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W2066791280 abstract "Phospholipase D (PLD) 1The abbreviations used are: PLD, phospholipase D; PC, phosphatidylcholine; PIP2, phosphatidylinositol 4,5-bisphosphate; PIP3, phosphatidylinositol 4,5-trisphosphate; PI, phosphatidylinositol; PA, phosphatidic acid; PKC, protein kinase C; ARF, ADP-ribosylation factor; GTPγS, guanosine 5′-O-(3-thiotriphosphate); LPA, lysophosphatidic acid; DAG, diacylglycerol. 1The abbreviations used are: PLD, phospholipase D; PC, phosphatidylcholine; PIP2, phosphatidylinositol 4,5-bisphosphate; PIP3, phosphatidylinositol 4,5-trisphosphate; PI, phosphatidylinositol; PA, phosphatidic acid; PKC, protein kinase C; ARF, ADP-ribosylation factor; GTPγS, guanosine 5′-O-(3-thiotriphosphate); LPA, lysophosphatidic acid; DAG, diacylglycerol. (1Exton, J. H. (1997) Physiol. Rev., in press.Google Scholar) is present in bacteria, fungi, plants, and animals. It is widely distributed in mammalian cells, where it is regulated by a variety of hormones, growth factors, and other extracellular signals. Its major substrate is phosphatidylcholine (PC), which is hydrolyzed to phosphatidic acid (PA) and choline, but it can also act on phosphatidylethanolamine and phosphatidylinositol in some organisms and tissues. It also catalyzes a phosphatidyl transfer reaction in which a primary alcohol acts as nucleophilic acceptor in place of H2O. The resulting production of phosphatidyl alcohol represents a specific assay for PLD. PLD has been partially purified from many sources (1Exton, J. H. (1997) Physiol. Rev., in press.Google Scholar) and has recently been cloned from yeast, bacteria, plant, and mammalian sources (2Morris A.J. Engebrecht J.A. Frohman M.A. Trends Pharmacol. Sci. 1996; 17: 182-185Abstract Full Text PDF PubMed Scopus (176) Google Scholar). The enzymes from Saccharomyces, Ricinus(castor bean), and Streptomyces have several sequences that are conserved in the human enzyme (Fig. 1) (2Morris A.J. Engebrecht J.A. Frohman M.A. Trends Pharmacol. Sci. 1996; 17: 182-185Abstract Full Text PDF PubMed Scopus (176) Google Scholar), and these presumably represent components of the catalytic site. These sequences are also found in cardiolipin synthase and phosphatidylserine synthase from Escherichia coli (2Morris A.J. Engebrecht J.A. Frohman M.A. Trends Pharmacol. Sci. 1996; 17: 182-185Abstract Full Text PDF PubMed Scopus (176) Google Scholar, 3Ponting C.P. Kerr I.D. Protein Sci. 1996; 5: 914-922Crossref PubMed Scopus (283) Google Scholar) (Fig. 1). These enzymes also catalyze phosphatidyl transfer, suggesting that PLD is a member of a larger family of enzymes (2Morris A.J. Engebrecht J.A. Frohman M.A. Trends Pharmacol. Sci. 1996; 17: 182-185Abstract Full Text PDF PubMed Scopus (176) Google Scholar, 3Ponting C.P. Kerr I.D. Protein Sci. 1996; 5: 914-922Crossref PubMed Scopus (283) Google Scholar). The first reported mammalian PLD (hPLD1a) has 1072 amino acids and a molecular mass of 124 kDa (4Hammond S.M. Altshuller Y.M. Sung T-C. Rudge S.A. Rose K. Engebrecht J.A. Morris A.J. Frohman M.A. J. Biol. Chem. 1995; 270: 29640-29643Abstract Full Text Full Text PDF PubMed Scopus (597) Google Scholar). It is specific for PC and was obtained by using the yeast PLD gene (SPO14) (5Rose K. Rudge S.A. Frohman M.A. Morris A.J. Engebrecht J.A. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 12151-12155Crossref PubMed Scopus (197) Google Scholar) to identify a human expressed sequence tag for screening a HeLa cDNA library. A shorter splice variant of hPLD1a with 1034 amino acids (hPLD1b) (Fig. 1), which has similar regulatory properties, has been identified (6Hammond S.M. Jenco J.M. Nakashima S. Cadwallader K. Gu Q-m. Cook S. Nozawa Y. Prestwich G.D. Frohman M.A. Morris A.J. J. Biol. Chem. 1997; 272: 3860-3868Abstract Full Text Full Text PDF PubMed Scopus (496) Google Scholar), and another PLD (PLD2) (Fig. 1), which has 932 amino acids and 51% amino acid sequence identity to hPLD1a, has been cloned from a mouse embryonic library (7Colley W.C. Sung T-C. Roll R. Jenco J. Hammond S.M. Altshuller Y. Bar-Sagi D. Morris A.J. Frohman M.A. Curr. Biol. 1997; 7: 191-201Abstract Full Text Full Text PDF PubMed Scopus (634) Google Scholar). In our laboratory, enzymes corresponding to hPLD1a and hPLD1b have been cloned from rat tissues. 2S.-K. Park, J. I. Provost, C. D. Bae, W.-T. Ho, and J. H. Exton, submitted for publication. The regulation of these cloned enzymes will be discussed below. Other PLDs have been identified in human tissues and C6 glioma cells (8Ribbes G. Henry J. Cariven C. Pontarotti P. Chap H. Record M. Biochem. Biophys. Res. Commun. 1996; 224: 206-211Crossref PubMed Scopus (12) Google Scholar, 9Yoshimura S-i. Nakashima S. Ohguchi K. Sakai H. Shinoda J. Sakai N. Nozawa Y. Biochem. Biophys. Res. Commun. 