JBC PeproTech; Our Business is Cytokines!

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Balsinde, J.
Right arrow Articles by Dennis, E. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Balsinde, J.
Right arrow Articles by Dennis, E. A.
Social Bookmarking
Add to CiteULike   Add to Complore   Add to Connotea   Add to Del.icio.us   Add to Digg   Add to Reddit   Add to Technorati  
What's this?

Volume 272, Number 26, Issue of June 27, 1997 pp. 16069-16072
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.

MINIREVIEW:
Function and Inhibition of Intracellular Calcium-independent Phospholipase A2*

Jesús Balsinde and Edward A. Dennis Dagger

From the Department of Chemistry and Biochemistry, University of California at San Diego, La Jolla, California 92093-0601

INTRODUCTION
Inhibition of iPLA2
Function of Group VI iPLA2 in Membrane Phospholipid Remodeling
Other Proposed Functions for Intracellular iPLA2s
Concluding Remarks
FOOTNOTES
REFERENCES

INTRODUCTION

Our previous Minireview (1) considered the three main kinds of phospholipase A2 (PLA2)1: the well characterized Groups I, II, and III small Ca2+-dependent secretory phospholipase A2s (sPLA2), the 85-kDa Group IV Ca2+-dependent cytosolic phospholipase A2 (cPLA2), and the 80-kDa Ca2+-independent cytosolic phospholipase A2 (iPLA2). In the ensuing years, it has become clear that PLA2 represents a growing superfamily of enzymes with many additional sPLA2s (Groups IIC, V, and IX), further definition of the 80-kDa iPLA2 (Group VI), and two Ca2+-independent PLA2s specific for platelet-activating factor (PAF) (Groups VII and VIII) (2).

All of the well studied sPLA2s appear to use a His-Asp catalytic mechanism and require Ca2+ to be bound tightly in the active site of the enzyme. The well characterized iPLA2 appears to require a central Ser for catalysis and of course, no Ca2+. Interestingly, the Group IV cPLA2 does not use Ca2+ for catalysis, but rather the Ca2+ dependence seems to relate to a calcium lipid-binding domain (CaLB or C-2 domain) at the N-terminal end responsible for association of the enzyme with the membrane. Thus, the catalytic mechanism and active site Ser do not involve Ca2+ (3-5); therefore a mechanistic distinction between the Group IV cPLA2 and the iPLA2s may not be warranted at this time. This is relevant because most of the inhibitors that work on the Group IV cPLA2 also act on the Group VI iPLA2 (6, 7). Inhibitor specificity will be discussed in the next section.

We (8) recently surveyed all of the reported Ca2+-independent PLA2 activities. While there exists a group of lysosomal iPLA2s and a group of characterized ectoenzymes with broad specificity, which may actually be general lipases (8), sequenced and well characterized intracellular iPLA2s are limited to the 80-kDa Group VI iPLA2 and the 29-kDa Group VIII enzyme, which is a PAF acetyl hydrolase (9). The latter hydrolyzes the acetyl chain present at the sn-2 position of PAF and perhaps acts on oxidized phospholipids as well but not on normal phospholipids carrying unoxidized long chain fatty acids at the sn-2 position (9). This enzyme and a secreted Group VII PAF acetyl hydrolase, both of which are really iPLA2s with a particular substrate specificity, have been considered elsewhere (2).

The Group VI 80-kDa iPLA2 was first identified in P388D1 macrophages (10), purified (11), further characterized (12), and then cloned and sequenced by Jones and co-workers (13) from CHO cells. The CHO iPLA2 has been shown to represent a species variant of that present in P388D1 macrophage-like cells, where the iPLA2 has also been cloned and sequenced (14). The sequence of the Group VI iPLA2 reveals the presence of eight ankyrin-like domains and the G-X-S-X-G motif commonly found in other lipases. Interestingly, no known consensus sequences for posttranslational modification, such as phosphorylation sites, are apparent in the Group VI iPLA2 (13, 14). This is compatible with the possibility that the Group VI iPLA2 acts to remodel membrane phospholipids as a sort of housekeeping enzyme as will be discussed later.

Inhibition of iPLA2

The functional significance of intracellular iPLA2 can most easily be investigated using selective inhibitors. Unfortunately, no specific iPLA2 inhibitors currently exist. As indicated above, the apparent presence of an active site Ser residue in Group VI iPLA2 is similar to that of the Group IV cPLA2. Thus, the cPLA2 inhibitors currently available, which were designed as site-directed inhibitors, all inhibit the Group VI iPLA2 as well. These include arachidonyl trifluoromethyl ketone (6), arachidonyl tricarbonyl (6), and methyl arachidonyl fluorophosphonate (7). These three compounds contain an arachidonyl tail and function as transition-state analogues in a reversible or irreversible manner. The arachidonyl tail was intended to confer selectivity to the inhibitors and to facilitate their access to the cPLA2 active site (15, 16), as this enzyme selectively hydrolyzes arachidonate-containing phospholipids (17, 18). Remarkably, even though the iPLA2 is not AA-specific (11), these inhibitors work even better on the iPLA2 than on the cPLA2 (6, 7). Furthermore, palmityl trifluoromethyl ketone and palmityl tricarbonyl are as good inhibitors of both the Group IV cPLA2 and Group VI iPLA2 as their arachidonyl analogs (6, 12).

