Mammalian Lipid Phosphate Phosphohydrolases
1998; Elsevier BV; Volume: 273; Issue: 38 Linguagem: Inglês
10.1074/jbc.273.38.24281
ISSN1083-351X
AutoresDavid N. Brindley, David W. Waggoner,
Tópico(s)Pancreatic function and diabetes
Resumophosphatidate phosphohydrolase phosphatidate diacylglycerol pyrophosphate human lipid phosphate phosphohydrolase (a family of phosphohydrolases equivalent to phosphatidate phosphohydrolase, Type 2) mouse glucose 6-phosphatase mitogen-activated protein kinase phospholipase D rat ceramide 1-phosphate sphingosine 1-phosphate diacylglycerol. Phosphatidate phosphohydrolase (PAP)1 was first identified as being involved in glycerolipid synthesis (1Brindley D.N. Brindley D.N. Phosphatidate Phosphohydrolase. 1. CRC Press, Inc., Boca Raton, FL1988: 1-77Google Scholar). A second PAP activity (PAP-2) was subsequently characterized in mammalian cells based upon a lack of requirement for bivalent cations and insensitivity to inhibition by N-ethylmaleimide (2Jamal Z. Martin A. Gómez-Muñoz A. Brindley D.N. J. Biol. Chem. 1991; 266: 2988-2996Abstract Full Text PDF PubMed Google Scholar). This review will concentrate on the Type 2 phosphohydrolases that hydrolyze a variety of lipid phosphates (3Brindley D.N. Waggoner D.W. Chem. Phys. Lipids. 1996; 80: 45-57Crossref PubMed Scopus (105) Google Scholar, 4Kanoh H. Kai M. Wada I. Biochim. Biophys. Acta. 1997; 1348: 56-62Crossref PubMed Scopus (31) Google Scholar). Because the precise biological functions of these phosphohydrolases are not known, we propose to rename the PAP-2 family (Table I) as lipid phosphate phosphohydrolases (LPPs).Table INomenclature of LPP formerly known as PAP-2Suggested namePrevious nameRef.GenBank™ no.mLPP-1mPAP-27Kai M. Wada I. Imai S. Sakane F. Kanoh H. J. Biol. Chem. 1996; 271: 18931-18938Abstract Full Text Full Text PDF PubMed Scopus (105) Google ScholarD84376rLPP-1rPAP2U90556hLPP-1hPAP-2a13Kai M. Wada I. Imai S-I. Sakana F. Kanoh H. J. Biol. Chem. 1997; 272: 24572-24578Abstract Full Text Full Text PDF PubMed Scopus (149) Google ScholarAB000888PAP2-α114Leung D.W. Tompkins C.K. White T. DNA Cell Biol. 1998; 17: 377-388Crossref PubMed Scopus (48) Google ScholarAF014402PAP-2a16Roberts R. Sciorra V.A. Morris A.J. J. Biol. Chem. 1998; 273: 22059-22067Abstract Full Text Full Text PDF PubMed Scopus (157) Google ScholarAF017116hLPP-1aPAP-2α214Leung D.W. Tompkins C.K. White T. DNA Cell Biol. 1998; 17: 377-388Crossref PubMed Scopus (48) Google ScholarAF014403hLPP-2PAP-2γAF035959PAP-2c15Hooks S.B. Ragan S.P. Lynch K.R. FEBS Lett. 1998; 427: 188-192Crossref PubMed Scopus (74) Google ScholarAF056083PAP-2c16Roberts R. Sciorra V.A. Morris A.J. J. Biol. Chem. 1998; 273: 22059-22067Abstract Full Text Full Text PDF PubMed Scopus (157) Google ScholarAF047760hLPP-3hPAP-2b13Kai M. Wada I. Imai S-I. Sakana F. Kanoh H. J. Biol. Chem. 1997; 272: 24572-24578Abstract Full Text Full Text PDF PubMed Scopus (149) Google ScholarAB000889hPAP-2βAF043329hPAP-2b16Roberts R. Sciorra V.A. Morris A.J. J. Biol. Chem. 1998; 273: 22059-22067Abstract Full Text Full Text PDF PubMed Scopus (157) Google ScholarAF017786The known mammalian LPPs are shown together with the other names that have been applied to them. The predicted amino acid sequences for the three hLPP-1s that have been deposited in GenBank™ differ slightly. Those for hLPP-2 and hLPP-3 are identical.D. W. Waggoner and D. N. Brindley, unpublished data.D. Leung, unpublished data. Open table in a new tab The known mammalian LPPs are shown together with the other names that have been applied to them. The predicted amino acid sequences for the three hLPP-1s that have been deposited in GenBank™ differ slightly. Those for hLPP-2 and hLPP-3 are identical. D. W. Waggoner and D. N. Brindley, unpublished data. D. Leung, unpublished data. LPP has been purified and characterized (5Fleming I.N. Yeaman S.J. Biochem. J. 1995; 308: 983-989Crossref PubMed Scopus (42) Google Scholar, 6Waggoner D.W. Martin A. Dewald J. Gómez-Muñoz A. Brindley D.N. J. Biol. Chem. 1995; 270: 19422-19429Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar, 7Kai M. Wada I. Imai S. Sakane F. Kanoh H. J. Biol. Chem. 1996; 271: 18931-18938Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar, 8Siess E.A. Hofstetter M.M. FEBS Lett. 1996; 381: 169-173Crossref PubMed Scopus (26) Google Scholar, 9English D. Martin M. Akard L.P. Allen R. Widlanski T.S. Garcia J.G.N. Siddiqui R.A. Biochem. J. 1997; 324: 941-950Crossref PubMed Scopus (35) Google Scholar). LPP purified from rat liver dephosphorylates lyso-PA, C-1-P, S-1-P (10Waggoner D.W. Gómez-Muñoz A. Dewald J. Brindley D.N. J. Biol. Chem. 1996; 271: 16506-16509Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar), and DGPP (11Dillon D.A. Chen X. Zeimetz G.M. Wu W-I. Waggoner D.W. Dewald J. Brindley D.N. Carman G.M. J. Biol. Chem. 1997; 272: 10361-10366Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar) with efficiencies similar to PA. These substrates are mutually competitive, indicating that the dephosphorylation occurs at the same active site. LPP is not a general phospholipase C (2Jamal Z. Martin A. Gómez-Muñoz A. Brindley D.N. J. Biol. Chem. 1991; 266: 2988-2996Abstract Full Text PDF PubMed Google Scholar) and it will not dephosphorylate water-soluble phosphate esters (2Jamal Z. Martin A. Gómez-Muñoz A. Brindley D.N. J. Biol. Chem. 1991; 266: 2988-2996Abstract Full Text PDF PubMed Google Scholar). The reaction