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• W2027145809 abstract "We report the cloning and characterization of a novel membrane-bound, calcium-independent PLA2, named cPLA2-γ. The sequence encodes a 541-amino acid protein containing a domain with significant homology to the catalytic domain of the 85-kDa cPLA2 (cPLA2-α). cPLA2-γ does not contain the regulatory calcium-dependent lipid binding (CaLB) domain found in cPLA2-α. However, cPLA2-γ does contain two consensus motifs for lipid modification, a prenylation motif (−CCLA) at the C terminus and a myristoylation site at the N terminus. We present evidence that the isoprenoid precursor [3H]mevalonolactone is incorporated into the prenylation motif of cPLA2-γ. Interestingly, cPLA2-γ demonstrates a preference for arachidonic acid at the sn-2position of phosphatidylcholine as compared with palmitic acid. cPLA2-γ encodes a 3-kilobase message, which is highly expressed in heart and skeletal muscle, suggesting a specific role in these tissues. Identification of cPLA2-γ reveals a newly defined family of phospholipases A2 with homology to cPLA2-α. We report the cloning and characterization of a novel membrane-bound, calcium-independent PLA2, named cPLA2-γ. The sequence encodes a 541-amino acid protein containing a domain with significant homology to the catalytic domain of the 85-kDa cPLA2 (cPLA2-α). cPLA2-γ does not contain the regulatory calcium-dependent lipid binding (CaLB) domain found in cPLA2-α. However, cPLA2-γ does contain two consensus motifs for lipid modification, a prenylation motif (−CCLA) at the C terminus and a myristoylation site at the N terminus. We present evidence that the isoprenoid precursor [3H]mevalonolactone is incorporated into the prenylation motif of cPLA2-γ. Interestingly, cPLA2-γ demonstrates a preference for arachidonic acid at the sn-2position of phosphatidylcholine as compared with palmitic acid. cPLA2-γ encodes a 3-kilobase message, which is highly expressed in heart and skeletal muscle, suggesting a specific role in these tissues. Identification of cPLA2-γ reveals a newly defined family of phospholipases A2 with homology to cPLA2-α. Phospholipases A2(PLA2) 1The abbreviations used are: cPLA2cytosolic phospholipase A2CaLBcalcium-dependent lipid bindingiPLA2cytosolic calcium-independent PLA2MAPmitogen-activated proteinESTexpressed sequence tagPCphosphatidylcholineCHOChinese hamster ovaryPAGEpolyacrylamide gel electrophoresis.1The abbreviations used are: cPLA2cytosolic phospholipase A2CaLBcalcium-dependent lipid bindingiPLA2cytosolic calcium-independent PLA2MAPmitogen-activated proteinESTexpressed sequence tagPCphosphatidylcholineCHOChinese hamster ovaryPAGEpolyacrylamide gel electrophoresis. are a diverse group of enzymes that hydrolyze the sn-2 fatty acids from phospholipids and play a role in a wide range of physiological functions. Of particular interest is the role of these enzymes in the production of factors involved in mediating the inflammatory response. The phospholipases A2 family is large, and individual members can be classified according to localization (extracellularversus intracellular), sequence homology, and biochemical characteristics (1Dennis E.A. Trends Biochem. Sci. 1997; 22: 1-2Abstract Full Text PDF PubMed Scopus (756) Google Scholar). Known PLA2 members include the secreted PLA2s and the cytosolic PLA2s. To date only two cytosolic PLA2 sequences have been reported: the calcium-dependent PLA2 (cPLA2-α) and the calcium-independent PLA2 (iPLA2) (2Clark J.D. Lin L.