1996; 225: 494-499Crossref PubMed Scopus (49) Google Scholar), and their partial sequences indicate similarity, if not identity, to hPLD1. PLD has been purified to a very high degree from pig lung microsomes (10Okahuma S-i. Yamashita S. J. Biol. Chem. 1994; 269: 31207-31213Abstract Full Text PDF PubMed Google Scholar). It is specific for PC and has a molecular mass of 190 kDa and a pH optimum of 6.6. Another PLD has been substantially enriched from pig brain membranes (11Brown H.A. Gutowski S. Kahn R.A. Sternweis P.C. J. Biol. Chem. 1995; 270: 14935-14943Abstract Full Text Full Text PDF PubMed Scopus (132) Google Scholar). It has a molecular mass of 95 kDa, based on hydrodynamic measurements, and is markedly stimulated by PIP2 and the small G proteins ARF and RhoA. Other PLDs have been purified to a limited extent, including various forms from rat brain that differ in their pH optima and responses to Ca2+, PIP2, oleate, or detergents (1Exton, J. H. (1997) Physiol. Rev., in press.Google Scholar, 12Liscovitch M. Chalifa-Caspi V. Chem. Phys. Lipids. 1996; 80: 37-44Crossref PubMed Scopus (30) Google Scholar), and cytosolic PLDs that are Ca2+-responsive and differ in their substrate specificity (1Exton, J. H. (1997) Physiol. Rev., in press.Google Scholar, 12Liscovitch M. Chalifa-Caspi V. Chem. Phys. Lipids. 1996; 80: 37-44Crossref PubMed Scopus (30) Google Scholar). These differences suggest the existence of PLD isozymes, but since the enzymes are far from homogeneous, this is unclear. The subcellular localization of PLD activity shows some interesting features. The enzyme is enriched in plasma membranes from many tissues but is also present in high activity in Golgi and nuclei (13Provost J.J. Fudge J. Israelit S. Siddiqi A.R. Exton J.H. Biochem. J. 1996; 319: 285-291Crossref PubMed Scopus (72) Google Scholar, 14Ktistakis N.T. Brown H.A. Sternweis P.C. Roth M.G. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 4952-4956Crossref PubMed Scopus (181) Google Scholar, 15Ktistakis N.T. Brown H.A. Waters M.G. Sternweis P.C. Roth M.G. J. Cell Biol. 1996; 134: 295-306Crossref PubMed Scopus (328) Google Scholar, 16Whatmore J. Morgan C.P. Cunningham E. Collison K.S. Willison K.R. Cockcroft S. Biochem. J. 1996; 320: 785-794Crossref PubMed Scopus (66) Google Scholar, 17Balboa M.A. Insel P.A. J. Biol. Chem. 1995; 270: 29843-29847Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar). There is significant activity in cytosol but not in mitochondria. In liver, the plasma membrane enzyme responds more to RhoA than ARF, whereas the reverse is true for that in other subcellular fractions (13Provost J.J. Fudge J. Israelit S. Siddiqi A.R. Exton J.H. Biochem. J. 1996; 319: 285-291Crossref PubMed Scopus (72) Google Scholar). Whether these differences reflect differences in the subcellular distribution of PLD isozymes (7Colley W.C. Sung T-C. Roll R. Jenco J. Hammond S.M. Altshuller Y. Bar-Sagi D. Morris A.J. Frohman M.A. Curr. Biol. 1997; 7: 191-201Abstract Full Text Full Text PDF PubMed Scopus (634) Google Scholar) or other factors remains to be determined. Studies of PLD isozymes expressed in fibroblasts indicate that PLD2 localizes predominantly in the plasma membrane, whereas PLD1 is perinuclear, i.e. in endoplasmic reticulum, Golgi, and late endosomes (7Colley W.C. Sung T-C. Roll R. Jenco J. Hammond S.M. Altshuller Y. Bar-Sagi D. Morris A.J. Frohman M.A. Curr. Biol. 1997; 7: 191-201Abstract Full Text Full Text PDF PubMed Scopus (634) Google Scholar). Brown et al. (18Brown H.A. Gutowski S. Moomaw C.R. Slaughter C. Sternweis P.C. Cell. 1993; 75: 1137-1144Abstract Full Text PDF PubMed Scopus (820) Google Scholar) discovered that PLD is strongly stimulated by PIP2, and this has been observed for most but not all (10Okahuma S-i. Yamashita S. J. Biol. Chem. 1994; 269: 31207-31213Abstract Full Text PDF PubMed Google Scholar, 19Nakamura S-i. Kiyohara Y. Jinnai H. Hitomi T. Ogino C. Yoshida K. Nishizuka Y. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 4300-4304Crossref PubMed Scopus (36) Google Scholar, 20Kanfer J.N. McCartney D.G. Freysz S.L. FEBS Lett. 1996; 383: 6-8Crossref PubMed Scopus (19) Google Scholar) preparations of the enzyme. PI-3,4,5-P3 is also effective (6Hammond S.M. Jenco J.M. Nakashima S. Cadwallader K. Gu Q-m. Cook S. Nozawa Y. Prestwich G.D. Frohman M.A. Morris A.J. J. Biol. Chem. 1997; 272: 3860-3868Abstract Full Text Full Text PDF PubMed Scopus (496) Google Scholar), 3D.-S. Min and J. H. Exton, unpublished observations. but other acidic phospholipids, including PI-3,4-P2, PI-4-P, and PI, are nearly or completely ineffective (18Brown H.A. Gutowski S. Moomaw C.R. Slaughter C. Sternweis P.C. Cell. 1993; 75: 1137-1144Abstract Full Text PDF PubMed Scopus (820) Google Scholar, 21Liscovitch M. Chalifa V. Pertile P. Chen C-S. Cantley L.C. J. Biol. Chem. 1994; 269: 21403-21406Abstract Full Text PDF PubMed Google Scholar). There is evidence that PIP2 is required for the activation of PLD in intact cells (22Pertile P. Liscovitch M. Chalifa V. Cantley L.C. J. Biol. Chem. 1995; 270: 5130-5135Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar), but it is unclear that physiological changes in PIP2or PIP3 levels control the enzyme in vivo. Studies with cloned, purified PLDs indicate that PIP2 and PIP3 directly activate the enzyme (6Hammond S.M. Jenco J.M. Nakashima S. Cadwallader K. Gu Q-m. Cook S. Nozawa Y. Prestwich G.D. Frohman M.A. Morris A.J. J. Biol. Chem. 