Unlike Two Peas in a Pod: Lipid Phosphate Phosphatases and

Review pubs.acs.org/CR

Unlike Two Peas in a Pod: Lipid Phosphate Phosphatases and Phosphatidate Phosphatases† Bernard P. C. Kok,‡ Ganesh Venkatraman,‡ Dora Capatos,‡ and David N. Brindley* Signal Transduction Research Group, Department of Biochemistry, School of Translational Medicine, University of Alberta, Edmonton, Alberta T6G 2S2, Canada 4.2.3. Hydrolysis of Other Extracellular Lipid Phosphates by LPPs 4.3. Noncatalytic Functions of LPPs 4.4. Intracellular Roles of LPPs 4.5. Regulation of LPP Expression 4.6. Concluding Remarks for the LPPs 5. Conclusions Associated Content Special Issue Paper Author Information Corresponding Author Author Contributions Notes Biographies Acknowledgments Abbreviations References

CONTENTS 1. Introduction 2. Historical Perspective 3. Phosphatidate Phosphatases (Lipins) 3.1. Involvement of Lipins in Glycerolipid Synthesis through Their Phosphatidate Phosphatase Activities 3.1.1. Domain Structure of PAP Enzymes 3.1.2. Regulation of PAP Activity 3.1.3. Roles of PAP Activity in Yeast, Worms, Flies, and Plants 3.2. Lipins as Transcriptional Regulators 3.3. Lipin-Deficient and Transgenic Overexpressing Models 3.4. Lipin Expression and Gene Polymorphisms in Human Health and Disease 3.5. Regulation of Lipin Compartmentalization 3.6. Transcriptional Regulation of the Lipins 3.7. Lipins and the Regulation of Hepatic Lipoprotein Secretion 3.8. Lipins and Inflammatory Signaling 3.9. Lipins: Redundancy, Compensation, and Selective Functions 3.10. Known and Putative Roles of Lipins in Lipid Signaling 3.11. Concluding Remarks for the Lipins 4. Lipid Phosphate Phosphatases 4.1. Structure of the LPPs and Related Proteins 4.1.1. Structure of the LPPs 4.1.2. Structure and Functions of the Sphingomyelin Synthases 4.1.3. Structure and Functions of the LPPRelated Proteins or Plasticity Related Genes (LPR/PRGs) 4.2. Role of Lipid Phosphate Phosphatases in Cell Signaling 4.2.1. LPPs and the Regulation of LPA Signaling through their Ecto-activities 4.2.2. Effect of LPPs on S1P Signaling © 2012 American Chemical Society

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1. INTRODUCTION Lipid phosphate phosphatases (LPPs), as the name suggests, are enzymes that catalyze the dephosphorylation of a variety of lipid phosphates, including phosphatidate (PA). These lipids are important mediators of signal transduction. By contrast, lipins are a family of proteins that function as phosphatidate phosphatases (PAPs). Unlike the LPPs, lipins act specifically on one substrate, phosphatidate (PA). Although the LPPs and lipins were originally both classified as phosphatidate phosphatases (PAPs), subsequent research has revealed that their structures, functions, and mechanisms of regulation are completely different. This review will summarize what is known about these two enzyme families.

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2. HISTORICAL PERSPECTIVE PAP activity was first characterized and studied in the 1950s with regard to the Kennedy pathway for glycerolipid biosynthesis.1 This pathway begins with the sequential acylation of glycerol-3-phosphate at the sn-1 and -2 positions to form phosphatidate (Figure 1). PAP activity then converts phosphatidate (PA) to diacylglycerol (DG), which is the precursor for the synthesis of phosphatidylcholine (PC), phosphatidylethanolamine (PE), and triacylglycerol (TG) (Figure 1). Early studies measured a PAP activity that was localized to microsomal membranes. It was natural to expect that the PAP activity would be located in these membranes, since this is where the other enzymes of the Kennedy pathway