-L. Kriz R.W. Ramesha C.S. Sultzman L.A. Lin A.Y. Milona N. Knopf J.L. Cell. 1991; 65: 1043-1051Abstract Full Text PDF PubMed Scopus (1454) Google Scholar, 3Sharp J.D. White D.L. Chiou X.G. Goodson T. Gamboa G.C. McClure D. Burgett S. Hoskins J. Skatrud P.L. Sportsman J.R. Becker G.W. Kang L.H. Roberts E.F. Kramer R.M. J. Biol. Chem. 1991; 266: 14850-14853Abstract Full Text PDF PubMed Google Scholar, 4Tang J. Kriz R. Wolfman N. Shaffer M. Seehra J. Jones S. J. Biol. Chem. 1997; 272: 8567-8575Abstract Full Text Full Text PDF PubMed Scopus (273) Google Scholar, 5Balboa M. Balsinde J. Jones S. Dennis E. J. Biol. Chem. 1997; 272: 8576-8580Abstract Full Text Full Text PDF PubMed Scopus (140) Google Scholar). cPLA2-α has a predicted molecular mass of 85 kDa and contains two domains, a calcium-dependentlipid binding (CaLB) domain and a catalytic domain (2Clark J.D. Lin L.-L. Kriz R.W. Ramesha C.S. Sultzman L.A. Lin A.Y. Milona N. Knopf J.L. Cell. 1991; 65: 1043-1051Abstract Full Text PDF PubMed Scopus (1454) Google Scholar, 6Nalefski E.A. Sultzman L.A. Martin D.M. Kriz R.W. Towler P.S. Knopf J.L. Clark J.D. J. Biol. Chem. 1994; 269: 18239-18249Abstract Full Text PDF PubMed Google Scholar). The catalytic domain contains a lipase consensus sequence and a novel catalytic triad that employs a serine, an aspartate, and an arginine instead of the usual serine, aspartate, and histidine found in many lipases and serine proteases (7Sharp J.D. Pickard R.T. Chiou X.G. Manetta J.V. Kovacevic S. Miller J.R. Varshavsky A.D. Roberts E.F. Strifler B.A. Brems D.N. Kramer R.M. J. Biol. Chem. 1994; 269: 23250-23254Abstract Full Text PDF PubMed Google Scholar, 8Pickard R. Chiou X. Strifler B. DeFelippis M. Hyslop P. Tebbe A. Yee Y. Reynolds L. Dennis E. Kramer R. Sharp J.D. J. Biol. Chem. 1996; 271: 19225-19231Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar, 9Derewenda Z. Sharp A. Trends Biochem. Sci. 1993; 18: 20-25Abstract Full Text PDF PubMed Scopus (197) Google Scholar). cPLA2-α activity is regulated by the activation of the CaLB domain in response to increased intracellular calcium (6Nalefski E.A. Sultzman L.A. Martin D.M. Kriz R.W. Towler P.S. Knopf J.L. Clark J.D. J. Biol. Chem. 1994; 269: 18239-18249Abstract Full Text PDF PubMed Google Scholar). The activated CaLB domain translocates the enzyme to its substrate in the nuclear envelope and endoplasmic reticulum (10Schievella A. Regier M. Smith W. Lin L.-L. J. Biol. Chem. 1995; 270: 30749-30754Abstract Full Text Full Text PDF PubMed Scopus (421) Google Scholar). cPLA2-α activity is also increased by the phosphorylation of a MAP kinase consensus site, in response to stimulation of cells with cytokines such as tumor necrosis factor and interleukin 1 (11Lin L.-L. Lin A.Y. DeWitt D.L. J. Biol. Chem. 1992; 267: 23451-23454Abstract Full Text PDF PubMed Google Scholar, 12Hoeck W.G. Ramesha C.S. Chang D.J. Fan N. Heller R.A. Proc. Natl. Acad. Sci. U. S. A. 1993; 90: 4475-4479Crossref PubMed Scopus (191) Google Scholar). These same cytokines have also been found to increase the expression of cPLA2-α (11Lin L.-L. Lin A.Y. DeWitt D.L. J. Biol. Chem. 1992; 267: 23451-23454Abstract Full Text PDF PubMed Google Scholar, 12Hoeck W.G. Ramesha C.S. Chang D.J. Fan N. Heller R.A. Proc. Natl. Acad. Sci. U. S. A. 1993; 90: 4475-4479Crossref PubMed Scopus (191) Google Scholar). Although there have been many studies that suggest the importance of cPLA2 in the generation of prostaglandins and leukotrienes, the most convincing data have come from studies using mice that are genetically deficient in cPLA2 (13Uozumi N. Kume K. Nagase T. Nakatani N. Ishii S. Tashiro F. Komagata Y. Maki K. Ikuta K. Ouchi Y. Miyazaki J. Shimizu T. Nature. 1997; 390: 618-622Crossref PubMed Scopus (636) Google Scholar, 14Bonventre J. Huang Z. Taheri M. O'Leary E. Li E. Moskowitz M. Sapirstein A. Nature. 