1997; 272: 3860-3868Abstract Full Text Full Text PDF PubMed Scopus (496) Google Scholar).3 There is abundant evidence that PLD is regulated by PKC in most mammalian cells. This comes from studies of the effects of phorbol esters, PKC inhibitors, down-regulation of the enzyme, and overexpression and deletion of specific PKC isozymes (1Exton, J. H. (1997) Physiol. Rev., in press.Google Scholar). Although a role for PKC in the actions of many agonists on PLD in many tissues/cells has been indicated, there are also instances where the enzyme does not seem to be involved (1Exton, J. H. (1997) Physiol. Rev., in press.Google Scholar). Since many of the agonists that activate PLD also stimulate the hydrolysis of PIP2 by PI-phospholipase C with subsequent production of diacylglycerol and activation of PKC, PC hydrolysis is often secondary to PIP2breakdown (1Exton, J. H. (1997) Physiol. Rev., in press.Google Scholar). Activation of PKC is also associated with translocation of the enzyme to cell membranes, and this relocalization is probably required for PKC activation of PLD, which is predominantly membrane-associated (Fig. 2). The most direct mechanism of control of PLD by PKC would be through phosphorylation of the enzyme. However, in those studies where the effects of PKC on PLD have been studied directly, activation does not involve ATP, i.e. a phosphorylation mechanism (6Hammond S.M. Jenco J.M. Nakashima S. Cadwallader K. Gu Q-m. Cook S. Nozawa Y. Prestwich G.D. Frohman M.A. Morris A.J. J. Biol. Chem. 1997; 272: 3860-3868Abstract Full Text Full Text PDF PubMed Scopus (496) Google Scholar,23Conricode K.M. Brewer K.A. Exton J.H. J. Biol. Chem. 1992; 267: 7199-7202Abstract Full Text PDF PubMed Google Scholar, 24Conricode K.M. Smith J.L. Burns D.J. Exton J.H. FEBS Lett. 1994; 342: 149-153Crossref PubMed Scopus (77) Google Scholar, 25Singer W.D. Brown H.A. Jiang X. Sternweis P.C. J. Biol. Chem. 1996; 271: 4504-4510Abstract Full Text Full Text PDF PubMed Scopus (235) Google Scholar).2,3 In particular, studies with cloned PLD purified from Sf9 cells indicate that PKCα and PKCβ can directly activate the enzyme in an ATP-independent manner (6Hammond S.M. Jenco J.M. Nakashima S. Cadwallader K. Gu Q-m. Cook S. Nozawa Y. Prestwich G.D. Frohman M.A. Morris A.J. J. Biol. Chem. 1997; 272: 3860-3868Abstract Full Text Full Text PDF PubMed Scopus (496) Google Scholar),3 but other isozymes are ineffective (24Conricode K.M. Smith J.L. Burns D.J. Exton J.H. FEBS Lett. 1994; 342: 149-153Crossref PubMed Scopus (77) Google Scholar).3 The interaction is not affected by staurosporine and involves the regulatory domain of PKC (25Singer W.D. Brown H.A. Jiang X. Sternweis P.C. J. Biol. Chem. 1996; 271: 4504-4510Abstract Full Text Full Text PDF PubMed Scopus (235) Google Scholar). This evidence of PLD regulation by protein-protein interaction does not preclude an additional phosphorylation-dependent mechanism in vivo. Evidence of a role for phosphorylation comes from cell studies with PKC inhibitors that act by interfering with ATP binding (1Exton, J. H. (1997) Physiol. Rev., in press.Google Scholar) and studies of the effects of ATP in cell-free systems (26Lopez I. Burns D.J. Lambeth J.D. J. Biol. Chem. 1995; 270: 19465-19472Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar). However, the latter may be complicated by changes in PIP2 synthesis (27Cockcroft S. Chem. Phys. Lipids. 1996; 80: 59-80Crossref PubMed Scopus (49) Google Scholar). It must also be recognized that PKC may act in vivo by phosphorylating a protein(s) involved in PLD regulation or altering the response of PLD to such a protein(s). As noted below, an important aspect of PKC action is its synergistic interaction with ARF and RhoA to activate PLD (Fig. 2). In contrast to other forms of mammalian PLD, PLD2 has a very high basal activity in vitro and in vivo (7Colley W.C. Sung T-C. Roll R. Jenco J. Hammond S.M. Altshuller Y. Bar-Sagi D. Morris A.J. Frohman M.A. Curr. Biol. 1997; 7: 191-201Abstract Full Text Full Text PDF PubMed Scopus (634) Google Scholar). It is stimulated by PIP2 but does not respond to PKC, Rho, or ARF. Brain cytosol contains an inhibitor selective for PLD2 (7Colley W.C. Sung T-C. Roll R. Jenco J. Hammond S.M. Altshuller Y. Bar-Sagi D. Morris A.J. Frohman M.A. Curr. Biol. 1997; 7: 191-201Abstract Full Text Full Text PDF PubMed Scopus (634) Google Scholar). ARF was discovered as a factor that stimulated cholera toxin-induced ADP-ribosylation of Gsα (26Lopez I. Burns D.J. Lambeth J.D. J. Biol. Chem. 1995; 270: 19465-19472Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar). It is now recognized to play a role in vesicle trafficking in Golgi and has been implicated in the fusion of microsomal vesicles and endosomes, the assembly of nuclear membranes, and the formation of clathrin-coated vesicles (28Moss J. Vaughan M. J. Biol. Chem. 1995; 270: 12327-12330Abstract Full Text Full Text PDF PubMed Scopus (272) Google Scholar). The activation of PLD by ARF was first recognized by the groups of Sternweis and Cockcroft (18Brown H.A. Gutowski S. Moomaw C.R. Slaughter C. Sternweis P.C. Cell. 1993; 75: 1137-1144Abstract Full Text PDF PubMed Scopus (820) Google Scholar, 29Cockcroft S. Thomas G.M.H. Fensome A. Geny B. Cunningham E. Gout I. Hiles I. Totty N.F. Truong O. Hsuan J.J. Science. 