catalyzed by LPP obeys a surface dilution kinetic model (5Fleming I.N. Yeaman S.J. Biochem. J. 1995; 308: 983-989Crossref PubMed Scopus (42) Google Scholar,10Waggoner D.W. Gómez-Muñoz A. Dewald J. Brindley D.N. J. Biol. Chem. 1996; 271: 16506-16509Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar, 11Dillon D.A. Chen X. Zeimetz G.M. Wu W-I. Waggoner D.W. Dewald J. Brindley D.N. Carman G.M. J. Biol. Chem. 1997; 272: 10361-10366Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar), which confirms that it is a lipid phosphate phosphohydrolase. Rat liver LPP had low activity toward dolichol phosphate (10Waggoner D.W. Gómez-Muñoz A. Dewald J. Brindley D.N. J. Biol. Chem. 1996; 271: 16506-16509Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar) and so appears to exhibit some substrate preference for certain lipid phosphate esters. A dolichol phosphate phosphatase has recently been purified from pig brain membranes, and this 33-kDa protein also dephosphorylated PA in the absence of Mg2+ (12Frank D.W. Waechter C.J. J. Biol. Chem. 1998; 273: 11791-11798Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar). However, the authors concluded that this enzyme was different from LPP because the former was inhibited by N-ethylmaleimide. The amino acid sequence of this polyisoprenyl phosphate phosphatase has not yet been published. Kai et al. (7Kai M. Wada I. Imai S. Sakane F. Kanoh H. J. Biol. Chem. 1996; 271: 18931-18938Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar) reported the first successful cloning of cDNA for mLPP-1 (Fig. 1, Table I). The cDNA predicts a 31.9-kDa protein (7Kai M. Wada I. Imai S. Sakane F. Kanoh H. J. Biol. Chem. 1996; 271: 18931-18938Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar), but the expressed protein in 293 cells (4Kanoh H. Kai M. Wada I. Biochim. Biophys. Acta. 1997; 1348: 56-62Crossref PubMed Scopus (31) Google Scholar) and in rat2 fibroblasts 2D. W. Waggoner, J. Dewald, D. A. Dillon, G. M. Carman, and D. N. Brindley, unpublished work. appears at 35 kDa on SDS-polyacrylamide gel electrophoresis because of N-glycosylation. Knowledge of the cDNA sequence of mLPP-1 facilitated the cloning of cDNAs for rat (U90556) and human proteins (Fig. 1). The deduced amino acid sequence for mLPP-1 shares 87 and 84% overall amino acid identity with rLPP-1 and hLPP-1, respectively. The splice variant, hLPP-1a, shares 72% identity with the amino acid sequence of mLPP-1 (14Leung D.W. Tompkins C.K. White T. DNA Cell Biol. 1998; 17: 377-388Crossref PubMed Scopus (48) Google Scholar). Three separate groups (Fig. 1; Table I) have cloned cDNA for another hLPP homolog (LPP-2), which has 56% amino acid sequence homology to hLPP-1 (15Hooks S.B. Ragan S.P. Lynch K.R. FEBS Lett. 1998; 427: 188-192Crossref PubMed Scopus (74) Google Scholar, 16Roberts R. Sciorra V.A. Morris A.J. J. Biol. Chem. 1998; 273: 22059-22067Abstract Full Text Full Text PDF PubMed Scopus (157) Google Scholar). Kai et al. (13Kai M. Wada I. Imai S-I. Sakana F. Kanoh H. J. Biol. Chem. 1997; 272: 24572-24578Abstract Full Text Full Text PDF PubMed Scopus (149) Google Scholar) identified a distinct cDNA that encodes for yet another hLPP and which we designate LPP-3 (Fig. 1; Table I). hLPP-3 appears to be the human homolog (13Kai M. Wada I. Imai S-I. Sakana F. Kanoh H. J. Biol. Chem. 1997; 272: 24572-24578Abstract Full Text Full Text PDF PubMed Scopus (149) Google Scholar) of the rat Dri42 gene product (17Barilà D. Plateroti M. Nobili F. Muda A.O. Xie Y. Morimoto T. Perozzi G. J. Biol. Chem. 1996; 271: 29928-29936Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar), because these two proteins share 94% amino acid sequence identity. Recombinant mLPP-1 and rLPP-1 dephosphorylate PA, lyso-PA, DGPP, C-1-P, and S-1-P with relatively similar efficiencies.2 By contrast, Kai et al. (13Kai M. Wada I. Imai S-I. Sakana F. Kanoh H. J. Biol. Chem. 1997; 272: 24572-24578Abstract Full Text Full Text PDF PubMed Scopus (149) Google Scholar) showed that hLPP-1 hydrolyzed PA and lyso-PA but had relatively little activity toward C-1-P and S-1-P. Both S-1-P and PA were good substrates for LPP-3 (hPAP-2b) (13Kai M. Wada I. Imai S-I. Sakana F. Kanoh H. J. Biol. Chem. 1997; 272: 24572-24578Abstract Full Text Full Text PDF PubMed Scopus (149) Google Scholar). Hookset al. (15Hooks S.B. Ragan S.P. Lynch K.R. FEBS Lett. 1998; 427: 188-192Crossref PubMed Scopus (74) Google Scholar) reported that LPP-1 and LPP-3 had about 30% higher activity against PA compared with lyso-PA but that LPP-2 had higher activity against lyso-PA. All three isoforms dephosphorylatedN-oleoylethanolamine PA. Work with enzymes overexpressed in Sf9 cells indicates that LPP-1 and LPP-3 may have a greater catalytic efficiency (V max/K m) for the glycerolipid substrates and that LPP-2 dephosphorylates the glycerolipid and sphingolipid substrates with similar efficiencies (16Roberts R. Sciorra V.A. Morris A.J. J. Biol. Chem. 1998; 273: 22059-22067Abstract Full Text Full Text PDF PubMed Scopus (157) Google Scholar). All tissues that have been examined express LPP activity against PA. The specific activity in rats is low in skeletal muscle and heart and highest in brain, lung, kidney, and spleen (6Waggoner D.W. Martin A. Dewald J. Gómez-Muñoz A. Brindley D.N. J. Biol. Chem. 1995; 270: 19422-19429Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar). mRNAs for LPP-1/1a are expressed widely and to a high