1997; 390: 622-625Crossref PubMed Scopus (757) Google Scholar). Studies demonstrate that cPLA2-α is essential for both the calcium ionophore, A23187, and lipopolysaccharide-induced prostaglandin E2 and leukotriene B4 production in peritoneal monocytes (13Uozumi N. Kume K. Nagase T. Nakatani N. Ishii S. Tashiro F. Komagata Y. Maki K. Ikuta K. Ouchi Y. Miyazaki J. Shimizu T. Nature. 1997; 390: 618-622Crossref PubMed Scopus (636) Google Scholar, 14Bonventre J. Huang Z. Taheri M. O'Leary E. Li E. Moskowitz M. Sapirstein A. Nature. 1997; 390: 622-625Crossref PubMed Scopus (757) Google Scholar). The possible importance of cPLA2 in asthma was also shown (13Uozumi N. Kume K. Nagase T. Nakatani N. Ishii S. Tashiro F. Komagata Y. Maki K. Ikuta K. Ouchi Y. Miyazaki J. Shimizu T. Nature. 1997; 390: 618-622Crossref PubMed Scopus (636) Google Scholar).The 85-kDa calcium-independent iPLA2, purified by two groups, shares no homology with cPLA2-α except, like other lipases, it contains the critical consensus sequence, GXSXG (4Tang J. Kriz R. Wolfman N. Shaffer M. Seehra J. Jones S. J. Biol. Chem. 1997; 272: 8567-8575Abstract Full Text Full Text PDF PubMed Scopus (273) Google Scholar, 5Balboa M. Balsinde J. Jones S. Dennis E. J. Biol. Chem. 1997; 272: 8576-8580Abstract Full Text Full Text PDF PubMed Scopus (140) Google Scholar, 15Ackermann E. Dennis E. Biochim. Biophys. Acta. 1995; 1259: 125-136Crossref PubMed Scopus (129) Google Scholar). Interestingly, iPLA2 contains a domain of eight ankyrin repeats, which may be involved in protein-protein interactions (4Tang J. Kriz R. Wolfman N. Shaffer M. Seehra J. Jones S. J. Biol. Chem. 1997; 272: 8567-8575Abstract Full Text Full Text PDF PubMed Scopus (273) Google Scholar). iPLA2possesses no clear preference for a fatty acid at the sn-2position, and it is thought to play a role in the remodeling of phospholipids (16Balsinde J. Balboa M. Dennis E. J. Biol. Chem. 1997; 272: 29317-29321Abstract Full Text Full Text PDF PubMed Scopus (197) Google Scholar).Although cPLA2-α and iPLA2 are the only intracellular PLA2s that have been cloned, many other PLA2 activities, which presently seem to be distinct from cPLA2-α and iPLA2, have been reported (17Hazen S. Stuppy R. Gross R. J. Biol. Chem. 1990; 265: 10622-10630Abstract Full Text PDF PubMed Google Scholar, 18Hazen S. Ford D. Gross R. J. Biol. Chem. 1991; 266: 5629-5633Abstract Full Text PDF PubMed Google Scholar, 19McHowat J. Creer M. Am. J. Physiol. 1997; 272: H1972-H1980Crossref PubMed Google Scholar). The relationship of the enzymes responsible for these activities to the known PLA2 enzymes will be clear only upon sequence determination.Our initial efforts to identify additional PLA2enzymes failed using low stringency cross-hybridization techniques with cPLA2-α sequences. 2R. Kriz, unpublished results. 2R. Kriz, unpublished results. A search of the expressed sequence tag (EST) data base was quite successful, and two independent cPLA2-α related gene fragments were identified. Subsequent sequence analysis of the full-length clones revealed two novel homologs of cPLA2-α, designated cPLA2-β and cPLA2-γ. The characterization of cPLA2-β will be described elsewhere. 3C. Song, X. J. Chang, K. Bean, M. Proia, J. L. Knopf, and R. W. Kriz, manuscript in preparation. 3C. Song, X. J. Chang, K. Bean, M. Proia, J. L. Knopf, and R. W. Kriz, manuscript in preparation. Here, we report the sequence and characterization of a novel 60.9-kDa calcium-independent, membrane-associated cPLA2,cPLA2-γ.DISCUSSIONWe have identified a novel 60.9-kDa calcium-independent phospholipase A2, which we termed cPLA2-γ. cPLA2-γ contains 28.7% overall sequence identity with cPLA2-α and was identified by searching the EST data base for related proteins.A common motif found in many lipases is the consensus sequence, GXSXG, which is essential for enzymatic activity (9Derewenda