1994; 263: 523-526Crossref PubMed Scopus (585) Google Scholar) and has now been shown using PLD from many sources (1Exton, J. H. (1997) Physiol. Rev., in press.Google Scholar). The enzyme is stimulated by ARF1, -3, -5, and -6, i.e. all classes of ARF, and the myristoylated ARFs are more effective than the non-myristoylated forms (11Brown H.A. Gutowski S. Kahn R.A. Sternweis P.C. J. Biol. Chem. 1995; 270: 14935-14943Abstract Full Text Full Text PDF PubMed Scopus (132) Google Scholar, 30Massenburg D. Han J-S. Liyanage M. Patton W.A. Rhee S.G. Moss J. Vaughan M. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 11718-11722Crossref PubMed Scopus (245) Google Scholar). Studies with cloned PLD purified from Sf9 cells indicate that ARF interacts directly with the enzyme (6Hammond S.M. Jenco J.M. Nakashima S. Cadwallader K. Gu Q-m. Cook S. Nozawa Y. Prestwich G.D. Frohman M.A. Morris A.J. J. Biol. Chem. 1997; 272: 3860-3868Abstract Full Text Full Text PDF PubMed Scopus (496) Google Scholar).3 Some reports have indicated that cytosolic factors greatly enhance the effect of ARF on PLD (25Singer W.D. Brown H.A. Jiang X. Sternweis P.C. J. Biol. Chem. 1996; 271: 4504-4510Abstract Full Text Full Text PDF PubMed Scopus (235) Google Scholar,31Singer W.D. Brown H.A. Bokoch G.M. Sternweis P.C. J. Biol. Chem. 1995; 270: 14944-14950Abstract Full Text Full Text PDF PubMed Scopus (126) Google Scholar, 32Lambeth J.D. Kwak J-Y. Bowman E.P. Perry D. Uhlinger D.J. Lopez I. J. Biol. Chem. 1995; 270: 2431-2434Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar, 33Bourgoin S. Harbour D. Desmarais Y. Takai Y. Beaulileu A. J. Biol. Chem. 1995; 270: 3172-3178Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar, 34Takahashi K-i. Tago K. Okano H. Ohya Y. Katada T. Kanaho Y. J. Immunol. 1996; 156: 1229-1234PubMed Google Scholar, 35Shimooku K. Akisue T. Jinnai H. Hitomi T. Ogino C. Yoshida K. Nakamura S-i. Nishizuka Y. FEBS Lett. 1996; 387: 141-144Crossref PubMed Scopus (15) Google Scholar). Two of these factors are PKCα (25Singer W.D. Brown H.A. Jiang X. Sternweis P.C. J. Biol. Chem. 1996; 271: 4504-4510Abstract Full Text Full Text PDF PubMed Scopus (235) Google Scholar) and calmodulin (34Takahashi K-i. Tago K. Okano H. Ohya Y. Katada T. Kanaho Y. J. Immunol. 1996; 156: 1229-1234PubMed Google Scholar), but the nature of the others remains obscure. PLD activity is high in Golgi and responds to ARF (12Liscovitch M. Chalifa-Caspi V. Chem. Phys. Lipids. 1996; 80: 37-44Crossref PubMed Scopus (30) Google Scholar, 13Provost J.J. Fudge J. Israelit S. Siddiqi A.R. Exton J.H. Biochem. J. 1996; 319: 285-291Crossref PubMed Scopus (72) Google Scholar, 14Ktistakis N.T. Brown H.A. Sternweis P.C. Roth M.G. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 4952-4956Crossref PubMed Scopus (181) Google Scholar), and the stimulation is inhibited by brefeldin A, an inhibitor of ARF activation (14Ktistakis N.T. Brown H.A. Sternweis P.C. Roth M.G. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 4952-4956Crossref PubMed Scopus (181) Google Scholar). As will be discussed below, an important role for ARF-stimulated PLD in the regulation of vesicular transport in Golgi is indicated by the studies of Ktistakis et al. (15Ktistakis N.T. Brown H.A. Waters M.G. Sternweis P.C. Roth M.G. J. Cell Biol. 1996; 134: 295-306Crossref PubMed Scopus (328) Google Scholar). There is also limited evidence of a role for ARF in agonist regulation of PLD in vivo. In HEK cells expressing M3 muscarinic receptors, brefeldin A inhibited carbachol stimulation of PLD (36Rumenapp U. Geiszt M. Wahn F. Schmidt M. Jakobs K.H. Eur. J. Biochem. 1995; 234: 240-244Crossref PubMed Scopus (81) Google Scholar). In these cells, permeabilization caused a release of cytosolic ARF, which could be inhibited by adding GTPγS during permeabilization or by prior carbachol treatment (36Rumenapp U. Geiszt M. Wahn F. Schmidt M. Jakobs K.H. Eur. J. Biochem. 1995; 234: 240-244Crossref PubMed Scopus (81) Google Scholar). Treatment of HL-60 cells with chemotactic peptide also caused an increase in membrane-associated ARF and GTPγS-stimulated PLD activity (37Houle M.G. Kahn R.A. Naccache P.H. Bourgoin S. J. Biol. Chem. 1995; 270: 22795-22800Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar). These results are consistent with the effect of these agonists on PLD being mediated by membrane translocation of ARF. Rho family proteins regulate many cellular activities including those involving the actin cytoskeleton. The proteins include Rho, which controls the formation of focal adhesions and actin stress fibers, Rac, which regulates lamellipodia formation and membrane ruffling, and Cdc42, which controls the formation of filopodia (38Machesky L.M. Hall A. Trends Cell Biol. 1996; 6: 304-310Abstract Full Text PDF PubMed Scopus (254) Google Scholar, 39Ridley A.J. Cell. 1996; 6: 1256-1264Google Scholar). The first evidence that PLD could be regulated by Rho proteins