Due to the lack of selectivity of the aforementioned compounds, it is unlikely that they will find much use in defining the role of the iPLA2 in cell function, unless the process under study is truly Ca2+-independent. Inhibition studies employing the fatty acyl trifluoromethyl ketones, tricarbonyls, or fluorophosphonates in the absence of Ca2+ might selectively target the iPLA2, as this is the only one of the well studied cellular PLA2s that remains active under Ca2+-depleted conditions.

One common feature of the two best characterized intracellular iPLA2s, namely the Group VI enzyme present in P388D1 macrophages (12) and CHO cells (14) and a 40-kDa iPLA2 present in myocardial tissue and pancreatic islets (19), is their complete and irreversible inhibition by the mechanism-based inhibitor BEL. This inhibitor was first introduced as a serine protease inhibitor (20) but has been shown to be specific for iPLA2 over Ca2+-dependent sPLA2s (19, 21) and Group IV Ca2+-dependent cPLA2 (21). In addition, BEL does not affect a number of enzyme activities directly involved in cellular AA metabolism (22). Thus BEL has received great attention because of its possible use as a selective iPLA2 inhibitor in whole cell studies. As a matter of fact, much of what is currently believed to be mediated by iPLA2 enzymes has been derived from studies using BEL. Unfortunately, BEL has recently been found to inhibit another key enzyme in cellular phospholipid metabolism, the Mg2+-dependent phosphatidic acid phosphohydrolase (PAP-1) (23). The latter enzyme catalyzes the dephosphorylation of phosphatidic acid to yield 1,2-diacylglycerol (DAG), a central intermediate in glycerolipid synthesis as well as an important intracellular messenger molecule. Therefore, BEL cannot be used as a selective iPLA2 inhibitor in whole cell studies unless it is demonstrated that the process under study is independent of variations in cellular DAG levels as well as Ca2+; even then BEL is known to inhibit proteases and may affect other enzymes as well. The implications will be discussed in the next section.

Function of Group VI iPLA2 in Membrane Phospholipid Remodeling

There exists in cells an ongoing deacylation/reacylation cycle of membrane phospholipids, the so-called Lands cycle, whereby a pre-existing phospholipid is cleaved by an intracellular PLA2 to generate a 2-lysophospholipid, which in turn may be re-acylated with a different fatty acid to generate a new phospholipid (22, 24). This remodeling cycle constitutes the major route for incorporation of free AA into the phospholipids of cells at nanomolar levels of the free fatty acid (Fig. 1) (22, 24). The de novo route or Kennedy pathway constitutes, in addition, a second route for incorporation of AA into cellular phospholipids (Fig. 1). However, the Kennedy pathway appears to be relevant in terms of AA incorporation only when high, micromolar levels of free AA are available (25).

Fig. 1. De novo and remodeling pathways for incorporation of free fatty acid into phospholipids. In the de novo pathway free fatty acid, provided to the cell or liberated by endogenous phospholipases, is incorporated via fatty acyl-CoA into glycerol phosphate (GP) or dihydroxyacetone phosphate (DHAP) and into the resulting lysophosphatidic acid (LysoPA) by fatty acyl-CoA acyltransferases to form phosphatidic acid (PA). In mammalian cells, the phosphatidic acid can be converted to phosphatidylinositol (PI) or can be converted to diacylglycerol (DG), which is the precursor for phosphatidylcholine (PC) and phosphatidylethanolamine (PE), which in turn forms phosphatidylserine (PS). In contrast, in the remodeling pathway, preformed phosphatidylinositol, phosphatidylserine, phosphatidylcholine, or phosphatidylethanolamine is acted on by iPLA2 to produce lysophosphatidylinositol, lysophosphatidylserine, lysophosphatidylcholine, or lysophosphatidylethanolamine; these can be reacylated by acyltransferases using fatty acyl-CoA. Adapted with permission from Ref. 22.
[View Larger Version of this Image (184K GIF file)]

Thus, AA incorporation into phospholipids under normal conditions is strikingly dependent on a PLA2 that generates the 2-lysophospholipid used in the acylation reaction. Macrophages and macrophage cell lines possess a high capacity to incorporate AA into their membrane phospholipids (26, 27). This process occurs in a Ca2+-independent manner (22, 26), suggesting the involvement of an iPLA2. Consistent with this observation, BEL inhibits AA esterification in a dose-dependent and saturatable manner, and the decrease in AA incorporation directly correlates with inhibition of both cellular iPLA2 activity and steady-state lysophospholipid levels (22). Although the lack of BEL specificity now raises some doubt about the firmness of this conclusion, it is important to stress here that AA esterification via phospholipid remodeling is independent of variations in DAG levels. Moreover, BEL does not reduce the cellular steady-state levels of DAG.2 Thus, the possible parallel inhibition of PAP-1 by BEL should not affect the basal rate of AA incorporation into phospholipids.