Z. Sharp A. Trends Biochem. Sci. 1993; 18: 20-25Abstract Full Text PDF PubMed Scopus (197) Google Scholar, 26Ollis D.L. Cheah E. Cygler M. Dijkstra B. Frolow F. Franken S.M. Harel M. Remington S.J. Silman I. Schrag J. Sussman J.L. Verschueren K.H.G. Goldman A. Protein Eng. 1992; 5: 197-211Crossref PubMed Scopus (1830) Google Scholar). cPLA2-γ contains the sequence GVS82GS, which is similar but slightly different from the consensus. However, this sequence aligns with the sequence in cPLA2-α, and the change from glycine to serine also occurs in the corresponding region of cPLA2-α, GLS228GS (7Sharp J.D. Pickard R.T. Chiou X.G. Manetta J.V. Kovacevic S. Miller J.R. Varshavsky A.D. Roberts E.F. Strifler B.A. Brems D.N. Kramer R.M. J. Biol. Chem. 1994; 269: 23250-23254Abstract Full Text PDF PubMed Google Scholar). Mutation of serine-228 and aspartate-549 was shown to abolish cPLA2-α activity, consistent with their role in the putative catalytic triad (7Sharp J.D. Pickard R.T. Chiou X.G. Manetta J.V. Kovacevic S. Miller J.R. Varshavsky A.D. Roberts E.F. Strifler B.A. Brems D.N. Kramer R.M. J. Biol. Chem. 1994; 269: 23250-23254Abstract Full Text PDF PubMed Google Scholar, 8Pickard R. Chiou X. Strifler B. DeFelippis M. Hyslop P. Tebbe A. Yee Y. Reynolds L. Dennis E. Kramer R. Sharp J.D. J. Biol. Chem. 1996; 271: 19225-19231Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar). Catalytic triads of lipases and serine proteases also frequently contain critical histidines; however, mutation of these residues in the catalytic domain of cPLA2-α had no affect on activity (8Pickard R. Chiou X. Strifler B. DeFelippis M. Hyslop P. Tebbe A. Yee Y. Reynolds L. Dennis E. Kramer R. Sharp J.D. J. Biol. Chem. 1996; 271: 19225-19231Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar, 9Derewenda Z. Sharp A. Trends Biochem. Sci. 1993; 18: 20-25Abstract Full Text PDF PubMed Scopus (197) Google Scholar, 26Ollis D.L. Cheah E. Cygler M. Dijkstra B. Frolow F. Franken S.M. Harel M. Remington S.J. Silman I. Schrag J. Sussman J.L. Verschueren K.H.G. Goldman A. Protein Eng. 1992; 5: 197-211Crossref PubMed Scopus (1830) Google Scholar). Surprisingly, mutation of arginine-200, in what is thought to be the novel catalytic triad of cPLA2-α, abrogated cPLA2-α activity (8Pickard R. Chiou X. Strifler B. DeFelippis M. Hyslop P. Tebbe A. Yee Y. Reynolds L. Dennis E. Kramer R. Sharp J.D. J. Biol. Chem. 1996; 271: 19225-19231Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar). These amino acids may serve as a catalytic triad, providing the active site for hydrolysis, or it is possible that the arginine may function in another but unknown critical role, such as in transition state stabilization (8Pickard R. Chiou X. Strifler B. DeFelippis M. Hyslop P. Tebbe A. Yee Y. Reynolds L. Dennis E. Kramer R. Sharp J.D. J. Biol. Chem. 1996; 271: 19225-19231Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar). We have also shown that serine, aspartate, and arginine are conserved in cPLA2-γ, providing further evidence that these amino acids are important and may indeed be part of a novel catalytic triad.cPLA2-α is regulated by at least two post-translational mechanisms: 1) calcium-induced membrane association through its CaLB domain and 2) phosphorylation of serine-505 by a MAP kinase (6Nalefski E.A. Sultzman L.A. Martin D.M. Kriz R.W. Towler P.S. Knopf J.L. Clark J.D. J. Biol. Chem. 1994; 269: 18239-18249Abstract Full Text PDF PubMed Google Scholar, 10Schievella A. Regier M. Smith W. Lin L.-L. J. Biol. Chem. 1995; 270: 30749-30754Abstract Full Text Full Text PDF PubMed Scopus (421) Google Scholar,30Lin L.