New Developments in Phospholipase D (1997)

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 a an of PKC is interaction with ARF and RhoA to activate PLD (Fig. 2). In to other forms of mammalian PLD, PLD2 has a very high activity in 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 to PKC, or cytosol an 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 that stimulated ADP-ribosylation of (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 recognized to a role in in Golgi and has been in the of and the of membranes, and the of J. M. J. Biol. Chem. 1995; 270: Full Text Full Text PDF PubMed Scopus Google Scholar). The activation of PLD by ARF was first recognized by the 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, S. A. Cunningham E. I. I. J.J. 1994; PubMed Scopus Google Scholar) and has been using PLD from many sources (1Exton, J. H. (1997) Physiol. Rev., in press.Google Scholar). The enzyme is stimulated by and i.e. all of ARF, and the are more effective than the 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, D. M. J. M. Proc. Natl. Acad. Sci. U. S. A. 1994; PubMed Scopus Google Scholar). Studies with cloned PLD purified from Sf9 cells indicate that ARF 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 have that cytosolic factors the 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 W.D. Brown H.A. Sternweis P.C. J. Biol. Chem. 1995; 270: Full Text Full Text PDF PubMed Scopus Google Scholar, J.D. D. D.J. I. J. Biol. Chem. 1995; 270: Full Text Full Text PDF PubMed Scopus Google Scholar, S. D. Y. Y. A. J. Biol. Chem. 1995; 270: Full Text Full Text PDF PubMed Scopus Google Scholar, K. H. Y. T. Y. J. 1996; Google Scholar, K. T. Jinnai H. Hitomi T. Ogino C. Yoshida K. S-i. Nishizuka Y. FEBS Lett. 1996; PubMed Scopus Google Scholar). 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 K. H. Y. T. Y. J. 1996; Google Scholar), but the of the remains PLD activity is high in Golgi and responds to ARF M. Chalifa-Caspi V. Chem. Phys. Lipids. 1996; 80: 37-44Crossref PubMed Scopus (30) Google Scholar, 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 is by an of ARF activation 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). will be discussed an role for PLD in the regulation of in Golgi is by the studies of et al. 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 regulation of PLD in vivo. In cells A of PLD U. M. M. J. Biochem. 1995; PubMed Scopus Google Scholar). In these cells, a of cytosolic ARF, which be by or by U. M. M. J. Biochem. 1995; PubMed Scopus Google Scholar). of cells with also an in membrane-associated ARF and PLD activity M.G. Kahn R.A. S. J. Biol. Chem. 1995; 270: Full Text Full Text PDF PubMed Scopus Google Scholar). These are with the of these agonists on PLD by membrane translocation of family proteins many including those the The proteins which the of and which and membrane and which the of A. Trends Cell Biol. 1996; Full Text PDF PubMed Scopus Google Scholar, A.J. Cell. 1996; Scholar). The first evidence that PLD be regulated by proteins from a by et al. D.J. Lambeth J.D. J. Biol. Chem. 1993; Full Text PDF PubMed Google Scholar). This that the of on PLD in plasma membranes was by a protein that from proteins and their In subsequent studies using plasma membranes from rat liver, cells, and it was found that RhoA was the most effective protein to activate PLD, but or some activity M. Exton J.H. J. Biol. Chem. 1994; 269: Full Text PDF PubMed Google Scholar, A.R. Smith J.L. M. Exton J.H. J. Biol. Chem. 1995; 270: Full Text Full Text PDF PubMed Scopus Google Scholar, I. D.J. Lambeth J.D. J. Biol. Chem. 1995; 270: Full Text Full Text PDF PubMed Scopus Google Scholar). RhoA also 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, W.D. Brown H.A. Sternweis P.C. J. Biol. Chem. 1995; 270: Full Text Full Text PDF PubMed Scopus Google Scholar, K. T. Jinnai H. Hitomi T. Ogino C. Yoshida K. S-i. Nishizuka Y. FEBS Lett. 1996; PubMed Scopus Google Scholar, H. K. T. T. Y. N. S. T. Y. J. Biol. Chem. 1995; 270: Full Text Full Text PDF PubMed Scopus Google Scholar). Studies with cloned PLD purified from Sf9 cells indicate that RhoA directly with the enzyme and that and are also (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 a of RhoA and ARF in activation of 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, K. T. Jinnai H. Hitomi T. Ogino C. Yoshida K. S-i. Nishizuka Y. FEBS Lett. 1996; PubMed Scopus Google Scholar, A.R. Smith J.L. M. Exton J.H. J. Biol. Chem. 1995; 270: