J. Engle S.J. Seilhamer J.J. Tischfield J.A. Biochim. Biophys. Acta. 1994; 1215: 115-120Crossref PubMed Scopus (50) Google Scholar), and mouse (16Balboa M.A. Balsinde J. Winstead M.V. Tischfield J.A. Dennis E.A. J. Biol. Chem. 1996; 271: 32381-32384Abstract Full Text Full Text PDF PubMed Scopus (197) Google Scholar). 2M. V. Winstead and J. A. Tischfield, unpublished results. 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 V 3Dennis (1Dennis E.A. J. Biol. Chem. 1994; 269: 13057-13060Abstract Full Text PDF PubMed Google Scholar) 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. (6Chen J. Engle S.J. Seilhamer J.J. Tischfield J.A. Biochim. Biophys. Acta. 1994; 1215: 115-120Crossref PubMed Scopus (50) Google Scholar). The group V PLA2 gene is expressed highly in heart, placenta, and, to a lesser extent, lung and liver (4Chen J. Engle S.J. Seilhamer J.J. Tischfield J.A. J. Biol. Chem. 1994; 269: 2365-2368Abstract Full Text PDF PubMed Google Scholar, 6Chen J. Engle S.J. Seilhamer J.J. Tischfield J.A. Biochim. Biophys. Acta. 1994; 1215: 115-120Crossref PubMed Scopus (50) Google Scholar). Further, group V, rather than group IIA as was previously believed, appears to be the primary ∼14-kDa PLA2 expressed by P388D1macrophage-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 (4Chen J. Engle S.J. Seilhamer J.J. Tischfield J.A. J. Biol. Chem. 1994; 269: 2365-2368Abstract Full Text PDF PubMed Google Scholar).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 (4Chen J. Engle S.J. Seilhamer J.J. Tischfield J.A. J. Biol. Chem. 1994; 269: 2365-2368Abstract Full Text PDF PubMed Google Scholar, 5Chen J. Engle S.J. Seilhamer J.J. Tischfield J.A. J. Biol. Chem. 1994; 269: 23018-23024Abstract Full Text PDF PubMed Google Scholar, 6Chen J. Engle S.J. Seilhamer J.J. Tischfield J.A. Biochim. Biophys. Acta. 1994; 1215: 115-120Crossref PubMed Scopus (50) Google Scholar). 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. 1Dennis E.A. J. Biol. Chem. 1994; 269: 13057-13060Abstract Full Text PDF PubMed Google Scholar). 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+ (17Marshall L.A. McCarte-Roshak A. Biochem. Pharmacol. 1992; 44: 1849-1858Crossref PubMed Scopus (26) Google Scholar). It is also important to recognize that the demonstration of substrate preferences for each of the ∼14-kDa PLA2s (e.g. Refs. 4Chen J. Engle S.J. Seilhamer J.J. Tischfield J.A. J. Biol. Chem. 1994; 269: 2365-2368Abstract Full Text PDF PubMed Google Scholar, 5Chen J. Engle S.J. Seilhamer J.J. Tischfield J.A. J. Biol. Chem. 1994; 269: 23018-23024Abstract Full Text PDF PubMed Google Scholar, 6Chen J. Engle S.J. Seilhamer J.J. Tischfield J.A. Biochim. Biophys. Acta. 1994; 1215: 115-120Crossref PubMed Scopus (50) Google Scholar) 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 (1Dennis E.A. J. Biol. Chem. 1994; 269: 13057-13060Abstract Full Text PDF PubMed Google Scholar), such assay data should not be generalized to characterize activity in vivo.Table IProperties of ∼14-kDa mammalian PLA 2 sCharacteristicsGroupIBHumanIIAHumanIICRatVHumanNo. of amino acids in mature protein126124130118No. of cysteines in mature protein14141612Pre/propeptide+/++/−+/?+/−Level of mRNA expressionPancreas ≫ lungPlacenta > synovia = plateletsTestisHeart > placenta > lung > liver Open table in a new tab Low Molecular Weight PLA2 Genomics and EvolutionThe human group IB PLA2 gene has been shown to reside on chromosome 12 (18Johnson L.K. Frank S. Vadas P. Pruzanski W. Lusis A.J. Seilhamer J.J. Adv. Exp. Med. Biol. 1990; 275: 17-34Crossref PubMed Scopus (31) Google Scholar), 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 (7Tischfield J.A. Xia Y-R. Shih D.M. Klisak I. Chen J. Engle S.J. Siakotos A.N. Winstead M.V. Seilhamer J.J. Allamand V. Gyapay G. Lusis A.J. Genomics. 1996; 32: 328-333Crossref PubMed Scopus (91) Google Scholar). 