-L. Wartmann M. Lin A.Y. Knopf J.L. Seth A. Davis R.J. Cell. 1993; 72: 269-278Abstract Full Text PDF PubMed Scopus (1643) Google Scholar). The phosphorylation site and the CaLB domain of cPLA2-α are not conserved in the sequence of cPLA2-γ, suggesting a different regulatory mechanism. Interestingly, cPLA2-γ contains a potential prenylation motif at its C terminus and a putative signal for myristoylation at its N terminus. Initial studies have failed to indicate that the myristoylation site is utilized, whereas the prenylation site is indeed utilized. The isoprenoid precursor [3H]mevalonolactone is readily incorporated into cPLA2-γ expressed in COS cells. We do not know, however, if the modifying isoprenoid is a farnesyl or a geranylgeranyl. Generally, in the consensus sequence CAAX, when the C-terminal (X) amino acid is a methionine, serine, glutamine, or alanine, this signals that the lipid will be farnesyl (27Clarke S. Annu. Rev. Biochem. 1992; 61: 355-386Crossref PubMed Scopus (788) Google Scholar), whereas a leucine signals that the modifying lipid is a geranylgeranyl. However, there is also a motif XXCC, CXC, or CCXX found on the Rab family of proteins that modifies the two cysteines with geranylgeranyl (31Shen F. Seabra M.C. J. Biol. Chem. 1996; 271: 3692-3698Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar). Because both of these motifs match the cPLA2-γ sequence (−CCLA), we do not know which of these isoprenoids is modifying the protein.One of the most striking differences between cPLA2-α and -γ is the lack of a lipid binding CaLB domain in cPLA2-γ. The presence of lipidation motifs suggests that these regions may function as the CaLB domain in cPLA2-α, localizing the enzyme to the membrane and being critical for activity. However, in a preliminary study, cPLA2-γ mutant protein that disrupts the possible N- and C-terminal lipid modification sites did not affect its activity in a phopholipid vesicle assay. 4K. Underwood, unpublished data. Moreover, this mutant protein fails to alter its association with the membrane fraction. However, it remains possible that lipid modification may be important in the subcellular localization of cPLA2-γ and/or its ability to associate with other proteins. Interestingly, Ras shows increased affinity toward other proteins when it is prenylated compared with its nonprenylated form, and it has been shown that oncogenic forms of Ras need to be modified to transform cells (29Zhang F. Casey P. Annu. Rev. Biochem. 1996; 65: 241-269Crossref PubMed Scopus (1725) Google Scholar). Therefore, it is possible that lipid modifications may play a role in regulating the activity of cPLA2-γ in the cells.cPLA2-γ will hydrolyze fatty acids at the sn-1 and sn-2 position of phosphatidylcholine. This suggests that cPLA2-γ contains PLA1 and PLA2activity. The evidence that cPLA2-γ contains PLA2 activity is also confirmed by its ability to cleave 1-O-hexadecyl-2-arachindonyl-phosphatidylcholine. However, we do not know whether the sn-1 cleavage is PLA1activity or if it is cleavage of the lysophospholipid. The kinetics of the reactions suggest that it is PLA1 activity, as the hydrolysis of sn-1 would show a time-dependent lag as compared with sn-2 hydrolysis if sequential cleavage were taking place, unless cleavage of sn-1 from lysophospholipid occurs rapidly. Taken together, all of these data provide evidence that cPLA2-γ is an enzyme with PLA2 activity and a probable PLA1 activity.cPLA2-γ prefers arachidonic acid to palmitic acid in thesn-2 position of phosphatidylcholine. However, this preference is modest in comparison to the strong preference that cPLA2-α displays for arachidonic acid, 3.5-foldversus 24.5-fold, respectively. The substrate specificity of cPLA2-γ should be considered cautiously, however, because of the artificial nature of the substrate presentation. The selectivity of the