The nucleotide sequence for the Group VI murine iPLA2 is now available (14). This has enabled us to utilize more convincing molecular biological approaches, such as antisense inhibition studies, to ascertain the role of the Group VI iPLA2 in cellular phospholipid metabolism. Antisense inhibition of the Group VI iPLA2 has confirmed that this enzyme does play a role in phospholipid remodeling as iPLA2-depleted cells show a significant reduction of their capacity to incorporate AA into membrane phospholipids.2 Moreover, the decreased incorporation of AA into phospholipids that iPLA2-depleted cells manifest is not further decreased by BEL,2 demonstrating that this compound is indeed targeting the iPLA2 in the previous experiments (22).

Collectively, these findings suggest that the Group VI iPLA2 is responsible for phospholipid fatty acid remodeling under resting conditions. Hence this enzyme appears to regulate the main pathway through which the cells incorporate AA and other unsaturated fatty acids into their membrane phospholipids. In addition to its obvious importance in cellular metabolism, the rate of AA incorporation into phospholipids also determines the amount of free fatty acid available under resting conditions. This is relevant because free AA availability is a limiting factor for eicosanoid biosynthesis. By regulating basal AA esterification reactions, the Group VI iPLA2 may also play a key role in regulating the amount of prostaglandins synthesized by resting cells.

On the other hand, there is now strong evidence for the existence of different AA pools within the cells (21, 28) that can be utilized by distinct Ca2+-dependent PLA2s during cell activation (21). The role of CoA-independent transacylase in regulating the asymmetric distribution of AA among different phospholipid subclasses has recently become evident (24). However, as the iPLA2-mediated reaction precedes the action of the CoA-independent transacylase, it is possible that the iPLA2 determines both the subcellular distribution of this fatty acid among the different cellular compartments and the relative amount of fatty acid present in each compartment before further remodeling reactions catalyzed by the CoA-independent transacylase take place (Fig. 2).

Fig. 2. A model for PLA2-mediated pathways for AA metabolism in P388D1 macrophages. PAF receptor-mediated AA mobilization in lipopolysaccharide (LPS)-primed P388D1 macrophages involves the action of two distinct Ca2+-dependent PLA2s, i.e. cPLA2 and sPLA2, acting on different AA pools located at distinct cellular membranes. The iPLA2 mediates incorporation of AA at these two intracellular locations before further remodeling reactions take place. PGE2, prostaglandin E2; PLC, phospholipase C; FA, fatty acid; [1,4,5]-IP3, inositol 1,4,5-trisphosphate; R, fatty acid or alcohol; PX, phosphobase. Adapted with permission from Ref. 21.
[View Larger Version of this Image (117K GIF file)]

Other Proposed Functions for Intracellular iPLA2s

Based solely on BEL effects, the iPLA2 has been suggested to mediate AA release in different cells stimulated with various agonists (29-31). It is known, however, that during cell stimulation DAG levels rise appreciably, and this may influence agonist-induced AA release, either directly (by providing DAG substrate for the release) (32) or indirectly (by activating protein kinase C) (33). As discussed above, BEL has recently been found to inhibit cellular PAP-1 activity (23). It is likely that PAP-1 plays a role in raising intracellular DAG levels during signal transduction, particularly in those settings where the de novo phospholipid biosynthetic pathway is involved (34). Thus, the reported effects of BEL on agonist-induced AA release might also be due, at least in part, to inhibition of PAP-1 in addition to the iPLA2.

The following example may better illustrate the uncertainty of BEL effects on agonist-induced AA mobilization. In studies with glucose- and carbachol-stimulated pancreatic islets, Ramanadham et al. (29) proposed the iPLA2 as the major mediator of AA release on the basis of its inhibition by BEL. However, Konrad et al. (35) have suggested that the DAG lipase pathway constitutes the major route for AA release in the same system. The results by these two groups could be reconciled if BEL was inhibiting DAG generation in the work by Ramanadham et al. (29). On the other hand, it is interesting to note that in systems where agonist-stimulated AA release appears not to depend on DAG-induced protein kinase C activation, such as PAF-stimulated P388D1 macrophages (36), BEL is ineffective in inhibiting this release (21).

Involvement of an iPLA2 in stimulus-induced AA release has also been suggested by Lennartz and colleagues (37, 38) in studies with human monocytes. During immunoglobulin G-mediated phagocytosis, human monocytes release AA in a Ca2+-independent manner (37). Consistent with the possible involvement of an iPLA2, AA release in this system is blocked by BEL (37). The process was later found to be dependent on protein kinase C activation (38). Thus, the BEL effects could be partly due to protein kinase C dependence on DAG, although the finding that the process takes place in the absence of Ca2+ lends credence to the possible involvement of an iPLA2.