Full Text Full Text PDF PubMed Scopus Google Scholar, H. K. T. T. Y. N. S. T. Y. J. Biol. Chem. 1995; 270: Full Text Full Text PDF PubMed Scopus Google the of but for and ARF on PLD. in the of ARF, there is evidence that RhoA on PLD is by cytosolic proteins K. T. Jinnai H. Hitomi T. Ogino C. Yoshida K. S-i. Nishizuka Y. FEBS Lett. 1996; PubMed Scopus Google Scholar, I. D.J. Lambeth J.D. J. Biol. Chem. 1995; 270: Full Text Full Text PDF PubMed Scopus 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, I. D.J. Lambeth J.D. J. Biol. Chem. 1995; 270: Full Text Full Text PDF PubMed Scopus Google Scholar, K. Y. Nakashima S. Nozawa Y. J. Biol. Chem. 1996; 271: Full Text Full Text PDF PubMed Scopus Google Scholar).3 that proteins have been used to the of RhoA in regulation of vivo. These the of that RhoA and the activation of PLD in fibroblasts by Exton J.H. J. Biol. Chem. 1996; 271: Full Text Full Text PDF PubMed Scopus Google Scholar). which and the activation of PLD by in intact cells and by and in cells M. U. C. J. C. J. Biol. Chem. 1996; 271: Full Text Full Text PDF PubMed Scopus Google Scholar). The also activation of PLD in cells K. Y. Nakashima S. N. K. H. Nozawa Y. Biochem. Biophys. Res. Commun. 1996; Scopus Google Scholar). these a role for RhoA in of PLD, be observed since the small G protein also PIP2 synthesis by A. M.A. Cell. 1994; Full Text PDF PubMed Scopus Google Scholar), and the changes in PLD be secondary to in PIP2 levels M. U. C. S. J. C. J. Biochem. 1996; PubMed Scopus Google Scholar). of the of PLD must be or must membrane-associated for must also be present in membranes or there is evidence for membrane relocalization of ARF U. M. M. J. Biochem. 1995; PubMed Scopus Google Scholar, M.G. Kahn R.A. S. J. Biol. Chem. 1995; 270: Full Text Full Text PDF PubMed Scopus Google Scholar), and this is a for PKC membrane translocation of family proteins has also been reported recently Exton J.H. J. Biol. Chem. 1996; 271: Full Text Full Text PDF PubMed Scopus Google Scholar, Exton J.H. J. Biol. Chem. 1996; 271: Full Text Full Text PDF PubMed Scopus Google Scholar, A. C. J. Biol. Chem. 1997; 272: Full Text Full Text PDF PubMed Scopus Google Scholar), and this is probably an of the mechanism of PLD activation by agonists (Fig. 2). are recognized as of cell 1996; PubMed Scopus Google Scholar). and or phorbol PLD activity in several cell A. A. J. Biol. Chem. 1994; 269: Full Text PDF PubMed Google Scholar, J. Biol. Chem. 1995; 270: Full Text Full Text PDF PubMed Scopus Google Scholar, A. J. Biol. Chem. 1996; 271: Full Text Full Text PDF PubMed Scopus Google Scholar, Y. Nakashima S. K. Y. H. Nozawa Y. J. 1996; Google Scholar) and the of the enzyme by phorbol ARF, or RhoA in cell A. C. J. Biol. 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Chem. 1996; 271: Full Text Full Text PDF PubMed Scopus (19) Google Scholar). a of has been reported to PLD S. P. H. J. Biol. Chem. 1996; 271: Full Text Full Text PDF PubMed Scopus Google Scholar). Although has a it does not act by binding an that is 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 effects by several The first is by the of membranes by altering their by changes in PC and and choline, the of the membranes be substantially A mechanism is by This would probably in the membrane but with proteins in the membrane or proteins have been to have their by in J. H. (1997) Physiol. 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Biol. 1996; Full Text Full Text PDF PubMed Google Scholar). PLD has been in production and in in response to Lambeth J.D. Chem. Phys. Lipids. 1996; 80: PubMed Scopus Google Scholar). The of the which is to activation of is by and by the of Lambeth J.D. Chem. Phys. Lipids. 1996; 80: PubMed Scopus Google Scholar). These which in the control of are by in L.C. D. K.A. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: PubMed Scopus (89) Google Scholar, D. L.C. J. Biol. Chem. 1993; Full Text PDF PubMed Google Scholar). However, these studies also evidence for the of D. L.C. J. Biol. Chem. 1993; Full Text PDF PubMed Google Scholar) and indicate that the to activate the enzyme D. L.C. J. Biol. Chem. 1993; Full Text PDF PubMed Google Scholar). Although have recently been in the and regulation of PLD, major In particular, the various isozymes to be identified and their and regulatory this The by which growth factors, hormones, and other agonists the enzyme to be with on the of PKC, ARF, and but most the physiological of PLD to be and molecular also major in this