extent in prostate, aorta, bladder, uterus, kidney, lung, and heart (13Kai M. Wada I. Imai S-I. Sakana F. Kanoh H. J. Biol. Chem. 1997; 272: 24572-24578Abstract Full Text Full Text PDF PubMed Scopus (149) Google Scholar, 14Leung D.W. Tompkins C.K. White T. DNA Cell Biol. 1998; 17: 377-388Crossref PubMed Scopus (48) Google Scholar, 18Ulrix W. Swinnen J.V. Heynes W. Verhoven G. J. Biol. Chem. 1998; 273: 4660-4665Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar). hLPP-1a may be the predominant isoform expressed in heart, whereas hLPP-1 appears predominant in kidney, lung, placenta, and liver (14Leung D.W. Tompkins C.K. White T. DNA Cell Biol. 1998; 17: 377-388Crossref PubMed Scopus (48) Google Scholar). The expression of mRNA for LPP-2 was more restrictive, being found mainly in brain, pancreas, and placenta (15Hooks S.B. Ragan S.P. Lynch K.R. FEBS Lett. 1998; 427: 188-192Crossref PubMed Scopus (74) Google Scholar). mRNA for LPP-3 was expressed relatively uniformly in all human tissues examined (13Kai M. Wada I. Imai S-I. Sakana F. Kanoh H. J. Biol. Chem. 1997; 272: 24572-24578Abstract Full Text Full Text PDF PubMed Scopus (149) Google Scholar). mLPP-1 was expressed predominantly in plasma membranes (4Kanoh H. Kai M. Wada I. Biochim. Biophys. Acta. 1997; 1348: 56-62Crossref PubMed Scopus (31) Google Scholar, 7Kai M. Wada I. Imai S. Sakane F. Kanoh H. J. Biol. Chem. 1996; 271: 18931-18938Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar), in agreement with the distribution reported for LPP activity in liver and adipose tissue (2Jamal Z. Martin A. Gómez-Muñoz A. Brindley D.N. J. Biol. Chem. 1991; 266: 2988-2996Abstract Full Text PDF PubMed Google Scholar, 3Brindley D.N. Waggoner D.W. Chem. Phys. Lipids. 1996; 80: 45-57Crossref PubMed Scopus (105) Google Scholar). The Dri42 protein resides in the endoplasmic reticulum of epithelial cells of intestinal mucosa (17Barilà D. Plateroti M. Nobili F. Muda A.O. Xie Y. Morimoto T. Perozzi G. J. Biol. Chem. 1996; 271: 29928-29936Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar). By contrast, Kai et al. (13Kai M. Wada I. Imai S-I. Sakana F. Kanoh H. J. Biol. Chem. 1997; 272: 24572-24578Abstract Full Text Full Text PDF PubMed Scopus (149) Google Scholar) concluded that hLPP-3 should have a post-Golgi localization based on the sensitivity of its oligosaccharide chain to endo-β-glycosidase (13Kai M. Wada I. Imai S-I. Sakana F. Kanoh H. J. Biol. Chem. 1997; 272: 24572-24578Abstract Full Text Full Text PDF PubMed Scopus (149) Google Scholar). The existence of a phosphatase superfamily was first proposed by Stukey and Carman (19Stukey J. Carman G.M. Protein Sci. 1997; 6: 469-472Crossref PubMed Scopus (222) Google Scholar) and expanded further by Hemricka et al. (20Hemricka W. Renirie R. Dekker H.L. Bernett P. Wever R. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 2145-2149Crossref PubMed Scopus (172) Google Scholar) and Neuwald (21Neuwald A.F. Protein Sci. 1997; 6: 1764-1767Crossref PubMed Scopus (121) Google Scholar). This superfamily, to which the mammalian LPPs belong (Table II), includes bacterial acid phosphatases and DGPPase (22Icho T. Raetz C.R.H. J. Bacteriol. 1983; 153: 722-730Crossref PubMed Google Scholar, 23Dillon D.A. Wu W.-I. Riedel B. Wissing J.B. Dowhan W. Carman G.M. J. Biol. Chem. 1996; 271: 30548-30553Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar), yeast DGPPase (24Toke D.A. Bennett W.L. Dillon D.A. Wu W.-I. Chen X. Ostrander D.B. Oshiro J. Cremesti A. Voelker D.R. Fischl A.S. Carman G.M. J. Biol. Chem. 1998; 273: 3278-3284Abstract Full Text Full Text PDF PubMed Scopus (101) Google Scholar), dihydrosphingosine/phytosphingosine phosphate phosphatase (25Mao C. Wadleigh M. Jenkins G.M. Hannun Y.A. Obeid L.M. J. Biol. Chem. 1997; 272: 28690-28694Abstract Full Text Full Text PDF PubMed Scopus (141) Google Scholar, 26Mandala S.M. Thornton R. Tu Z. Kurtz M.B. Nickels J. Broach J. Menzeleev R. Spiegel S. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 150-155Crossref PubMed Scopus (235) Google Scholar), lipid phosphate phosphatase (27Toke D.A. Bennett W.L. Oshiro J. Wu W.-I. Voelker D.R. Carman G.M. J. Biol. Chem. 1998; 273: 14331-14338Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar), fungal haloperoxidases (28Simons B.H. Barnett P. Vollenbroek E.G.M. Dekker H.L. Muusers A.O. Messerschmidt A. Wever R. Eur. J. Biochem. 1995; 229: 566-574Crossref PubMed Scopus (70) Google Scholar), mammalian G6Pase (29Shelly L.L. Lei K-J. Pan C-J. Sakata S.F. Ruppert S. Schutz G. Chou J.Y. J. Biol. Chem. 1993; 268: 21482-21485Abstract Full Text PDF PubMed Google Scholar, 30Lei K-J. Shelly L.L. Pan C-J. Sidbury J.B. Chou J.Y. Science. 1993; 242: 580-583Crossref Scopus (320) Google Scholar, 31Lei K-J. Shelley L.L. Lin B. Sidbury J.B. Chen Y.T. Nordlie R.C. Chou J.Y. J. Clin. Invest. 1995; 95: 234-240Crossref PubMed Google Scholar, 32Lei K-J. Pan C-J. Liu J-L. Shelly L.L. Chou J.Y. J. Biol. Chem. 1995; 270: 11882-11886Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar, 33Pan C-J. Lei K-J. Annabi B. Hemrika W. Chou J.Y. J. Biol. Chem. 1998; 273: 6144-6148Abstract Full Text Full Text PDF PubMed Scopus (152) Google Scholar), the Drosophila proteinwunen (34Zhang N. Zhang J. Purcell K.J. Cheng Y. Howard K. Nature. 