It is generally difficult to rationalize the involvement of a Ca2+-independent enzyme in processes such as AA release, which in most cases is strongly Ca2+-dependent. Wolf and Gross (39) have recently reported that a 40-kDa myocardial iPLA2 associates with calmodulin in a Ca2+-dependent manner, providing a mechanism through which Ca2+ may regulate a Ca2+-independent enzyme. According to these authors, myocardial iPLA2 is inactive when associated with calmodulin. Dissociation of the complex due to decreases in the Ca2+ concentration or addition of calmodulin antagonists renders the iPLA2 ready to attack phospholipids and release AA (39). This mechanism has been proposed to mediate the cardiac cycle-dependent alterations in PLA2-catalyzed release of AA (39).

Before the reported association with calmodulin, the 40-kDa iPLA2 activity from myocardial tissue and pancreatic islets was reported to associate to phosphofructokinase or an antigenically related protein (40, 41). Due to their very distinct biochemical properties and molecular sizes, it appears clear that the 40-kDa iPLA2 activity identified in myocardium and pancreatic islets is different from the Group VI enzyme present in P388D1 macrophages and CHO cells (41). However, as a common feature, the two proteins exist as catalytic complexes of about 340 kDa (11). The Group VI iPLA2 has been shown to possess eight ankyrin repeats, which may mediate self-aggregation or interaction with other proteins (13). It is possible that the 40-kDa myocardial iPLA2 activity possesses similar motifs that mediate its interaction with other proteins such as phosphofructokinase and calmodulin; however, the sequence of the 40-kDa protein has not yet been elucidated. Thus, its relationship with the Group VI iPLA2, if any, cannot be ascertained at this time. However, analogous to the Group VI iPLA2 (11), the 40-kDa activity is stimulated by ATP in vitro (40). Recent data by our laboratory have shown that, rather than stimulating enzyme activity, ATP stabilizes and protects the iPLA2 from inactivation during the assay; hence, higher activity is found in the presence than in the absence of ATP and other nucleotides (14). Thus there is no evidence that ATP plays a regulatory role for the Group VI iPLA2 in vivo.

Concluding Remarks

The importance of the intracellular iPLA2 in control of cell function has not been clearly established at present, despite the fact that iPLA2s have been found to exist in all cells and tissues examined. Currently, many new iPLA2s are being purified and characterized (8, 42-44). The widespread occurrence of iPLA2s suggests that this class of enzymes may play important roles in cell physiology. Fatty acid remodeling of membrane phospholipids in macrophages appears to be an event most likely mediated by intracellular iPLA2s. Currently, much of the data available on cellular iPLA2 function relies on the use of inhibitors that have been shown not to be selective for this class of enzymes. However, these inhibitors may offer leads for the development of more selective agents that may help to uncover new roles for intracellular iPLA2s in cellular functioning.

FOOTNOTES

*   This minireview will be reprinted in the 1997 Minireview Compendium, which will be available in December, 1997. This is the third article of six in "A Thematic Series on Phospholipases." Work in the authors' laboratory was supported by National Institutes of Health Grants HD 26171, GM 20501, and GM 51606.
Dagger    To whom correspondence should be addressed. Tel.: 619-534-3055; Fax: 619-534-7390; E-mail: edennis{at}ucsd.edu.
1   The abbreviations used are: PLA2, phospholipase A2; sPLA2, secretory Ca2+-dependent phospholipase A2; cPLA2, 85-kDa Ca2+-dependent cytosolic phospholipase A2; iPLA2, Ca2+-independent cytosolic phospholipase A2; BEL, bromoenol lactone; PAP-1, Mg2+-dependent phosphatidic acid phosphohydrolase; PAF, platelet-activating factor; AA, arachidonic acid; DAG, 1,2-diacylglycerol; CHO, Chinese hamster ovary.
2   J. Balsinde, M. A. Balboa, and E. A. Dennis, manuscript in preparation.