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synthesis. Several investigators attempted to purify PAP-1 from mammalian sources to homogeneity, but without success. Therefore, this early work had to rely on measuring PAP activity without the possibility of determining changes in protein or mRNA expression for this enzyme. Studies in the 1980s went on to characterize the translocation of the cytosolic PAP onto the endoplasmic reticulum, where it could act in the glycerolipid biosynthesis pathway.6 This translocation was stimulated by unsaturated fatty acids (FAs), acyl-CoA esters, and phosphatidate.7 Saturated fatty acids, such as palmitate, had relatively less effect than unsaturated fatty acids in cell-free systems and intact hepatocytes.7,8 These are all anionic amphiphiles, and the results suggested that increased negative charge on membranes is a component in the binding of the soluble PAP.9 It was proposed from this combined work on the translocation of PAP to membranes that the cytosolic pool of PAP acts as a reservoir of enzyme activity. This reservoir provides the capacity to respond to an increased FA load by recruiting PAP to the site where PA is produced and, therefore, stimulating the sequestration of FAs in TG. This effect will be discussed in more detail in terms of the membrane-association of the lipins in section 3.5. By contrast to the effects of anionic amphiphiles, treating the microsomal membranes with a variety of cationic amphiphilic drugs blocked PAP activity and also the binding of PAP to emulsions of PA.10 The potency of these cationic amphiphiles was proportional to their oil/water partition coefficients.11 This indicates that the displacement of PAP from the membranes depends on the partitioning of the cations into the membranes and the acquisition of a positive charge on the membrane surface. The importance of this displacement of PAP from membranes was demonstrated in rat hepatocytes incubated with different concentrations of the cationic amphiphile, chlorpromazine.12 The displacement of membrane-bound PAP by chlorpromazine was paralleled by a decrease in the conversion of PA to DG and decreases in the synthesis of TG and PC. The effects of cationic drugs in blocking PAP activity and in stimulating the activity of CDP-DG synthase (phosphatidate cytidylyltransferase) caused the diversion of glycerolipid synthesis toward the production of acidic phospholipids (Figure 1).13 It was proposed that these combined actions explain why amphiphilic cationic drugs have the side-effect of producing a phospholipidosis that is characterized by the accumulation of acidic phospholipids in lysosomes.14 The importance of PAP in metabolism is highlighted by the dynamic regulation of this activity in various metabolic states. PAP activity in the liver is increased in diabetes, in stress, in hypoxia, in alcoholic fatty liver, and during starvation.6,15 All of these conditions result in the increased supply of fatty acids from the plasma, which may exceed the requirements of various organs for β-oxidation.16 The increased expression of PAP activity under these conditions depended on the release of glucocorticoids as a part of the animal’s stress response.9 Subsequent studies with cultured hepatocytes confirmed the role of glucocorticoids and showed that glucagon through cAMP amplified this effect.17 Conversely, insulin antagonized the effects of both glucocorticoids and cAMP. This profile of hormonal regulation resembled that of several enzymes involved in regulating gluconeogenesis and amino acid catabolism.17b This response is compatible with the increases in hepatic PAP activity seen in starvation18 and diabetes.19 The

Figure 1. Lipins act as phosphatidate phosphatases (PAPs) in the glycerolipid biosynthesis pathway, which occurs mainly at the endoplasmic reticulum (ER). Two sequential acylations of glycerol3-phosphate produce phosphatidate. The lipins regulate the balance of phosphatidate (PA), which is the precursor for the acidic phospholipids, phosphatidylinositol (PI), and cardiolipin versus diacylglycerol, which is needed for triacylglycerol, phosphatidylcholine (PC), and phosphatidylethanolamine synthesis. Abbreviations: CDP, cytidine diphosphate; DGAT, diacylglycerol acyltransferase; GPAT, glycerol-3-phosphate acyltransferase; LPAAT, lysophosphatidate acyltransferase; PG, phosphatidylglycerol.

are mainly localized. However, surprisingly low rates of TG synthesis were obtained when microsomal fractions were subjected to in vitro assays using glycerol-3-phosphate and fatty acids as substrates.2 Instead, TG synthesis was stimulated when the cytosolic fraction was added to the assay, and it was noted that one of the stimulating factors was heat-labile. Subsequent studies demonstrated that this cytosolic factor was a soluble PAP enzyme,2a,3 which provides the major activity responsible for catalyzing the production of DG required for glycerolipid biosynthesis.1a This discovery of a soluble PAP activity was unexpected because of the membrane-bound PAP activity, which could readily convert PA to DG and no one before had measured detectable levels of cytosolic PAP activity. This discrepancy can be attributed to the substrate used in the assays for measuring PAP activity in vitro in the late 1950s and early 1960s. PA was often synthesized by hydrolyzing egg PC using a plant phospholipase D with high Ca2+ concentrations that were needed to stimulate this activity. PA isolated from this reaction was, therefore, chelated strongly with Ca2+, which was very difficult to displace. The Ca2+-salt form of PA is a poor substrate for the cytosolic PAP activity, whereas the membranebound PAP could readily act upon this substrate.4 It was later shown that the membrane-bound PAP activity was probably catalyzed by type 2 phosphatidate phosphatases (PAP-2),4 which are now called lipid phosphate phosphatases.5 Research in the 1990s showed that the endoplasmic reticulum was not the major location of PAP-2 (LPP) activity, but rather that it is found to a large extent in the plasma membrane. This location indicated that the LPPs are unlikely to participate in the glycerolipid biosynthesis pathway, and it was suggested that they probably regulate cell signaling.4 Conversely, the cytosolic PAP activity, which was described at the time as type 1 phosphatidate phosphatase (PAP-1), showed the properties and regulation expected of an enzyme involved in glycerolipid 5122