1997; 385: 64-67Crossref PubMed Scopus (176) Google Scholar), rat Dri42 (17Barilà D. Plateroti M. Nobili F. Muda A.O. Xie Y. Morimoto T. Perozzi G. J. Biol. Chem. 1996; 271: 29928-29936Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar), mammalian HIC-53 (if correctly identified, 35), and putative gene products from other organisms (19Stukey J. Carman G.M. Protein Sci. 1997; 6: 469-472Crossref PubMed Scopus (222) Google Scholar, 20Hemricka W. Renirie R. Dekker H.L. Bernett P. Wever R. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 2145-2149Crossref PubMed Scopus (172) Google Scholar, 21Neuwald A.F. Protein Sci. 1997; 6: 1764-1767Crossref PubMed Scopus (121) Google Scholar). There are three highly conserved domains within a larger motif that defines this superfamily (19Stukey J. Carman G.M. Protein Sci. 1997; 6: 469-472Crossref PubMed Scopus (222) Google Scholar) as illustrated in Table II and in yellow boxes in Fig. 1. The consensus sequences are juxtaposed to α-helical segments (36Messerschmidt A. Wever R. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 392-396Crossref PubMed Scopus (398) Google Scholar) or proposed membrane-spanning domains (Fig. 1). There are minor differences in amino acid composition between LPP-1 and LPP-2 versus hLPP-3 and rat Dri42 in the conserved domains (Fig. 1); however, LPP-3 differs substantially from LPP-1 and LPP-2 in the N and C termini.Table IIAmino acid sequence comparison of three domains constituting a novel phosphatase motifTwenty-seven proteins (excluding Dri42) that exhibit phosphatase activity and contain a novel phosphatase motif (30Lei K-J. Shelly L.L. Pan C-J. Sidbury J.B. Chou J.Y. Science. 1993; 242: 580-583Crossref Scopus (320) Google Scholar, 32Lei K-J. Pan C-J. Liu J-L. Shelly L.L. Chou J.Y. J. Biol. Chem. 1995; 270: 11882-11886Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar) were used to generate the proposed consensus domains. Numbers flanking the outside of domains 1 and 3 refer to the numbering of the first and last amino acid in those domains, respectively, from the linear sequence of the protein. The intervening numbers refer to the number of amino acids between the adjoining domains. Blue lettering indicates amino acids that are conserved in the consensus sequences, as indicated. TM, transmembrane domain, determined using TMPredict (36Messerschmidt A. Wever R. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 392-396Crossref PubMed Scopus (398) Google Scholar). X, any amino acid; b, branched chain amino acid; h, hydrophobic amino acid (I, L, F, M, V, W, Y); n, small neutral amino acid (A, C, G, S); Φ, aromatic amino acid (F, H, Y, W). Open table in a new tab Twenty-seven proteins (excluding Dri42) that exhibit phosphatase activity and contain a novel phosphatase motif (30Lei K-J. Shelly L.L. Pan C-J. Sidbury J.B. Chou J.Y. Science. 1993; 242: 580-583Crossref Scopus (320) Google Scholar, 32Lei K-J. Pan C-J. Liu J-L. Shelly L.L. Chou J.Y. J. Biol. Chem. 1995; 270: 11882-11886Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar) were used to generate the proposed consensus domains. Numbers flanking the outside of domains 1 and 3 refer to the numbering of the first and last amino acid in those domains, respectively, from the linear sequence of the protein. The intervening numbers refer to the number of amino acids between the adjoining domains. Blue lettering indicates amino acids that are conserved in the consensus sequences, as indicated. TM, transmembrane domain, determined using TMPredict (36Messerschmidt A. Wever R. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 392-396Crossref PubMed Scopus (398) Google Scholar). X, any amino acid; b, branched chain amino acid; h, hydrophobic amino acid (I, L, F, M, V, W, Y); n, small neutral amino acid (A, C, G, S); Φ, aromatic amino acid (F, H, Y, W). Results of experiments with G6Pase and chloroperoxidase demonstrate that the conserved amino acids in each domain (Fig. 1) are involved in the coordination and hydrolysis of the phosphate ester, which probably occurs through a phosphohistidine intermediate. Thirty-seven percent of mutant alleles in people with glycogen storage disease 1a contain a single point mutation in the codon for Arg-83 in G6Pase (31Lei K-J. Shelley L.L. Lin B. Sidbury J.B. Chen Y.T. Nordlie R.C. Chou J.Y. J. Clin. Invest. 1995; 95: 234-240Crossref PubMed Google Scholar). This arginine and histidines 119 and 176 of G6Pase are absolutely required for catalytic activity (32Lei K-J. Pan C-J. Liu J-L. Shelly L.L. Chou J.Y. J. Biol. Chem. 1995; 270: 11882-11886Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar, 33Pan C-J. Lei K-J. Annabi B. Hemrika W. Chou J.Y. J. Biol. Chem. 1998; 273: 6144-6148Abstract Full Text Full Text PDF PubMed Scopus (152) Google Scholar), and the two histidines are conserved within the phosphatase superfamily. In Curvularia inaequalis chloroperoxidase, Lys-353, Arg-360, Ser-402, Gly-403, Arg-490, and His-496 coordinate vanadate in the active site of the enzyme (36Messerschmidt A. Wever R. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 392-396Crossref PubMed Scopus (398) Google Scholar, 37Messerschmidt A. Prade L. Wever R. Biol. Chem. Hoppe-Seyler. 1997; 378: 309-315Crossref PubMed Scopus (286) Google Scholar). All of these residues are conserved in the phosphatase superfamily. Additionally, His-404, the conserved histidine in Domain 2 of chloroperoxidase (Table II), is believed to be the hydrogen donor in the reaction mechanism (36Messerschmidt A. Wever R. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 392-396Crossref PubMed Scopus (398) Google Scholar, 37Messerschmidt A. Prade L. Wever R. Biol. Chem. Hoppe-Seyler. 1997; 378: 309-315Crossref PubMed Scopus (286) Google Scholar) as is the equivalent histidine (His-119) in hG6Pase (33Pan C-J. Lei K-J. Annabi B. Hemrika W. Chou J.Y. J. Biol. Chem. 1998; 273: 6144-6148Abstract Full Text Full Text PDF PubMed Scopus (152) Google Scholar). The conserved histidine (His-176) of hG6Pase is proposed to be the phosphoryl acceptor during catalysis (33Pan C-J. Lei K-J. Annabi B. Hemrika W. Chou J.Y. J. Biol. Chem. 1998; 273: 6144-6148Abstract Full Text Full Text PDF PubMed Scopus (152) Google Scholar). Chloroperoxidase exhibits both vanadate-dependent peroxidase activity and vanadate-inhibitable phosphatase activity. Moreover, the peroxidase activity of chloroperoxidase is inhibited by phosphate, and the phosphatase activity of G6Pase is inhibited by vanadate (38Stankiewicz P.J. Tracey A.S. Crans D.C. Sigel H. Sigel A. Metal Ions in Biological Systems. 31. Marcel Dekker, Inc., New York1995: 660-662Google Scholar). These results indicate that the binding of phosphate and vanadate is mutually exclusive and may occur at the same site (20Hemricka W. Renirie R. Dekker H.L. Bernett P. Wever R. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 2145-2149Crossref PubMed Scopus (172) Google Scholar). These results suggest that the three-dimensional architecture of the active sites of chloroperoxidase, G6Pase, and the LPPs is conserved and that this family of enzymes shares a similar catalytic mechanism. However, mutational studies have yet to be performed for the LPPs to verify this proposal. The hydrophobicity plots (39Hoffmann K. Stoffel W. Biol. Chem. Hoppe-Seyler. 1993; 347: 166-170Google Scholar) of the LPPs and Dri42 are almost superimposable, suggesting that their three-dimensional structures are similar. There are six putative membrane-spanning regions that areboxed in Fig. 1, and this is compatible with their being integral membrane proteins. Barilà et al. (17Barilà D. Plateroti M. Nobili F. Muda A.O. Xie Y. Morimoto T. Perozzi G. J. Biol. Chem. 1996; 271: 29928-29936Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar) concluded that the hydrophobic transmembrane domains 1, 3, and 5 had a signal/anchor function and that membrane insertion of Dri42 was achieved co-translationally by the action of a series of alternating insertion and halt transfer signals, resulting in the exposure of both termini to the cytosolic side. All LPPs contain a consensusN-glycosylation site in the loop between transmembrane regions 3 and 4 (Fig. 1). This is the only glycosylation site that was demonstrated in LPP-1 (7Kai M. Wada I. Imai S. Sakane F. Kanoh H. J. Biol. Chem. 1996; 271: 18931-18938Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar), LPP-3 (13Kai M. Wada I. Imai S-I. Sakana F. Kanoh H. J. Biol. Chem. 1997; 272: 24572-24578Abstract Full Text Full Text PDF PubMed Scopus (149) Google Scholar), and Dri42 (17Barilà D. Plateroti M. Nobili F. Muda A.O. Xie Y. Morimoto T. Perozzi G. J. Biol. Chem. 1996; 271: 29928-29936Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar). Glycosylation can be blocked in cells with tunicamycin (7Kai M. Wada I. Imai S. Sakane F. Kanoh H. J. Biol. Chem. 1996; 271: 18931-18938Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar), and the LPP isoforms are sensitive to N-glycanase (6Waggoner D.W. Martin A. Dewald J. Gómez-Muñoz A. Brindley D.N. J. Biol. Chem. 1995; 270: 19422-19429Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar, 7Kai M. Wada I. Imai S. Sakane F. Kanoh H. J. Biol. Chem. 1996; 271: 18931-18938Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar, 13Kai M. Wada I. Imai S-I. Sakana F. Kanoh H. J. Biol. Chem. 1997; 272: 24572-24578Abstract Full Text Full Text PDF PubMed Scopus (149) Google Scholar, 17Barilà D. Plateroti M. Nobili F. Muda A.O. Xie Y. Morimoto T. Perozzi G. J. Biol. Chem. 1996; 271: 29928-29936Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar) and sialidase (13Kai M. Wada I. Imai S-I. Sakana F. Kanoh H. J. Biol. Chem. 1997; 272: 24572-24578Abstract Full Text Full Text PDF PubMed Scopus (149) Google Scholar). The presence of the glycosylation site restricts the topology of LPPs such that the loop containing this site should be extracellular (at the plasma membrane) or luminal (in endoplasmic reticulum membranes). This conclusion is consistent with the topology of Dri42 (17Barilà D. Plateroti M. Nobili F. Muda A.O. Xie Y. Morimoto T. Perozzi G. J. Biol. Chem. 1996; 271: 29928-29936Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar) and G6Pase (33Pan C-J. Lei K-J. Annabi B. Hemrika W. Chou J.Y. J. Biol. Chem. 1998; 273: 6144-6148Abstract Full Text Full Text PDF PubMed Scopus (152) Google Scholar). There is no obvious preprotein leader sequence that targets the processing of the LPP proteins via traditional routes, and the mechanism of targeting is unknown. This is also true for chloroperoxidase (28Simons B.H. Barnett P. Vollenbroek E.G.M. Dekker H.L. Muusers A.O. Messerschmidt A. Wever R. Eur. J. Biochem. 1995; 229: 566-574Crossref PubMed Scopus (70) Google Scholar) and G6Pase (30Lei K-J. Shelly L.L. Pan C-J. Sidbury J.B. Chou J.Y. Science. 1993; 242: 580-583Crossref Scopus (320) Google Scholar). Fig. 1 also identifies several putative phosphorylation sites for the LPPs. The identification of LPP in plasma membranes led to the hypothesis that it is involved in cell signaling (3Brindley D.N. Waggoner D.W. Chem. Phys. Lipids. 