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 (4Chen J. Engle S.J. Seilhamer J.J. Tischfield J.A. J. Biol. Chem. 1994; 269: 2365-2368Abstract Full Text PDF PubMed Google Scholar, 5Chen J. Engle S.J. Seilhamer J.J. Tischfield J.A. J. Biol. Chem. 1994; 269: 23018-23024Abstract Full Text PDF PubMed Google Scholar, 6Chen J. Engle S.J. Seilhamer J.J. Tischfield J.A. Biochim. Biophys. Acta. 1994; 1215: 115-120Crossref PubMed Scopus (50) Google Scholar, 19Seilhamer J.J. Randall T.L. Yamanaka M. Johnson L.K. DNA. 1986; 5: 519-527Crossref PubMed Scopus (208) Google Scholar, 20Seilhamer J.J. Pruzanski W. Vadas P. Plant S. Miller J.A. Kloss J. Johnson L.K. J. Biol. Chem. 1989; 264: 5335-5338Abstract Full Text PDF PubMed Google Scholar, 21Kramer R.M. Hession C. Johansen B. Hayes G. McGray P. Chow E.P. Tizard R. Pepinsky R.B. J. Biol. Chem. 1989; 264: 5768-5775Abstract Full Text PDF PubMed Google Scholar). In addition, the human and rat group V (4Chen J. Engle S.J. Seilhamer J.J. Tischfield J.A. J. Biol. Chem. 1994; 269: 2365-2368Abstract Full Text PDF PubMed Google Scholar, 6Chen J. Engle S.J. Seilhamer J.J. Tischfield J.A. Biochim. Biophys. Acta. 1994; 1215: 115-120Crossref PubMed Scopus (50) Google Scholar) and the mouse group IIA (22Kennedy B.P. Payette P. Mudgett J. Vadas P. Pruzanski V. Kwan M. Tang C. Rancourt D.E. Cromlish W.A. J. Biol. Chem. 1996; 270: 22378-22385Abstract Full Text Full Text PDF Scopus (308) Google Scholar) 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 (5Chen J. Engle S.J. Seilhamer J.J. Tischfield J.A. J. Biol. Chem. 1994; 269: 23018-23024Abstract Full Text PDF PubMed Google Scholar). 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 (14Davidson F.F. Dennis E.A. J. Mol. Evol. 1990; 31: 228-238Crossref PubMed Scopus (292) Google Scholar) in light of the subsequent discovery of groups IIC and V. 4J. Chen and J. A. Tischfield, unpublished data. 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 (14Davidson F.F. Dennis E.A. J. Mol. Evol. 1990; 31: 228-238Crossref PubMed Scopus (292) Google Scholar). 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 (14Davidson F.F. Dennis E.A. J. Mol. Evol. 1990; 31: 228-238Crossref PubMed Scopus (292) Google Scholar). 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.Figure 2Scheme for evolution of PLA2genes leading to the major present day PLA2 types, as modified from Davidson and Dennis (14Davidson F.F. Dennis E.A. J. Mol. Evol. 1990; 31: 228-238Crossref PubMed Scopus (292) Google Scholar). Solid vertical linesindicate ancestral lines associated with individual genes. Branch points indicate duplication of a gene. Dashed vertical linesindicate 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 Large Image Figure ViewerDownload Hi-res image Download (PPT)Revised View of PLA2 Gene Expression in Cell SignalingAlthough it is well documented that individual cells of different types contain multiple PLA2s (23Murakami M. Kudo I. Umeda M. Matsuzawa A. Takeda M. Komada M. Fujimori Y. Takahashi K. Inoue K. J. Biochem. ( Tokyo ). 1992; 111: 175-181Crossref PubMed Scopus (71) Google Scholar, 24Ackermann E.J. Kempner E.S. Dennis E.A. J. Biol. Chem. 1994; 269: 9227-9233Abstract Full Text PDF PubMed Google Scholar, 25Balsinde J. Barbour S.E. Bianco I.D. Dennis E.A. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 11060-11064Crossref PubMed Scopus (127) Google Scholar), 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 of These are in the and of arachidonic acid release and the subsequent production of example, in cells and mast cells arachidonic acid release in response to certain agonist can be shown to be and on the activities of both group IV cytosolic PLA2 and a low molecular weight PLA2 that believed to be group IIA. Balsinde J. Barbour S.E. Bianco I.D. Dennis E.A. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 11060-11064Crossref PubMed Scopus (127) Google Scholar) that mouse cells with and release arachidonic acid in two an of the cell within the first and a subsequent of in the It was subsequently shown that group IV PLA2 is for the release of arachidonic acid whereas a ∼14-kDa PLA2 on the of the cell was for the release of arachidonic acid J. Dennis E.A. J. Biol. Chem. 1996; 271: Full Text Full Text PDF PubMed Scopus Google Scholar). The data also that and arachidonic acid from different phospholipid within the (16Balboa M.A. Balsinde J. Winstead M.V. Tischfield J.A. Dennis E.A. J. Biol. Chem. 1996; 271: 32381-32384Abstract Full Text Full Text PDF PubMed Scopus (197) Google Scholar) that the ∼14-kDa enzyme in cells associated with the release of arachidonic acid is group V and not group IIA as was previously Whereas there was no mRNA for PLA2 groups IIA or IIC in either or activated cells, the group V mRNA was in for the highly conserved of rat group IIA which had previously been used in that as group IIA S.E. Dennis E.A. J. Biol. Chem. 1993; Full Text PDF PubMed Google Scholar), shown to in a on group V. However, more specific a exon region of mouse group V PLA2 expression by about whereas the was a human synovial fluid PLA2, group IIA, was used to detect expression of the cell PLA2. This result indicates that this and such in may not be to distinguish between PLA2 groups IIA and V (see activation of mast cells and release of such as and and is similar in several to the response observed in mouse mast cells by of on the cell R. B. J. Google Scholar) or with and or by with and by and activation M. R. J. Google Scholar) exhibit an of arachidonic acid release the first by a from 2 to These of arachidonic acid release are by and of prostaglandin which are by the prostaglandin 1 and the prostaglandin 2 respectively R. B. J. Google Scholar, M. R. J. Google Scholar). However, there is as to which PLA2s the arachidonic acid for and The from one group indicate that a ∼14-kDa PLA2 to is for whereas the group IV PLA2 to is for J. Biol. Chem. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar). In a second data suggest the i.e. a ∼14-kDa with is for Murakami M. H. J.E. J. Biol. Chem. 1996; 271: Full Text Full Text PDF PubMed Scopus Google Scholar). These may be a of differences in however, clearly that one of is a of the activity of a low molecular weight PLA2 that was initially believed to be group IIA. As described below, we now that Group IIA PLA2 in mast cell involvement of specific ∼14-kDa PLA2s in mast cell activation has been by the discovery of a mutation in the group IIA PLA2 gene of many mouse The gene is the of the gene, which has been shown to be in a form of known as The number of is in mouse that also the of mutation that is likely a mutation in the gene for group IIA PLA2, such that or no group IIA mRNA or (22Kennedy B.P. Payette P. Mudgett J. Vadas P. Pruzanski V. Kwan M. Tang C. Rancourt D.E. Cromlish W.A. J. Biol. Chem. 1996; 270: 22378-22385Abstract Full Text Full Text PDF Scopus (308) Google Scholar, M. Cell. Full Text PDF PubMed Scopus Google Scholar). Murakami M. H. J.E. J. Biol. Chem. 1996; 271: Full Text Full Text PDF PubMed Scopus Google Scholar) demonstrated that mast cells exhibit a response to and that one of this previously to group IIA PLA2, be by another PLA2 that has some properties in common with the group IIA Biol. Chem. S. M. Tischfield, J. and H. Biol. Chem. Scholar) demonstrated that mast cells from both and exhibit to activation and that both and production and ∼14-kDa PLA2 into the are similar in both nor cells group IIA or group IIC mRNA as by and the more of However, cells of both Group V and was secreted into the as by binding to human group IIA PLA2, and by a as an of the group IIA enzyme Biol. Chem. S. M. Tischfield, J. and H. Biol. Chem. Scholar). Also, it was shown that the PLA2 secreted from both mast cells release arachidonic acid in distal mouse cells, which then this arachidonic acid for prostaglandin