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Figure 2. (A) Overall domain structure of the Mus musculus lipin isoforms showing the conserved N-terminus and C-terminus domains of lipins (NLIP and CLIP). Numbers indicate residue number. The sumoylation motifs on lipin-1α and -1β (IKEE and IKHE) and the putative sumoylation motif on lipin-2 (LKEE) are shown. The positions of the polybasic nuclear localization sequence (NLS) as well as the catalytic DxDxT and transcriptional coactivator LxxIL motifs are also shown. (B) Multiple sequence alignment of protein sequences from mouse isoforms of lipins made using Clustal W2. Numbers indicate residue number. The polybasic nuclear localization sequence (NLS) is highlighted in red. The haloacid dehalogenase (HAD) domains I to IV are shown, and the sumoylation sites are outlined in gray. The DxDxt catalytic motif and the other residues involved in the active site are indicated in red lettering, and the conservation of phosphorylation sites is indicated in blue.

those of lipin-1α and -1β.23 PAP activity depends on a conserved C-terminus domain with sequence homology to the Haloacid Dehalogenase or HAD-like domain (Figure 2).24 This DxDxT catalytic motif is present in all HAD-like domains, together with a characteristic and conserved sequence of αhelices and β-sheets.24b,25

increased PAP activity in the liver probably provides an increased capacity to sequester excess FAs that are mobilized from adipose tissue under these conditions.6,16b,20 Although much of the importance and regulation of lipid metabolism by PAP was elucidated in these early years, further detailed mechanistic studies were not forthcoming due to the difficulty in purifying the enzyme and identifying the gene(s) responsible for encoding the PAP(s). The identity of the PAP enzyme remained a mystery until Han et al.21 identified the yeast orthologue of PAP in 2006. These authors showed that a mammalian family of proteins known as lipins were related structurally to the yeast enzyme and that mammalian lipin-1 exhibits PAP activity.21 Each of the three members of this family, lipin-1α, -1β (splice variants of the Lpin1 gene), -2, and -3, were demonstrated to possess PA-specific- and Mg2+dependent PAP activities.22 Another splice variant, lipin-1γ, is enriched in the brain and its specific PAP activity is lower than

3. PHOSPHATIDATE PHOSPHATASES (LIPINS) Lipins were originally identified by positional cloning of lipin-1 in the fatty liver dystrophy ( f ld) mutant mouse strain.26 The fld mice were derived from a spontaneously occurring mutation in a mouse colony from Jackson Laboratories in 1988.27 These mice are characterized by having a fatty liver and hypertriglyceridemia in the preweaning period when they are consuming a relatively high fat diet through the milk. Importantly, the fatty liver spontaneously resolves at weaning, and this process is not impaired by continued suckling with 5123


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foster mothers.27 The most obvious phenotype of these mice is the complete lack of mature adipose tissue.28 It is likely that the lack of a fatty liver postweaning is partially related to fulfilling energy requirements because of the lack of adipose FA stores. Furthermore, the f ld mice undergo progressive peripheral neuropathy due to dymyelination of Schwann cells,29 which will be discussed in section 3.10. The identity of the gene responsible for the f ld mutation was not discovered until 2001, when Peterfy et al. showed that the f ld phenotype can be ascribed to homozygous recessive mutant alleles of the Lpin1 gene, which expresses two splice variants.26 Relatively little is known about the regulation of the alternative splicing of the Lpin1 gene; however, it has been shown that downregulation of a splicing factor, SFRS10, leads to increased lipin-1β expression.30 The other two members of the lipin family, lipin-2 and -3, were related to lipin-1 by sequence comparison.26 Further research showed that the lipins also act as transcriptional regulators involved in processes such as adipogenesis and fatty acid oxidation.25,31