1996; 80: 45-57Crossref PubMed Scopus (105) Google Scholar, 4Kanoh H. Kai M. Wada I. Biochim. Biophys. Acta. 1997; 1348: 56-62Crossref PubMed Scopus (31) Google Scholar). This could involve an intracellular site of action by dephosphorylating PA formed by PLD or DAG kinase (4Kanoh H. Kai M. Wada I. Biochim. Biophys. Acta. 1997; 1348: 56-62Crossref PubMed Scopus (31) Google Scholar). PA activates the NADPH oxidase system in neutrophils and stimulates protein kinases, phosphatidylinositol 4-kinase, phospholipase C-γ, and the Ras-Raf-MAP kinase pathway (3Brindley D.N. Waggoner D.W. Chem. Phys. Lipids. 1996; 80: 45-57Crossref PubMed Scopus (105) Google Scholar,40Gómez-Muñoz A. Abousalham A. Kikuchi Y. Waggoner D.W. Brindley D.N. Hannun Y.A. Sphingolipid-mediated Signal Transduction. Landes Co., Austin, TX1997: 103-120Crossref Google Scholar). 3To save space reviews cited rather than original articles. PA is also involved in stimulating the formation of the actin cytoskeleton (41Ha K.S. Exton J.H. J. Cell Biol. 1993; 123: 1789-1796Crossref PubMed Scopus (154) Google Scholar) and in microvesicle budding from Golgi membranes (42Ktistakis N.T. Brown A. Waters G.M. Sternweis P.C. Roth M.G. J. Cell Biol. 1996; 134: 295-306Crossref PubMed Scopus (329) Google Scholar). The LPPs could therefore attenuate signaling by PA while producing DAG, which might activate protein kinase Cs. Evidence was provided that LPP can dephosphorylate PA generated by PLD using ras-transformed fibroblasts, which have low LPP activity compared with control fibroblasts. Stimulation of PLD produced an increased formation of PA relative to DAG in ras-transformed compared with control fibroblasts (43Martin A. Gómez-Muñoz A. Waggoner D.W. Stone J.C. Brindley D.N. J. Biol. Chem. 1993; 268: 23924-23932Abstract Full Text PDF PubMed Google Scholar). Furthermore, PA accumulated as a function of time in culture for the ras-transformed fibroblasts compared with control cells (44Martin A. Duffy P.A. Liossis C. Gómez-Muñoz A. O'Brien L. Stone J.C. Brindley D.N. Oncogene. 1997; 14: 1571-1580Crossref PubMed Scopus (50) Google Scholar). Overexpression of hLPP-1 or hLPP-1a in ECV304 endothelial cells decreased PA concentrations by 50% (14Leung D.W. Tompkins C.K. White T. DNA Cell Biol. 1998; 17: 377-388Crossref PubMed Scopus (48) Google Scholar). LPP-1 mRNA expression was also diminished in human colon tumor tissue compared with matching tissue from normal colon (14Leung D.W. Tompkins C.K. White T. DNA Cell Biol. 1998; 17: 377-388Crossref PubMed Scopus (48) Google Scholar). It may also be significant that HIC-53, which codes for a putative protein having extensive sequence homology to LPP-1, has been described asras-recision gene (35Egawa K. Yoshiwara M. Shibanuma M. Nose K. FEBS Lett. 1995; 372: 74-77Crossref PubMed Scopus (14) Google Scholar). HIC-53 mRNA expression was decreased in MC3T3 cells transformed with v-Ki-ras, and the normal induction of the mRNA by H2O2 was abolished (35Egawa K. Yoshiwara M. Shibanuma M. Nose K. FEBS Lett. 1995; 372: 74-77Crossref PubMed Scopus (14) Google Scholar). However, Kai et al. (13Kai M. Wada I. Imai S-I. Sakana F. Kanoh H. J. Biol. Chem. 1997; 272: 24572-24578Abstract Full Text Full Text PDF PubMed Scopus (149) Google Scholar) did not demonstrate induction of mRNA for LPP-1 and LPP-3 by H2O2. Sphingolipids regulate cell differentiation and proliferation (40Gómez-Muñoz A. Abousalham A. Kikuchi Y. Waggoner D.W. Brindley D.N. Hannun Y.A. Sphingolipid-mediated Signal Transduction. Landes Co., Austin, TX1997: 103-120Crossref Google Scholar,45Hannun Y.A. Science. 1996; 274: 1855-1859Crossref PubMed Scopus (1500) Google Scholar),3 and they “cross-talk” with the glycerolipid signaling pathway (3Brindley D.N. Waggoner D.W. Chem. Phys. Lipids. 1996; 80: 45-57Crossref PubMed Scopus (105) Google Scholar, 40Gómez-Muñoz A. Abousalham A. Kikuchi Y. Waggoner D.W. Brindley D.N. Hannun Y.A. Sphingolipid-mediated Signal Transduction. Landes Co., Austin, TX1997: 103-120Crossref Google Scholar).3 Ceramides are formed by the agonist-induced activation of sphingomyelinase. They cause apoptosis and inhibit PA production by blocking PLD activation (40Gómez-Muñoz A. Abousalham A. Kikuchi Y. Waggoner D.W. Brindley D.N. Hannun Y.A. Sphingolipid-mediated Signal Transduction. Landes Co., Austin, TX1997: 103-120Crossref Google Scholar).3Little is known about the physiological effects of C-1-P, although it may regulate some aspects of synaptic vesicle function and a C-1-P phosphatase was located in synaptic vesicles and in plasma membranes (46Shinghal R. Scheller R.H. Bajalieh S.M. J. Neurochem. 1993; 61: 2279-2285Crossref PubMed Scopus (74) Google Scholar). Exogenous C-1-P stimulates cell division in fibroblasts (40Gómez-Muñoz A. Abousalham A. Kikuchi Y. Waggoner D.W. Brindley D.N. Hannun Y.A. Sphingolipid-mediated Signal Transduction. Landes Co., Austin, TX1997: 103-120Crossref Google Scholar).3 A major fate of ceramide is conversion to sphingosine, a compound that directly inhibits protein kinase C (40Gómez-Muñoz A. Abousalham A. Kikuchi Y. Waggoner D.W. Brindley D.N. Hannun Y.A. Sphingolipid-mediated Signal Transduction. Landes Co., Austin, TX1997: 103-120Crossref Google Scholar).3 Sphingosine also decreases protein kinase C activity through inhibition of PAP-1 and LPP activity with consequent decreases in DAG formation (1Brindley D.N. Brindley D.N. Phosphatidate Phosphohydrolase. 