came from a study by Bowman et al. (40Bowman E.P. Uhlinger D.J. Lambeth J.D. J. Biol. Chem. 1993; 268: 21509-21512Abstract Full Text PDF PubMed Google Scholar). This showed that the stimulatory effect of GTPγS on PLD in neutrophil plasma membranes was inhibited by RhoGDI, a protein that inhibits GDP dissociation from Rho proteins and thereby blocks their activation. In subsequent studies using plasma membranes from rat liver, HL-60 cells, and neutrophils, it was found that RhoA was the most effective Rho protein to activate PLD, but Rac1 or Cdc42Hs showed some activity (41Malcolm K.C. Ross A.H. Qiu R-G. Symons M. Exton J.H. J. Biol. Chem. 1994; 269: 25951-25954Abstract Full Text PDF PubMed Google Scholar, 42Siddiqi A.R. Smith J.L. Ross A.H. Qiu R-G. Symons M. Exton J.H. J. Biol. Chem. 1995; 270: 8466-8473Abstract Full Text Full Text PDF PubMed Scopus (148) Google Scholar, 43Kwak J-Y. Lopez I. Uhlinger D.J. Ryu S.H. Lambeth J.D. J. Biol. Chem. 1995; 270: 27093-27098Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar). RhoA also stimulates PLD in fractions from other cells and partially purified preparations of the enzyme (13Provost J.J. Fudge J. Israelit S. Siddiqi A.R. Exton J.H. Biochem. J. 1996; 319: 285-291Crossref PubMed Scopus (72) Google Scholar, 17Balboa M.A. Insel P.A. J. Biol. Chem. 1995; 270: 29843-29847Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar, 31Singer W.D. Brown H.A. Bokoch G.M. Sternweis P.C. J. Biol. Chem. 1995; 270: 14944-14950Abstract Full Text Full Text PDF PubMed Scopus (126) Google Scholar, 35Shimooku K. Akisue T. Jinnai H. Hitomi T. Ogino C. Yoshida K. Nakamura S-i. Nishizuka Y. FEBS Lett. 1996; 387: 141-144Crossref PubMed Scopus (15) Google Scholar, 44Kuribara H. Tago K. Yokozeki T. Sasaki T. Takai Y. Morii N. Narumiya S. Katada T. Kanaho Y. J. Biol. Chem. 1995; 270: 25667-25671Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar). Studies with cloned PLD purified from Sf9 cells indicate that RhoA interacts directly with the enzyme and that Rac1 and Cdc42 are also active (6Hammond S.M. Jenco J.M. Nakashima S. Cadwallader K. Gu Q-m. Cook S. Nozawa Y. Prestwich G.D. Frohman M.A. Morris A.J. J. Biol. Chem. 1997; 272: 3860-3868Abstract Full Text Full Text PDF PubMed Scopus (496) Google Scholar).3 Interestingly, a combination of RhoA and ARF results in synergistic activation of homogeneous or partially purified PLD (6Hammond S.M. Jenco J.M. Nakashima S. Cadwallader K. Gu Q-m. Cook S. Nozawa Y. Prestwich G.D. Frohman M.A. Morris A.J. J. Biol. Chem. 1997; 272: 3860-3868Abstract Full Text Full Text PDF PubMed Scopus (496) Google Scholar, 25Singer W.D. Brown H.A. Jiang X. Sternweis P.C. J. Biol. Chem. 1996; 271: 4504-4510Abstract Full Text Full Text PDF PubMed Scopus (235) Google Scholar, 35Shimooku K. Akisue T. Jinnai H. Hitomi T. Ogino C. Yoshida K. Nakamura S-i. Nishizuka Y. FEBS Lett. 1996; 387: 141-144Crossref PubMed Scopus (15) Google Scholar, 42Siddiqi A.R. Smith J.L. Ross A.H. Qiu R-G. Symons M. Exton J.H. J. Biol. Chem. 1995; 270: 8466-8473Abstract Full Text Full Text PDF PubMed Scopus (148) Google Scholar, 44Kuribara H. Tago K. Yokozeki T. Sasaki T. Takai Y. Morii N. Narumiya S. Katada T. Kanaho Y. J. Biol. Chem. 1995; 270: 25667-25671Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar).3This suggests the presence of separate but interacting sites for Rho and ARF on PLD. As in the case of ARF, there is evidence that RhoA action on PLD is enhanced by cytosolic proteins (35Shimooku K. Akisue T. Jinnai H. Hitomi T. Ogino C. Yoshida K. Nakamura S-i. Nishizuka Y. FEBS Lett. 1996; 387: 141-144Crossref PubMed Scopus (15) Google Scholar, 43Kwak J-Y. Lopez I. Uhlinger D.J. Ryu S.H. Lambeth J.D. J. Biol. Chem. 1995; 270: 27093-27098Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar) and by PKCα (6Hammond S.M. Jenco J.M. Nakashima S. Cadwallader K. Gu Q-m. Cook S. Nozawa Y. Prestwich G.D. Frohman M.A. Morris A.J. J. Biol. Chem. 1997; 272: 3860-3868Abstract Full Text Full Text PDF PubMed Scopus (496) Google Scholar, 25Singer W.D. Brown H.A. Jiang X. Sternweis P.C. J. Biol. Chem. 1996; 271: 4504-4510Abstract Full Text Full Text PDF PubMed Scopus (235) Google Scholar, 43Kwak J-Y. Lopez I. Uhlinger D.J. Ryu S.H. Lambeth J.D. J. Biol. Chem. 1995; 270: 27093-27098Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar, 45Ohguchi K. Banno Y. Nakashima S. Nozawa Y. J. Biol. Chem. 1996; 271: 4366-4372Abstract Full Text Full Text PDF PubMed Scopus (106) Google Scholar).3 Several bacterial toxins that inactivate Rho proteins have been used to demonstrate the involvement of RhoA in agonist regulation of PLDin vivo. These include the C3 exoenzyme of Clostridium botulinum that ADP-ribosylates RhoA and blocks the activation of PLD in Rat1 fibroblasts by LPA (46Malcolm K.C. Elliott C.M. Exton J.H. J. Biol. Chem. 1996; 271: 13135-13139Abstract Full Text Full Text PDF PubMed Scopus (138) Google Scholar). Likewise, Toxin B fromClostridium difficile, which glucosylates and inactivates Rho proteins, blocks the activation of PLD by carbachol in intact cells and by GTPγS and AlF4− in permeabilized cells (47Schmidt M. Rumenapp U. Bienek C. Keller J. von Eichel-Streiber C. Jakobs K.H. J. Biol. Chem. 1996; 271: 2422-2426Abstract Full Text Full Text PDF PubMed Scopus (107) Google Scholar). The toxin also inhibits IgE receptor-mediated activation of PLD in basophilic leukemia cells (48Ojio K. Banno Y. Nakashima S. Kato N. Watanabe K. Lyerly D.M. Miyata H. Nozawa Y. Biochem. Biophys. Res. Commun. 