REFERENCES

  1. Dennis, E. A. (1994) J. Biol. Chem. 269, 13057-13060 [Free Full Text]
  2. Dennis, E. A. (1997) Trends Biochem. Sci. 22, 1-2 [CrossRef][Medline] [Order article via Infotrieve]
  3. Reynolds, L. J., Hughes, L. L., Louis, A. I., Kramer, R. M., and Dennis, E. A. (1993) Biochim. Biophys. Acta 1167, 272-280 [Medline] [Order article via Infotrieve]
  4. Sharp, 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., and Kramer, R. M. (1994) J. Biol. Chem. 269, 23250-23254 [Abstract/Free Full Text]
  5. Pickard, R. T., Chiou, X. G., Strifler, B. A., DeFelippis, M. R., Hyslop, P. A., Tebbe, A. L., Yee, Y. K., Reynolds, L. J., Dennis, E. A., Kramer, R. M., and Sharp, J. D. (1996) J. Biol. Chem. 271, 19225-19231 [Abstract/Free Full Text]
  6. Conde-Frieboes, K., Reynolds, L. J., Lio, Y. C., Hale, M. R., Wasserman, H. H., and Dennis, E. A. (1996) J. Am. Chem. Soc. 118, 5519-5525 [CrossRef]
  7. Lio, Y. C., Reynolds, L. J., Balsinde, J., and Dennis, E. A. (1996) Biochim. Biophys. Acta 1302, 55-60 [Medline] [Order article via Infotrieve]
  8. Ackermann, E. J., and Dennis, E. A. (1995) Biochim. Biophys. Acta 1259, 125-136 [Medline] [Order article via Infotrieve]
  9. Hattori, M., Adachi, H., Tsujimoto, M., Arai, H., and Inoue, K. (1994) J. Biol. Chem. 269, 23150-23155 [Abstract/Free Full Text]
  10. Ross, M. I., Deems, R. A., Jesaitis, A. J., Dennis, E. A., and Ulevitch, R. J. (1985) Arch. Biochem. Biophys. 238, 247-258 [CrossRef][Medline] [Order article via Infotrieve]
  11. Ackermann, E. J., Kempner, E. S., and Dennis, E. A. (1994) J. Biol. Chem. 269, 9227-9233 [Abstract/Free Full Text]
  12. Ackermann, E. J., Conde-Frieboes, K., and Dennis, E. A. (1995) J. Biol. Chem. 270, 445-450 [Abstract/Free Full Text]
  13. Tang, J., Kriz, R. W., Wolfman, N., Shaffer, M., Seehra, J., and Jones, S. S. (1997) J. Biol. Chem. 272, 8567-8575 [Abstract/Free Full Text]
  14. Balboa, M. A., Balsinde, J., Jones, S. S., and Dennis, E. A. (1997) J. Biol. Chem. 272, 8576-8580 [Abstract/Free Full Text]
  15. Street, I. P., Lin, H. K., Laliberté, F., Ghomashchi, F., Wang, Z., Perrier, H., Tremblay, N. M., Huang, Z., Weech, P. K., and Gelb, M. H. (1993) Biochemistry 32, 5935-5940 [CrossRef][Medline] [Order article via Infotrieve]
  16. Huang, Z., Payette, P., Abdullah, K., Cromlish, W. A., and Kennedy, B. P. (1996) Biochemistry 35, 3712-3721 [CrossRef][Medline] [Order article via Infotrieve]
  17. Clark, J. D., Milona, N., and Knopf, J. L. (1990) Proc. Natl. Acad. Sci. U. S. A. 87, 7708-7712 [Abstract/Free Full Text]
  18. Kramer, R. M., Roberts, E. F., Manetta, J., and Putnam, J. E. (1991) J. Biol. Chem. 266, 5268-5272 [Abstract/Free Full Text]
  19. Hazen, S. L., Zupan, L. A., Weiss, R. H., Getman, D. P., and Gross, R. W. (1991) J. Biol. Chem. 266, 7227-7232 [Abstract/Free Full Text]
  20. Daniels, S. B., and Katzenellenbogen, J. A. (1986) Biochemistry 25, 1436-1444 [CrossRef][Medline] [Order article via Infotrieve]
  21. Balsinde, J., and Dennis, E. A. (1996) J. Biol. Chem. 271, 6758-6765 [Abstract/Free Full Text]