1. CRC Press, Inc., Boca Raton, FL1988: 1-77Google Scholar, 2Jamal Z. Martin A. Gómez-Muñoz A. Brindley D.N. J. Biol. Chem. 1991; 266: 2988-2996Abstract Full Text PDF PubMed Google Scholar, 3Brindley D.N. Waggoner D.W. Chem. Phys. Lipids. 1996; 80: 45-57Crossref PubMed Scopus (105) Google Scholar, 40Gómez-Muñoz A. Abousalham A. Kikuchi Y. Waggoner D.W. Brindley D.N. Hannun Y.A. Sphingolipid-mediated Signal Transduction. Landes Co., Austin, TX1997: 103-120Crossref Google Scholar).3 Sphingosine also increases PA concentrations by stimulating DAG kinase and PLD activities in some cells (40Gómez-Muñoz A. Abousalham A. Kikuchi Y. Waggoner D.W. Brindley D.N. Hannun Y.A. Sphingolipid-mediated Signal Transduction. Landes Co., Austin, TX1997: 103-120Crossref Google Scholar).3 Some effects of sphingosine are mediated by conversion to S-1-P, a potent activator of PLD, Ca2+mobilization, and cell proliferation by the activation of MAP kinase (40Gómez-Muñoz A. Abousalham A. Kikuchi Y. Waggoner D.W. Brindley D.N. Hannun Y.A. Sphingolipid-mediated Signal Transduction. Landes Co., Austin, TX1997: 103-120Crossref Google Scholar).3 The ability of the LPPs to hydrolyze PA, lyso-PA, C-1-P, or S-1-P indicates that these enzymes can potentially attenuate signaling by these lipids while simultaneously generating other signals through the formation of DAG, ceramide, and sphingosine. LPPs could also act as “ecto-enzymes,” which regulate signaling by exogenous lyso-PA and S-1-P that may be secreted as autocrine or paracrine mediators. For example, newly formed lyso-PA in thrombin-activated platelets is released and is believed to stimulate wound repair (47Moolenaar W.H. J. Biol. Chem. 1995; 270: 12949-12952Abstract Full Text Full Text PDF PubMed Scopus (572) Google Scholar).3 In addition, lyso-PA production through activation of secretory phospholipase A2 may represent a proinflammatory pathway (48Fourcade O. Simon M-F. Viodé C. Rugani N. Leballe F. Ragab A. Fournié B. Sarda L. Chap H. Cell. 1995; 80: 919-927Abstract Full Text PDF PubMed Scopus (496) Google Scholar). Lyso-PA acts through specific receptors (49An S. Dickens W.A. Bleu T. Hallmark O.G. Goetzl E.J. J. Biol. Chem. 1998; 273: 7906-7910Abstract Full Text Full Text PDF PubMed Scopus (492) Google Scholar)3 and increases tyrosine kinase activities, phospholipase C-γ, Ca2+ mobilization, arachidonate release, PLD, MAP kinase, focal adhesion kinase, and stress fiber formation (3Brindley D.N. Waggoner D.W. Chem. Phys. Lipids. 1996; 80: 45-57Crossref PubMed Scopus (105) Google Scholar, 40Gómez-Muñoz A. Abousalham A. Kikuchi Y. Waggoner D.W. Brindley D.N. Hannun Y.A. Sphingolipid-mediated Signal Transduction. Landes Co., Austin, TX1997: 103-120Crossref Google Scholar, 47Moolenaar W.H. J. Biol. Chem. 1995; 270: 12949-12952Abstract Full Text Full Text PDF PubMed Scopus (572) Google Scholar).3 Exogenous PA, lyso-PA, and S-1-P decrease adenylate cyclase activity through a pertussis toxin-sensitive mechanism (3Brindley D.N. Waggoner D.W. Chem. Phys. Lipids. 1996; 80: 45-57Crossref PubMed Scopus (105) Google Scholar, 47Moolenaar W.H. J. Biol. Chem. 1995; 270: 12949-12952Abstract Full Text Full Text PDF PubMed Scopus (572) Google Scholar).3 Overexpression of mLPP-1 in rat fibroblasts increases the ability of intact cells to dephosphorylate exogenous 32P-labeled lyso-PA and C-1-P and release 32Pi in the culture medium. 4D. W. Waggoner, R. Jasinska, Z-X. Zhang, C. P. Igrul, J. Dewald, and D. N. Brindley, unpublished work. These results confirm that at least a portion of the LPP-1 activity can function as an ecto-enzyme. This conclusion could identify LPP-1 as the ecto-PAP (9English D. Martin M. Akard L.P. Allen R. Widlanski T.S. Garcia J.G.N. Siddiqui R.A. Biochem. J. 1997; 324: 941-950Crossref PubMed Scopus (35) Google Scholar, 50Perry D.K. Stevens V.L. Widlanski T.S. Lambeth J.D. J. Biol. Chem. 1993; 268: 25302-25310Abstract Full Text PDF PubMed Google Scholar) or ecto-lyso-PAP (51Xie M. Lowe M.G. Arch. Biochem. Biophys. 1994; 312: 254-259Crossref PubMed Scopus (31) Google Scholar) reported previously. The definition of the “ecto-phosphohydrolase” in work published so far relies on the assumption that the transmembrane movement of lipid phosphates is slow (unless specifically catalyzed by translocases).32Pi from labeled PA and lyso-PA is also released quickly into the culture medium, whereas intracellular Pi is not rapidly secreted. Work from Dr. D. English 5D. English, personal communication. indicates a role for ecto-LPP in modulating neutrophil migration in response to PA. This chemotaxis involves a tyrosine kinase-dependent activation of intracellular Ca2+ mobilization and consequent induction of actin polymerization (52Siddiqui R.A. English D. Biochim. Biophys. Acta. 1997; 1349: 82-96Google Scholar). Thus, ecto-LPP could degrade exogenous bioactive lipid phosphates and by doing so generate new signals to direct cell migration. The latter situation is exemplified by thewunen gene product, which dephosphorylates PA. 6H. Kanoh, personal communication. Expression of thewunen product in the gut of Drosophila embryos transforms a permissive environment into a repulsive one and guides germ cells to the mesoderm (34Zhang N. Zhang J. Purcell K.J. Cheng Y. Howard K. Nature. 