1996; 234: 591-596Crossref Scopus (18) Google Scholar). While these observations support a role for RhoA in agonist stimulation of PLD, caution should be observed since the small G protein also regulates PIP2 synthesis by PI-4-P 5-kinase (49Chong L.D. Traynor-Kaplan A. Bokoch G.M. Schwartz M.A. Cell. 1994; 79: 507-513Abstract Full Text PDF PubMed Scopus (593) Google Scholar), and the changes in PLD could be secondary to alterations in PIP2 levels (50Schmidt M. Rumenapp U. Nehls C. Ott S. Keller J. Von Eichel-Streiber C. Jakobs K.H. Eur. J. Biochem. 1996; 240: 707-712Crossref PubMed Scopus (42) Google Scholar). Because of the location of its substrate, PLD must be or must become membrane-associated for activity. Thus its regulators must also be present in membranes or translocate there. As described above, there is evidence for agonist-induced membrane relocalization of ARF (36Rumenapp U. Geiszt M. Wahn F. Schmidt M. Jakobs K.H. Eur. J. Biochem. 1995; 234: 240-244Crossref PubMed Scopus (81) Google Scholar, 37Houle M.G. Kahn R.A. Naccache P.H. Bourgoin S. J. Biol. Chem. 1995; 270: 22795-22800Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar), and this is a well known phenomenon for PKC isozymes. Agonist-induced membrane translocation of Rho family proteins has also been reported recently (46Malcolm K.C. Elliott C.M. Exton J.H. J. Biol. Chem. 1996; 271: 13135-13139Abstract Full Text Full Text PDF PubMed Scopus (138) Google Scholar, 51Fleming I.N. Elliott C.M. Exton J.H. J. Biol. Chem. 1996; 271: 33067-33073Abstract Full Text Full Text PDF PubMed Scopus (138) Google Scholar, 52Abousalham A. Liossis C. O'Brien L. Brindley D.N. J. Biol. Chem. 1997; 272: 1069-1075Abstract Full Text Full Text PDF PubMed Scopus (100) Google Scholar), and this is probably an important component of the mechanism of PLD activation by certain agonists (Fig. 2). Ceramides are being increasingly recognized as important regulators of cell function (53Hannun Y.A. Science. 1996; 274: 1855-1859Crossref PubMed Scopus (1493) Google Scholar). C6- and C2-ceramides inhibit agonist or phorbol myristate acetate-stimulated PLD activity in several cell lines (54Gomez-Munoz A. Martin A. O'Brien L. Brindley D.N. J. Biol. Chem. 1994; 269: 8937-8943Abstract Full Text PDF PubMed Google Scholar, 55Jones M.J. Murray A.W. J. Biol. Chem. 1995; 270: 5007-5013Abstract Full Text Full Text PDF PubMed Scopus (147) Google Scholar, 56Venable M.E. Bielawska A. Obeid L.M. J. Biol. Chem. 1996; 271: 24800-24805Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar, 57Nakamura Y. Nakashima S. Ojio K. Banno Y. Miyata H. Nozawa Y. J. Immunol. 1996; 156: 256-262PubMed Google Scholar) and block the stimulation of the enzyme by GTPγS plus phorbol myristate acetate, ARF, or RhoA in cell extracts (52Abousalham A. Liossis C. O'Brien L. Brindley D.N. J. Biol. Chem. 1997; 272: 1069-1075Abstract Full Text Full Text PDF PubMed Scopus (100) Google Scholar, 56Venable M.E. Bielawska A. Obeid L.M. J. Biol. Chem. 1996; 271: 24800-24805Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar), but dihydro derivatives are ineffective. Since the ceramides also block the membrane translocation of ARF, RhoA, and Ca2+-dependent PKC isozymes (52Abousalham A. Liossis C. O'Brien L. Brindley D.N. J. Biol. Chem. 1997; 272: 1069-1075Abstract Full Text Full Text PDF PubMed Scopus (100) Google Scholar, 55Jones M.J. Murray A.W. J. Biol. Chem. 1995; 270: 5007-5013Abstract Full Text Full Text PDF PubMed Scopus (147) Google Scholar), part of the inhibition could be due to these effects. In contrast to ceramides, sphingosine and its metabolite sphingosine-1-P activate PLD (58Spiegel S. Milstien S. Chem. Phys. Lipids. 1996; 80: 27-36Crossref PubMed Scopus (24) Google Scholar). It is probable that their effects are partly mediated by a sphingosine-1-P receptor coupled to a G protein(s) (59Bunemann M. Liliom K. Brandts B.K. Pott L. Tseng J-L. Desiderio D.M. Sun G. Miller D. Tigyi G. EMBO J. 1996; 15: 5527-5534Crossref PubMed Scopus (119) Google Scholar, 60Postma F.R. Jalink K. Hengeveld T. Moolenaar W.H. EMBO J. 1996; 15: 2388-2395Crossref PubMed Scopus (265) Google Scholar). The existence of cytosolic proteins that enhance the effects of RhoA and ARF on PLD has already been described. The actin-binding protein gelsolin also stimulates PLD but only in the presence of nucleoside triphosphates (61Steed P.M. Nagar S. Wennogle L.P. Biochemistry. 1996; 35: 5229-5237Crossref PubMed Scopus (62) Google Scholar). A role for PLD in control of the actin cytoskeleton has been proposed (62Ha K.