  22. Balsinde, J., Bianco, I. D., Ackermann, E. J., Conde-Frieboes, K., and Dennis, E. A. (1995) Proc. Natl. Acad. Sci. U. S. A. 92, 8527-8531 [Abstract/Free Full Text]
  23. Balsinde, J., and Dennis, E. A. (1996) J. Biol. Chem. 271, 31937-31941 [Abstract/Free Full Text]
  24. Chilton, F. H., Fonteh, A. N., Surette, M. E., Triggiani, M., and Winkler, J. D. (1996) Biochim. Biophys. Acta 1299, 1-15 [Medline] [Order article via Infotrieve]
  25. Balsinde, J., and Dennis, E. A. (1996) Eur. J. Biochem. 235, 480-485 [Medline] [Order article via Infotrieve]
  26. Balsinde, J., Fernández, B., and Solís-Herruzo, J. A. (1994) Eur. J. Biochem. 221, 1013-1018 [Medline] [Order article via Infotrieve]
  27. Balsinde, J., Barbour, S. E., Bianco, I. D., and Dennis, E. A. (1994) Proc. Natl. Acad. Sci. U. S. A. 91, 11060-11064 [Abstract/Free Full Text]
  28. Fonteh, A. N., and Chilton, F. H. (1993) J. Immunol. 150, 563-570 [Abstract]
  29. Ramanadham, S., Gross, R. W., Han, X., and Turk, J. (1993) Biochemistry 32, 337-346 [CrossRef][Medline] [Order article via Infotrieve]
  30. Lehman, J. J., Brown, K. A., Ramanadham, S., Turk, J., and Gross, R. W. (1993) J. Biol. Chem. 268, 20713-20716 [Abstract/Free Full Text]
  31. Gross, R. W., Rudolph, A. E., Wang, J., Sommers, C. D., and Wolf, M. J. (1995) J. Biol. Chem. 270, 14855-14858 [Abstract/Free Full Text]
  32. Balsinde, J., Diez, E., and Mollinedo, F. (1991) J. Biol. Chem. 266, 15638-15643 [Abstract/Free Full Text]
  33. Nishizuka, Y. (1995) FASEB J. 9, 484-496 [Abstract]
  34. Martin, A., Gómez-Muñoz, A., Duffy, P. A., and Brindley, D. N. (1994) in Signal-activated Phospholipases (Liscovitch, M., ed), pp. 139-164, Landes Co., Austin
  35. Konrad, R. J., Major, C. D., and Wolf, B. A. (1994) Biochemistry 33, 13284-13294 [CrossRef][Medline] [Order article via Infotrieve]
  36. Balsinde, J., Balboa, M. A., Insel, P. A., and Dennis, E. A. (1997) Biochem. J. 321, 805-809
  37. Lennartz, M. R., Lefkowith, J. B., Bromley, F. A., and Brown, E. J. (1993) J. Leukocyte Biol. 54, 389-398 [Abstract]
  38. Karimi, K., and Lennartz, M. R. (1995) J. Immunol. 155, 5786-5794 [Abstract]
  39. Wolf, M. J., and Gross, R. W. (1996) J. Biol. Chem. 271, 20989-20992 [Abstract/Free Full Text]
  40. Hazen, S. L., and Gross, R. W. (1993) J. Biol. Chem. 268, 9892-9900 [Abstract/Free Full Text]
  41. Ramanadham, S., Wolf, M. J., Ma, Z., Li, B., Wang, J., Gross, R. W., and Turk, J. (1996) Biochemistry 35, 5464-5471 [CrossRef][Medline] [Order article via Infotrieve]
  42. Portilla, D., and Dai, G. (1996) J. Biol. Chem. 271, 15451-15457 [Abstract/Free Full Text]
  43. Farooqui, A. A., Yang, H. C., and Horrocks, L. A. (1995) Brain Res. Rev. 21, 152-161 [CrossRef][Medline] [Order article via Infotrieve]
  44. Thomson, F. J., and Clark, M. A. (1995) Biochem. J. 306, 305-309
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.
Add to CiteULike CiteULike   Add to Complore Complore   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us   Add to Digg Digg   Add to Reddit Reddit   Add to Technorati Technorati    What's this?