1997; 385: 64-67Crossref PubMed Scopus (176) Google Scholar). There is relatively little information concerning LPP regulation. Kaiet al. (13Kai M. Wada I. Imai S-I. Sakana F. Kanoh H. J. Biol. Chem. 1997; 272: 24572-24578Abstract Full Text Full Text PDF PubMed Scopus (149) Google Scholar) demonstrated that the mRNA for LPP-3, but not LPP-1, increased up to 3-fold after treating quiescent HeLa cells with epidermal growth factor. Recent work has identifiedLPP-1 as being an androgen-regulated gene in human prostatic adenocarcinoma cells (18Ulrix W. Swinnen J.V. Heynes W. Verhoven G. J. Biol. Chem. 1998; 273: 4660-4665Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar). Expression of Dri42 in rat intestinal mucosa is increased during epithelial differentiation (17Barilà D. Plateroti M. Nobili F. Muda A.O. Xie Y. Morimoto T. Perozzi G. J. Biol. Chem. 1996; 271: 29928-29936Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar). The involvement of mammalian LPPs in signaling functions is supported by the properties of other homologs. Mastoparan stimulates the production of PA, which is then converted to DGPP by PA kinase (53Carman G.M. Biochim. Biophys. Acta. 1997; 1348: 45-55Crossref PubMed Scopus (70) Google Scholar,54Munnik T. de Vrije T. Irvine R.F. Musgrave A. J. Biol. Chem. 1996; 271: 15708-15715Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar). Yeast DGPPases dephosphorylate DGPP rather than PA because the specificity constant (V max/K m) is about 10 times higher for DGPP than for PA (11Dillon D.A. Chen X. Zeimetz G.M. Wu W-I. Waggoner D.W. Dewald J. Brindley D.N. Carman G.M. J. Biol. Chem. 1997; 272: 10361-10366Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar, 24Toke D.A. Bennett W.L. Dillon D.A. Wu W.-I. Chen X. Ostrander D.B. Oshiro J. Cremesti A. Voelker D.R. Fischl A.S. Carman G.M. J. Biol. Chem. 1998; 273: 3278-3284Abstract Full Text Full Text PDF PubMed Scopus (101) Google Scholar, 55Wu W-I. Liu Y. Riedel B. Wissing J.B. Fischl A.S. Carman G.M. J. Biol. Chem. 1996; 271: 1868-1876Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar). DGPP could signal in its own right or serve as the precursor of PA while preventing PA hydrolysis (53Carman G.M. Biochim. Biophys. Acta. 1997; 1348: 45-55Crossref PubMed Scopus (70) Google Scholar, 54Munnik T. de Vrije T. Irvine R.F. Musgrave A. J. Biol. Chem. 1996; 271: 15708-15715Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar). An LPP-l gene, distinct from that of DGPPase, has also been identified in Saccharomyces cerevisiae, and the encoded phosphatase exhibited the following substrate preference: PA > lyso-PA > DGPP (27Toke D.A. Bennett W.L. Oshiro J. Wu W.-I. Voelker D.R. Carman G.M. J. Biol. Chem. 1998; 273: 14331-14338Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar). Deletion mutants of LPP-1 and DGPPase showed decreased concentrations of phosphatidylinositol with the greatest decrease in the double mutant. PA concentrations were also increased in the DGPPase and LPP1/DGPPase double mutant (27Toke D.A. Bennett W.L. Oshiro J. Wu W.-I. Voelker D.R. Carman G.M. J. Biol. Chem. 1998; 273: 14331-14338Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar). Yeast deletion mutants of DGPPase (24Toke D.A. Bennett W.L. Dillon D.A. Wu W.-I. Chen X. Ostrander D.B. Oshiro J. Cremesti A. Voelker D.R. Fischl A.S. Carman G.M. J. Biol. Chem. 1998; 273: 3278-3284Abstract Full Text Full Text PDF PubMed Scopus (101) Google Scholar), LPP1 (27Toke D.A. Bennett W.L. Oshiro J. Wu W.-I. Voelker D.R. Carman G.M. J. Biol. Chem. 1998; 273: 14331-14338Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar), and phytosphingosine phosphate phosphatases (also known as lipid-binding proteins 1 and 2) (26Mandala S.M. Thornton R. Tu Z. Kurtz M.B. Nickels J. Broach J. Menzeleev R. Spiegel S. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 150-155Crossref PubMed Scopus (235) Google Scholar) demonstrate normal growth, cell morphology, and mating, but lipid-binding protein mutants have dramatically enhanced survival to heat shock (56Jenkins G.M. Richards A. Wahl T. Mao C. Obeid L. Hannun Y. J. Biol. Chem. 1997; 272: 32566-32572Abstract Full Text Full Text PDF PubMed Scopus (261) Google Scholar). Overexpression of lipid-binding protein 1 (also called Lcb3) confers resistance to the inhibition of cell growth by sphingosine (25Mao C. Wadleigh M. Jenkins G.M. Hannun Y.A. Obeid L.M. J. Biol. Chem. 1997; 272: 28690-28694Abstract Full Text Full Text PDF PubMed Scopus (141) Google Scholar). We are at an exciting point where various LPP isoforms have been identified. The regulation of LPP homologs has not been investigated in detail. Another area of uncertainty is the full extent of the LPP family and whether other LPPs exist with relatively little sequence homology. The exact subcellular localization for each mammalian LPP is not yet known. Therefore, we do not know the extent to which different lipid phosphates have access to the LPP isoforms. The identification of lyso-PA and S-1-P as physiological extracellular messengers and our observations that LPPs can dephosphorylate these exogenous substrates imply a role for the LPPs in modulating extracellular signaling. Equally we need to understand the roles of the LPP isoforms in dephosphorylating intracellular signals from lipid phosphates. These studies can now be undertaken to elucidate the functions of each LPP isoform in regulating signal transduction.
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