enzyme using a natural membrane as a substrate may be a more relevant method to determine the preferred physiological substrate for this enzyme.The preferred substrate for an enzyme provides a clue to its physiological role, as can its distribution within tissues. cPLA2-γ is highly expressed in heart and skeletal muscle. The calcium independence of this enzyme may be important for its high expression in muscle, where contractions cause large fluxes in calcium concentrations. Therefore, it may be necessary in this environment to regulate a phospholipase in a calcium-independent manner, such as phosphorylation. As previously stated, cPLA2-α activity is also regulated by MAP kinase phosphorylation of serine-505. This serine is not conserved in the sequence of cPLA2-γ; however, there are several potential protein kinase C phosphorylation sites, which may be utilized to regulate the enzyme.cPLA2-γ may be highly expressed in these muscles because heart and skeletal muscle encounter physical stress upon increased load. It may be necessary to regulate the remodeling of the phospholipid bilayer when cells undergo stress. This speculation is substantiated by the reports of several calcium-independent phospholipases expressed in heart (17Hazen S. Stuppy R. Gross R. J. Biol. Chem. 1990; 265: 10622-10630Abstract Full Text PDF PubMed Google Scholar, 18Hazen S. Ford D. Gross R. J. Biol. Chem. 1991; 266: 5629-5633Abstract Full Text PDF PubMed Google Scholar, 19McHowat J. Creer M. Am. J. Physiol. 1997; 272: H1972-H1980Crossref PubMed Google Scholar). Hazen et al. (18Hazen S. Ford D. Gross R. J. Biol. Chem. 1991; 266: 5629-5633Abstract Full Text PDF PubMed Google Scholar) and McHowat and Creer (19McHowat J. Creer M. Am. J. Physiol. 1997; 272: H1972-H1980Crossref PubMed Google Scholar) have identified membrane-bound, calcium-independent PLA2 activity that prefers the myocardia-abundant lipid, plasmologen, as a substrate. They have shown increased hydrolysis of plasmologen under hypoxic conditions, such as in ischemia. It is believed that in ischemia, a PLA2activity leads to the accumulation of lysophospholipids and subsequent injury to the heart tissue because of disruptions of the membrane. As the PLA2 activity of this myocardial membrane-bound enzyme was shown to increase under hypoxic conditions, it was suggested that this calcium-independent PLA2 is physiologically involved in ischemia (18Hazen S. Ford D. Gross R. J. Biol. Chem. 1991; 266: 5629-5633Abstract Full Text PDF PubMed Google Scholar). Because cPLA2-γ is abundantly expressed in heart, and its properties (including calcium independence and membrane localization) are similar to that reported in heart muscle, it may be that cPLA2-γ is involved in ischemia-induced injury to heart muscle.In summary, we have described the molecular cloning and initial characterization of a novel 60.9-kDa membrane-associated, calcium-independent PLA2, cPLA2-γ. This enzyme shares identity with cPLA2-α and contains the potential critical amino acids for the catalytic site but is missing the key elements that regulate the activity of cPLA2-α. This suggests that the mechanisms of regulation for cPLA2-γ will be different from that of cPLA2-α and quite possibly employs the use of the lipid modification. Defining the mechanisms of regulation and the physiological substrate of cPLA2-γ should shed some light on the physiological role of this newly identified PLA2. Phospholipases A2(PLA2) 1The abbreviations used are: cPLA2cytosolic phospholipase A2CaLBcalcium-dependent lipid bindingiPLA2cytosolic calcium-independent PLA2MAPmitogen-activated proteinESTexpressed sequence tagPCphosphatidylcholineCHOChinese hamster ovaryPAGEpolyacrylamide gel electrophoresis.1The abbreviations used