This article has been cited by other articles:


Home page
 J. Physiol.Home page
V. M. Bolotina
Orai, STIM1 and iPLA2{beta}: a view from a different perspective
J. Physiol., July 1, 2008; 586(13): 3035 - 3042.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Heart Circ. Physiol.Home page
K. M. Park, M. Trucillo, N. Serban, R. A. Cohen, and V. M. Bolotina
Role of iPLA2 and store-operated channels in agonist-induced Ca2+ influx and constriction in cerebral, mesenteric, and carotid arteries
Am J Physiol Heart Circ Physiol, March 1, 2008; 294(3): H1183 - H1187.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
W. Tian, G. T. Wijewickrama, J. H. Kim, S. Das, M. P. Tun, N. Gokhale, J. W. Jung, K. P. Kim, and W. Cho
Mechanism of Regulation of Group IVA Phospholipase A2 Activity by Ser727 Phosphorylation
J. Biol. Chem., February 15, 2008; 283(7): 3960 - 3971.
[Abstract] [Full Text] [PDF]

Home page
 BloodHome page
L. Blanc, C. Barres, P. Bette-Bobillo, and M. Vidal
Reticulocyte-secreted exosomes bind natural IgM antibodies: involvement of a ROS-activatable endosomal phospholipase iPLA2
Blood, November 1, 2007; 110(9): 3407 - 3416.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
S. Bao, Y. Li, X. Lei, M. Wohltmann, W. Jin, A. Bohrer, C. F. Semenkovich, S. Ramanadham, I. Tabas, and J. Turk
Attenuated Free Cholesterol Loading-induced Apoptosis but Preserved Phospholipid Composition of Peritoneal Macrophages from Mice That Do Not Express Group VIA Phospholipase A2
J. Biol. Chem., September 14, 2007; 282(37): 27100 - 27114.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
Z. Xie, M. C. Gong, W. Su, J. Turk, and Z. Guo
Group VIA Phospholipase A2 (iPLA2beta) Participates in Angiotensin II-induced Transcriptional Up-regulation of Regulator of G-protein Signaling-2 in Vascular Smooth Muscle Cells
J. Biol. Chem., August 31, 2007; 282(35): 25278 - 25289.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
N. Panupinthu, L. Zhao, F. Possmayer, H. Z. Ke, S. M. Sims, and S. J. Dixon
P2X7 Nucleotide Receptors Mediate Blebbing in Osteoblasts through a Pathway Involving Lysophosphatidic Acid
J. Biol. Chem., February 2, 2007; 282(5): 3403 - 3412.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
S. Bao, H. Song, M. Wohltmann, S. Ramanadham, W. Jin, A. Bohrer, and J. Turk
Insulin Secretory Responses and Phospholipid Composition of Pancreatic Islets from Mice That Do Not Express Group VIA Phospholipase A2 and Effects of Metabolic Stress on Glucose Homeostasis
J. Biol. Chem., July 28, 2006; 281(30): 20958 - 20973.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
G. T. Wijewickrama, J.-H. Kim, Y. J. Kim, A. Abraham, Y. Oh, B. Ananthanarayanan, M. Kwatia, S. J. Ackerman, and W. Cho
Systematic Evaluation of Transcellular Activities of Secretory Phospholipases A2: HIGH ACTIVITY OF GROUP V PHOSPHOLIPASES A2 TO INDUCE EICOSANOID BIOSYNTHESIS IN NEIGHBORING INFLAMMATORY CELLS
J. Biol. Chem., April 21, 2006; 281(16): 10935 - 10944.
[Abstract] [Full Text] [PDF]

Home page
 J. Lipid Res.Home page
R. Perez, X. Matabosch, A. Llebaria, M. A. Balboa, and J. Balsinde
Blockade of arachidonic acid incorporation into phospholipids induces apoptosis in U937 promonocytic cells
J. Lipid Res., March 1, 2006; 47(3): 484 - 491.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
R. Perez, M. A. Balboa, and J. Balsinde
Involvement of Group VIA Calcium-Independent Phospholipase A2 in Macrophage Engulfment of Hydrogen Peroxide-Treated U937 Cells
J. Immunol., February 15, 2006; 176(4): 2555 - 2561.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
S. Bao, A. Bohrer, S. Ramanadham, W. Jin, S. Zhang, and J. Turk
Effects of Stable Suppression of Group VIA Phospholipase A2 Expression on Phospholipid Content and Composition, Insulin Secretion, and Proliferation of INS-1 Insulinoma Cells
J. Biol. Chem., January 6, 2006; 281(1): 187 - 198.
[Abstract] [Full Text] [PDF]

Home page
 J. Lipid Res.Home page
A. Denys, A. Hichami, and N. A. Khan
n-3 PUFAs modulate T-cell activation via protein kinase C-{alpha} and -{varepsilon} and the NF-{kappa}B signaling pathway
J. Lipid Res., April 1, 2005; 46(4): 752 - 758.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
R. Pawliczak, C. Logun, P. Madara, M. Lawrence, G. Woszczek, A. Ptasinska, M. L. Kowalski, T. Wu, and J. H. Shelhamer
Cytosolic Phospholipase A2 Group IV{alpha} but Not Secreted Phospholipase A2 Group IIA, V, or X Induces Interleukin-8 and Cyclooxygenase-2 Gene and Protein Expression through Peroxisome Proliferator-activated Receptors {gamma} 1 and 2 in Human Lung Cells
J. Biol. Chem., November 19, 2004; 279(47): 48550 - 48561.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
R. Perez, R. Melero, M. A. Balboa, and J. Balsinde
Role of Group VIA Calcium-independent Phospholipase A2 in Arachidonic Acid Release, Phospholipid Fatty Acid Incorporation, and Apoptosis in U937 Cells Responding to Hydrogen Peroxide
J. Biol. Chem., September 24, 2004; 279(39): 40385 - 40391.
[Abstract] [Full Text] [PDF]

Home page
 J. Leukoc. Biol.Home page
I. F. Liberty, L. Raichel, Z. Hazan-Eitan, I. Pessach, N. Hadad, F. Schlaeffer, and R. Levy
Cytosolic phospholipase A2 is responsible for prostaglandin E2 and leukotriene B4 formation in phagocyte-like PLB-985 cells: studies of differentiated cPLA2-deficient PLB-985 cells
J. Leukoc. Biol., July 1, 2004; 76(1): 176 - 184.
[Abstract] [Full Text] [PDF]