-W. Exton J.H. J. Cell Biol. 1993; 123: 1789-1796Crossref PubMed Scopus (154) Google Scholar, 63Cross M.J. Roberts S. Ridley A.J. Hodgkin M.N. Stewart A. Claesson-Welsh L. Wakelam M.J.O. Curr. Biol. 1996; 6: 588-597Abstract Full Text Full Text PDF PubMed Google Scholar), but the mechanisms involved are unclear. Inhibitors of PLD have been identified (64Geny B. Paris S. Dubois T. Franco M. Lukowski S. Chardin P. Russo Marie F. Eur. J. Biochem. 1995; 231: 31-39Crossref PubMed Scopus (19) Google Scholar, 65Han J.-S. Chung J.-K. Kang H.-S. Donaldson J. Bae Y.S. Rhee S.G. J. Biol. Chem. 1996; 271: 11163-11169Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar, 66Kim J.H. Suh Y.J. Lee T.G. Kim Y. Bae S.S. Kim M.J. Lambeth J.D. Suh P.-G. Ryu S.H. J. Biol. Chem. 1996; 271: 25213-25219Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar, 67Lukowski S. Lecomte M.-C. Mira J.-P. Marin P. Gautero H. Russo-Maris F. Geny B. J. Biol. Chem. 1996; 271: 24164-24171Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar). One of these is heat-labile with a molecular mass of 150 kDa (65Han J.-S. Chung J.-K. Kang H.-S. Donaldson J. Bae Y.S. Rhee S.G. J. Biol. Chem. 1996; 271: 11163-11169Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar). Its partial sequence (65Han J.-S. Chung J.-K. Kang H.-S. Donaldson J. Bae Y.S. Rhee S.G. J. Biol. Chem. 1996; 271: 11163-11169Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar) indicates that it is synaptojanin, which exhibits PIP2phosphatase activity (68McPherson P.S. Garcia E.P. Slepnev V.I. David C. Zhang X. Grabs D. Sossin W.S. Bauerfeind R. Nemoto Y. de Camilli P. Nature. 1996; 379: 353-357Crossref PubMed Scopus (491) Google Scholar) and presumably inhibits PLD by decreasing PIP2. Another inhibitor that has a molecular mass of 30 kDa and does not bind PIP2 has been identified (66Kim J.H. Suh Y.J. Lee T.G. Kim Y. Bae S.S. Kim M.J. Lambeth J.D. Suh P.-G. Ryu S.H. J. Biol. Chem. 1996; 271: 25213-25219Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar). Fodrin, a non-erythroid form of spectrin, has been reported to inhibit PLD (67Lukowski S. Lecomte M.-C. Mira J.-P. Marin P. Gautero H. Russo-Maris F. Geny B. J. Biol. Chem. 1996; 271: 24164-24171Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar). Although fodrin has a PH domain, it apparently does not act by binding PIP2. Brain contains an 18-kDa inhibitor that is selective for PLD2 (7Colley W.C. Sung T-C. Roll R. Jenco J. Hammond S.M. Altshuller Y. Bar-Sagi D. Morris A.J. Frohman M.A. Curr. Biol. 1997; 7: 191-201Abstract Full Text Full Text PDF PubMed Scopus (634) Google Scholar). PLD could exert its biological effects by several mechanisms. The first is by changing the properties of cellular membranes by altering their lipid composition. Thus, by causing local changes in PC and PA and releasing polar choline, the physical properties of the membranes could be substantially changed. A second mechanism is by generating PA. This lipid would probably remain in the membrane but could interact with proteins located in the membrane or cytosol. Many proteins have been shown to have their activities changed by PA in vitro(1Exton, J. H. (1997) Physiol. Rev., in press.Google Scholar), but evidence that they are targets of the lipid in vivois largely lacking. Since transphosphatidylation may be a major function of PLD in vivo, the possibility should be considered that the products of this reaction may also have signaling functions. A third mechanism of biological action of PLD arises from the fact that PA is rapidly converted to DAG in most cells through the action of phosphatidate phosphohydrolase. Thus the late phase of activation of PKC produced by agonists in many cells is mainly attributable to DAG derived from PLD action (1Exton, J. H. (1997) Physiol. Rev., in press.Google Scholar, 69Ha K.-S. Exton J.H. J. Biol. Chem. 1993; 268: 10534-10539Abstract Full Text PDF PubMed Google Scholar). A fourth function of PLD is the generation of LPA through the action of a specific phospholipase A2 on PA. LPA is becoming recognized as a major extracellular signal produced by activated platelets and probably other cells (70Moolenaar W.H. J. Biol. Chem. 1995; 270: 12949-12952Abstract Full Text Full Text PDF PubMed Scopus (569) Google Scholar). A final possibility relates to the formation of choline. Because of its high resting cellular levels, this compound probably does not have a signaling function, but it could serve as a substrate for acetylcholine synthesis in neurons (71Klein J. Chalifa V. Liscovitch M. Loffelholz K. J. Neurochem. 1995; 65: 1445-1455Crossref PubMed Scopus (111) Google Scholar). Roles for PLD have been proposed for many cellular functions, but space permits consideration of only a few. The potential function of PLD in the regulation of cell proliferation remains controversial. PA and bacterial PLD are mitogenic in several cell lines (1Exton, J. H. (1997) Physiol. Rev., in press.Google Scholar, 72Boarder M.R. Trends Pharmacol. Sci. 1995; 15: 57-62Abstract Full Text PDF Scopus (131) Google Scholar), although some of the effects may be due to LPA contamination or formation (1Exton, J. H. (1997) Physiol. Rev., in press.Google Scholar,70Moolenaar W.H. J. Biol. Chem. 1995; 270: 12949-12952Abstract Full Text Full Text PDF PubMed Scopus (569) Google Scholar), and there is a lack of correlation between PLD activity and mitogenesis in some cell lines (73Paul A. Plevin R. Trends Pharmacol. Sci. 1994; 15: 174-175Abstract Full Text PDF PubMed Scopus (5) Google Scholar). Other signaling pathways are undoubtedly involved in growth control. In Saccharomyces cerevisiae, PLD was first recognized as the product of theSPO14 gene, which is essential for meiosis (5Rose K. Rudge S.A. Frohman M.A. Morris A.J. Engebrecht J.A. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 12151-12155Crossref PubMed Scopus (197) Google Scholar). The mechanisms by which PLD could control the cell cycle are unknown. However, Raf-1 kinase, which is involved in signal transduction from several receptors, has a binding site for PA and is translocated to membranes under conditions where PLD is activated (74Ghosh S. Strum J.C. Sciorra V.A. Daniel L. Bell R.M. J. Biol. Chem. 1996; 271: 8472-8480Abstract Full Text Full Text PDF PubMed Scopus (378) Google Scholar). As alluded to above, PLD has been implicated in the regulation of vesicle trafficking by ARF in Golgi. In Chinese hamster ovary cell lines displaying high basal PLD activity in Golgi, ARF is not necessary for coatamer assembly (15Ktistakis N.T. Brown H.A. Waters M.G. Sternweis P.C. Roth M.G. J. Cell Biol. 1996; 134: 295-306Crossref PubMed Scopus (328) Google Scholar). The formation of coated vesicles is also inhibited by ethanol, which reduces PA formation due to the production of phosphatidylethanol, and treatment of Golgi membranes with bacterial PLD promotes coatamer binding (15Ktistakis N.T. Brown H.A. Waters M.G. Sternweis P.C. Roth M.G. J. Cell Biol. 1996; 134: 295-306Crossref PubMed Scopus (328) Google Scholar). Studies with ethanol and exogenous PLD in other cell types have also provided evidence that PLD is involved in vesicle transport (27Cockcroft S. Chem. Phys. Lipids. 1996; 80: 59-80Crossref PubMed Scopus (49) Google Scholar). It is not known whether its action is due to the generation of PA, a membrane fusigen, or to other membrane lipid changes. Colley et al. (7Colley W.C. Sung T-C. Roll R. Jenco J. Hammond S.M. Altshuller Y. Bar-Sagi D. Morris A.J. Frohman M.A. Curr. Biol. 1997; 7: 191-201Abstract Full Text Full Text PDF PubMed Scopus (634) Google Scholar) have observed that PLD2 provokes cortical reorganization mediated by actin polymerization and undergoes redistribution from the plasma membrane in serum-stimulated cells. They have postulated that PLD1 and PLD2 are involved in vesicle translocation from the perinuclear region and in receptor-mediated endocytosis, respectively. Other studies have implicated PA in the control of actin polymerization (62Ha K.-W. Exton J.H. J. Cell Biol. 1993; 123: 1789-1796Crossref PubMed Scopus (154) Google Scholar, 63Cross M.J. Roberts S. Ridley A.J. Hodgkin M.N. Stewart A. Claesson-Welsh L. Wakelam M.J.O. Curr. Biol. 1996; 6: 588-597Abstract Full Text Full Text PDF PubMed Google Scholar). PLD has been implicated in O·̄2 production and degranulation in neutrophils in response to chemotactic peptide (75Olson S.C. Lambeth J.D. Chem. Phys. Lipids. 1996; 80: 3-19Crossref PubMed Scopus (54) Google Scholar). The generation of the bactericidal O2 species, which is due to activation of NADPH oxidase, is inhibited by ethanol and mimicked by the addition of PA (75Olson S.C. Lambeth J.D. Chem. Phys. Lipids. 1996; 80: 3-19Crossref PubMed Scopus (54) Google Scholar). These data, which implicate PA in the control of NADPH oxidase, are supported by in vitro findings (76McPhail L.C. Qualliotine-Mann D. Waite K.A. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 7931-7935Crossref PubMed Scopus (89) Google Scholar, 77Qualliotine-Mann D. Agwu D.E. Ellenburg M.D. McCall C.E. McPhail L.C. J. Biol. Chem. 1993; 268: 23843-23849Abstract Full Text PDF PubMed Google Scholar). However, these studies also provide evidence for the involvement of DAG (77Qualliotine-Mann D. Agwu D.E. Ellenburg M.D. McCall C.E. McPhail L.C. J. Biol. Chem. 1993; 268: 23843-23849Abstract Full Text PDF PubMed Google Scholar) and indicate that the two lipids synergize to activate the enzyme (77Qualliotine-Mann D. Agwu D.E. Ellenburg M.D. McCall C.E. McPhail L.C. J. Biol. Chem. 1993; 268: 23843-23849Abstract Full Text PDF PubMed Google Scholar). Although substantial advances have recently been made in the enzymology and regulation of PLD, major questions remain. In particular, the various isozymes need to be identified and their structure/function relationships and regulatory properties defined. Molecular biological approaches should now make this possible. The mechanisms by which growth factors, hormones, and other agonists regulate the enzyme need to be clarified, with emphasis on the roles of PKC, Rho proteins, ARF, and certain lipids. Finally, but most importantly, the physiological functions of PLD need to be defined, and molecular biological approaches should also provide major help in this area." @default.
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W2066791280 title "New Developments in Phospholipase D" @default.
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