are: cPLA2cytosolic phospholipase A2CaLBcalcium-dependent lipid bindingiPLA2cytosolic calcium-independent PLA2MAPmitogen-activated proteinESTexpressed sequence tagPCphosphatidylcholineCHOChinese hamster ovaryPAGEpolyacrylamide gel electrophoresis. are a diverse group of enzymes that hydrolyze the sn-2 fatty acids from phospholipids and play a role in a wide range of physiological functions. Of particular interest is the role of these enzymes in the production of factors involved in mediating the inflammatory response. The phospholipases A2 family is large, and individual members can be classified according to localization (extracellularversus intracellular), sequence homology, and biochemical characteristics (1Dennis E.A. Trends Biochem. Sci. 1997; 22: 1-2Abstract Full Text PDF PubMed Scopus (756) Google Scholar). Known PLA2 members include the secreted PLA2s and the cytosolic PLA2s. To date only two cytosolic PLA2 sequences have been reported: the calcium-dependent PLA2 (cPLA2-α) and the calcium-independent PLA2 (iPLA2) (2Clark J.D. Lin L.-L. Kriz R.W. Ramesha C.S. Sultzman L.A. Lin A.Y. Milona N. Knopf J.L. Cell. 1991; 65: 1043-1051Abstract Full Text PDF PubMed Scopus (1454) Google Scholar, 3Sharp J.D. White D.L. Chiou X.G. Goodson T. Gamboa G.C. McClure D. Burgett S. Hoskins J. Skatrud P.L. Sportsman J.R. Becker G.W. Kang L.H. Roberts E.F. Kramer R.M. J. Biol. Chem. 1991; 266: 14850-14853Abstract Full Text PDF PubMed Google Scholar, 4Tang J. Kriz R. Wolfman N. Shaffer M. Seehra J. Jones S. J. Biol. Chem. 1997; 272: 8567-8575Abstract Full Text Full Text PDF PubMed Scopus (273) Google Scholar, 5Balboa M. Balsinde J. Jones S. Dennis E. J. Biol. Chem. 1997; 272: 8576-8580Abstract Full Text Full Text PDF PubMed Scopus (140) Google Scholar). cPLA2-α has a predicted molecular mass of 85 kDa and contains two domains, a calcium-dependentlipid binding (CaLB) domain and a catalytic domain (2Clark J.D. Lin L.-L. Kriz R.W. Ramesha C.S. Sultzman L.A. Lin A.Y. Milona N. Knopf J.L. Cell. 1991; 65: 1043-1051Abstract Full Text PDF PubMed Scopus (1454) Google Scholar, 6Nalefski E.A. Sultzman L.A. Martin D.M. Kriz R.W. Towler P.S. Knopf J.L. Clark J.D. J. Biol. Chem. 1994; 269: 18239-18249Abstract Full Text PDF PubMed Google Scholar). The catalytic domain contains a lipase consensus sequence and a novel catalytic triad that employs a serine, an aspartate, and an arginine instead of the usual serine, aspartate, and histidine found in many lipases and serine proteases (7Sharp J.D. Pickard R.T. Chiou X.G. Manetta J.V. Kovacevic S. Miller J.R. Varshavsky A.D. Roberts E.F. Strifler B.A. Brems D.N. Kramer R.M. J. Biol. Chem. 1994; 269: 23250-23254Abstract Full Text PDF PubMed Google Scholar, 8Pickard R. Chiou X. Strifler B. DeFelippis M. Hyslop P. Tebbe A. Yee Y. Reynolds L. Dennis E. Kramer R. Sharp J.D. J. Biol. Chem. 1996; 271: 19225-19231Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar, 9Derewenda Z. Sharp A. Trends Biochem. Sci. 1993; 18: 20-25Abstract Full Text PDF PubMed Scopus (197) Google Scholar). cPLA2-α activity is regulated by the activation of the CaLB domain in response to increased intracellular calcium (6Nalefski E.A. Sultzman L.A. Martin D.M. Kriz R.W. Towler P.S. Knopf J.L. Clark J.D. J. Biol. Chem. 1994; 269: 18239-18249Abstract Full Text PDF PubMed Google Scholar). The activated CaLB domain translocates the enzyme to its substrate in the nuclear envelope and endoplasmic reticulum (10Schievella A. Regier M. Smith W. Lin L.-L. J. Biol. Chem. 1995; 270: 30749-30754Abstract Full Text Full Text PDF PubMed Scopus (421) Google Scholar). cPLA2-α activity is also increased by the phosphorylation of a MAP kinase consensus site, in response to stimulation of cells with cytokines such as tumor necrosis factor and interleukin 1 (11Lin L.