Home page
 FASEB J.Home page
D. W. GILROY, J. NEWSON, P. SAWMYNADEN, D. A. WILLOUGHBY, and J. D. CROXTALL
A novel role for phospholipase A2 isoforms in the checkpoint control of acute inflammation
FASEB J, March 1, 2004; 18(3): 489 - 498.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
N. M. Munoz, Y. J. Kim, A. Y. Meliton, K. P. Kim, S.-K. Han, E. Boetticher, E. O'Leary, S. Myou, X. Zhu, J. V. Bonventre, et al.
Human Group V Phospholipase A2 Induces Group IVA Phospholipase A2-independent Cysteinyl Leukotriene Synthesis in Human Eosinophils
J. Biol. Chem., October 3, 2003; 278(40): 38813 - 38820.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
W. K. Han, A. Sapirstein, C. C. Hung, A. Alessandrini, and J. V. Bonventre
Cross-talk between Cytosolic Phospholipase A2{alpha} (cPLA2{alpha}) and Secretory Phospholipase A2 (sPLA2) in Hydrogen Peroxide-induced Arachidonic Acid Release in Murine Mesangial Cells: sPLA2 REGULATES cPLA2{alpha} ACTIVITY THAT IS RESPONSIBLE FOR ARACHIDONIC ACID RELEASE
J. Biol. Chem., June 20, 2003; 278(26): 24153 - 24163.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
T. Smani, S. I. Zakharov, E. Leno, P. Csutora, E. S. Trepakova, and V. M. Bolotina
Ca2+-independent Phospholipase A2 Is a Novel Determinant of Store-operated Ca2+ Entry
J. Biol. Chem., March 28, 2003; 278(14): 11909 - 11915.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
Z. Guo, W. Su, Z. Ma, G. M. Smith, and M. C. Gong
Ca2+-independent Phospholipase A2 Is Required for Agonist-induced Ca2+ Sensitization of Contraction in Vascular Smooth Muscle
J. Biol. Chem., January 10, 2003; 278(3): 1856 - 1863.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
Y. J. Kim, K. P. Kim, S. K. Han, N. M. Munoz, X. Zhu, H. Sano, A. R. Leff, and W. Cho
Group V Phospholipase A2 Induces Leukotriene Biosynthesis in Human Neutrophils through the Activation of Group IVA Phospholipase A2
J. Biol. Chem., September 20, 2002; 277(39): 36479 - 36488.
[Abstract] [Full Text] [PDF]

Home page
 Plant Physiol.Home page
A. Holk, S. Rietz, M. Zahn, H. Quader, and G. F.E. Scherer
Molecular Identification of Cytosolic, Patatin-Related Phospholipases A from Arabidopsis with Potential Functions in Plant Signal Transduction
Plant Physiology, September 1, 2002; 130(1): 90 - 101.
[Abstract] [Full Text] [PDF]

Home page
 J. Pharmacol. Exp. Ther.Home page
E. Bloch-Shilderman, S. Abu-Raya, V. Trembovler, H. Boschwitz, A. Gruzman, M. Linial, and P. Lazarovici
Pardaxin Stimulation of Phospholipases A2 and Their Involvement in Exocytosis in PC-12 Cells
J. Pharmacol. Exp. Ther., June 1, 2002; 301(3): 953 - 962.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
K. A. Carnevale and M. K. Cathcart
Calcium-Independent Phospholipase A2 Is Required for Human Monocyte Chemotaxis to Monocyte Chemoattractant Protein 1
J. Immunol., September 15, 2001; 167(6): 3414 - 3421.
[Abstract] [Full Text] [PDF]

Home page
 J. Lipid Res.Home page
Y. J. Jiang, G. M. Hatch, D. Mymin, T. Dembinski, E. A. Kroeger, and P. C. Choy
Modulation of cytosolic phospholipase A2 by PPAR activators in human preadipocytes
J. Lipid Res., May 1, 2001; 42(5): 716 - 724.
[Abstract] [Full Text]

Home page
 HypertensionHome page
J.-H. Parmentier, M. M. Muthalif, A. T. Nishimoto, and K. U. Malik
20-Hydroxyeicosatetraenoic Acid Mediates Angiotensin II-Induced Phospholipase D Activation in Vascular Smooth Muscle Cells
Hypertension, February 1, 2001; 37(2): 623 - 629.
[Abstract] [Full Text] [PDF]

Home page
 J. Pharmacol. Exp. Ther.Home page
B. M. Marcic and E. G. Erdös
Protein Kinase C and Phosphatase Inhibitors Block the Ability of Angiotensin I-Converting Enzyme Inhibitors to Resensitize the Receptor to Bradykinin without Altering the Primary Effects of Bradykinin
J. Pharmacol. Exp. Ther., August 1, 2000; 294(2): 605 - 612.
[Abstract] [Full Text]

Home page
 J. Immunol.Home page
I. Walev, J. Klein, M. Husmann, A. Valeva, S. Strauch, H. Wirtz, O. Weichel, and S. Bhakdi
Potassium Regulates IL-1{beta} Processing Via Calcium-Independent Phospholipase A2
J. Immunol., May 15, 2000; 164(10): 5120 - 5124.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
T. A. Lagace, M. K. Storey, and N. D. Ridgway
Regulation of Phosphatidylcholine Metabolism in Chinese Hamster Ovary Cells by the Sterol Regulatory Element-binding Protein (SREBP)/SREBP Cleavage-activating Protein Pathway
J. Biol. Chem., May 5, 2000; 275(19): 14367 - 14374.
[Abstract] [Full Text] [PDF]

Home page