-L. Lin A.Y. DeWitt D.L. J. Biol. Chem. 1992; 267: 23451-23454Abstract Full Text PDF PubMed Google Scholar, 12Hoeck W.G. Ramesha C.S. Chang D.J. Fan N. Heller R.A. Proc. Natl. Acad. Sci. U. S. A. 1993; 90: 4475-4479Crossref PubMed Scopus (191) Google Scholar). These same cytokines have also been found to increase the expression of cPLA2-α (11Lin L.-L. Lin A.Y. DeWitt D.L. J. Biol. Chem. 1992; 267: 23451-23454Abstract Full Text PDF PubMed Google Scholar, 12Hoeck W.G. Ramesha C.S. Chang D.J. Fan N. Heller R.A. Proc. Natl. Acad. Sci. U. S. A. 1993; 90: 4475-4479Crossref PubMed Scopus (191) Google Scholar). Although there have been many studies that suggest the importance of cPLA2 in the generation of prostaglandins and leukotrienes, the most convincing data have come from studies using mice that are genetically deficient in cPLA2 (13Uozumi N. Kume K. Nagase T. Nakatani N. Ishii S. Tashiro F. Komagata Y. Maki K. Ikuta K. Ouchi Y. Miyazaki J. Shimizu T. Nature. 1997; 390: 618-622Crossref PubMed Scopus (636) Google Scholar, 14Bonventre J. Huang Z. Taheri M. O'Leary E. Li E. Moskowitz M. Sapirstein A. Nature. 1997; 390: 622-625Crossref PubMed Scopus (757) Google Scholar). Studies demonstrate that cPLA2-α is essential for both the calcium ionophore, A23187, and lipopolysaccharide-induced prostaglandin E2 and leukotriene B4 production in peritoneal monocytes (13Uozumi N. Kume K. Nagase T. Nakatani N. Ishii S. Tashiro F. Komagata Y. Maki K. Ikuta K. Ouchi Y. Miyazaki J. Shimizu T. Nature. 1997; 390: 618-622Crossref PubMed Scopus (636) Google Scholar, 14Bonventre J. Huang Z. Taheri M. O'Leary E. Li E. Moskowitz M. Sapirstein A. Nature. 1997; 390: 622-625Crossref PubMed Scopus (757) Google Scholar). The possible importance of cPLA2 in asthma was also shown (13Uozumi N. Kume K. Nagase T. Nakatani N. Ishii S. Tashiro F. Komagata Y. Maki K. Ikuta K. Ouchi Y. Miyazaki J. Shimizu T. Nature. 1997; 390: 618-622Crossref PubMed Scopus (636) Google Scholar). cytosolic phospholipase A2 calcium-dependent lipid binding cytosolic calcium-independent PLA2 mitogen-activated protein expressed sequence tag phosphatidylcholine Chinese hamster ovary polyacrylamide gel electrophoresis. cytosolic phospholipase A2 calcium-dependent lipid binding cytosolic calcium-independent PLA2 mitogen-activated protein expressed sequence tag phosphatidylcholine Chinese hamster ovary polyacrylamide gel electrophoresis. The 85-kDa calcium-independent iPLA2, purified by two groups, shares no homology with cPLA2-α except, like other lipases, it contains the critical consensus sequence, GXSXG (4Tang J. Kriz R. Wolfman N. Shaffer M. Seehra J. Jones S. J. Biol. Chem. 1997; 272: 8567-8575Abstract Full Text Full Text PDF PubMed Scopus (273) Google Scholar, 5Balboa M. Balsinde J. Jones S. Dennis E. J. Biol. Chem. 1997; 272: 8576-8580Abstract Full Text Full Text PDF PubMed Scopus (140) Google Scholar, 15Ackermann E. Dennis E. Biochim. Biophys. Acta. 1995; 1259: 125-136Crossref PubMed Scopus (129) Google Scholar). Interestingly, iPLA2 contains a domain of eight ankyrin repeats, which may be involved in protein-protein interactions (4Tang J. Kriz R. Wolfman N. Shaffer M. Seehra J. Jones S. J. Biol. Chem. 1997; 272: 8567-8575Abstract Full Text Full Text PDF PubMed Scopus (273) Google Scholar). iPLA2possesses no clear preference for a fatty acid at the sn-2position, and it is thought to play a role in the remodeling of phospholipids (16Balsinde J. Balboa M. Dennis E. J. Biol. Chem. 1997; 272: 29317-29321Abstract Full Text Full Text PDF PubMed Scopus (197) Google Scholar). Although cPLA2-α and iPLA2 are the only intracellular PLA2s that have been c" @default.
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