highly conserved serine or threonine residue at the end of the β-strand of motif II appears to help in the stabilization of reaction intermediates in the catalytic site (Figure 2).24b A conserved lysine residue in the α-helix of motif III also participates in coordination and stabilization of the substrate. Motif IV consists of an α-helix flanked by two β-strands. A conserved acidic residue at the end of the first β-strand of motif IV is involved in coordinating the Mg2+ ion along with the acidic residues in domain I; other HAD family members possess two acidic residues in motif IV (Figure 2).24b A recessive allele in the rat, which results from a mutation in the HAD motif IV, led to a complete loss of PAP activity and was associated with neuropathy and lipodystrophy as in the f ld mice.36 Lpin120884 is a partial loss-of-function allele where a tyrosine residue at position 873 on lipin-1β is mutated to an asparagine, resulting in a significant reduction in PAP activity.37 Expression of this lipin-1 allele together with a truncation mutation in the gene that encodes the neuronal cell adhesion molecule, Nrcam20884, acts synergistically to produce severe peripheral neuropathy and transitory hind limb paralysis in mice.37 Additionally, a rare autosomal recessive disease called Majeed syndrome38 is caused by a mutation of the conserved serine residue of motif II in the CLIP domain of lipin-2, which leads to an absolute loss of PAP activity.25 Mutation of the equivalent serine in mouse lipin-125 and in plant lipins39 also leads to the loss of PAP activity. 3.1.2. Regulation of PAP Activity. In contrast to the LPPs, which can dephosphorylate a variety of lipid substrates, the lipins appear to show a specific requirement for PA as a substrate.16b,40 PAP activity assays of the mammalian lipins showed that they do not dephosphorylate lysophosphatidate (LPA), sphingosine 1-phosphate (S1P), or ceramide 1phosphate (C1P), and Pah1p in yeast does not show catalytic activity toward diacylglycerol pyrophosphate.21,22 The PAP activity of the mammalian lipins depends on Mg2+, and it can be inhibited by the alkylating reagent N-ethyl maleimide.40,23a Furthermore, Mn2+ ions also have a concentration-dependent effect on the stimulation of PAP activity in the human lipin-1α, -β, and -γ isoforms in vitro.23a It should also be noted that the specific PAP activity of lipin-1α and -1β in vitro is higher than that of lipin-2 or lipin-3.41 The lipin-1 isoforms show little preference with regard to the species of the acyl chains at the sn-1 and sn-2 positions of PA when assayed in mixed PA/Triton X-100 micelles, with the exception of dipalmitoyl-PA and distearoyl-PA, which are poor substrates in the PAP reaction.23a The basic requirement is that at least one unsaturated fatty acyl moiety is needed for maximum activity. Both the mammalian lipins and yeast Pah1p demonstrate surface dilution kinetics.16b,23a,42 PAP activity is reduced in a dose-dependent manner when the surface concentration of PA is decreased in Triton-X-100/PA micelles.16b,22,23 The lipin proteins can assemble into homo- and hetero-oligomers.43 However, catalytic activity does not depend on the oligomerization state, since oligomers of catalytically inactive lipin mutants with wildtype lipin-1 are still active, with each subunit possessing its own independent activity.43 It was suggested from studies in yeast that Pah1p binds allosterically to PA and activates catalytic activity against PA in the active site due to positive cooperative kinetics in the surface dilution model.44 This result is supported by the presence of a polybasic region in lipin-1 (Figure 2), which also acts as a nuclear localization signal and dictates association with PA secondary to the active site.45

3.1. Involvement of Lipins in Glycerolipid Synthesis through Their Phosphatidate Phosphatase Activities

The PAP activity of the lipins is responsible for converting PA to DG in the Kennedy pathway of glycerolipid synthesis (Figure 1).21,32 This step is an important branch-point in phospholipid synthesis, since PA serves as the substrate for the synthesis of the acidic phospholipids such as phosphatidylinositol, phosphatidylglycerol, and cardiolipin,13 whereas DG is the precursor for PC, PE, and TG (Figure 1).1c The pathway for glycerolipid synthesis is localized mainly to endoplasmic reticulum membranes and, to some extent, mitochondrial membranes.33 It is interesting to note that each step of the pathway is catalyzed by multiple enzymatic isoforms, which are all membrane-bound, except for the lipins. In the case of the lipins, all three isoforms act as PAP enzymes.22 The lipins are differentially expressed depending on the tissue type.22,25 There appears to be some level of redundancy, since the absence of one lipin protein can, to some extent, be compensated for by the other isoforms.34 Lipin-1 appears to be the major lipin isoform in the adipose tissue, skeletal muscle, and heart.22 Lipin-2 is highly enriched in the liver, red blood cells, and specific regions of the brain25 whereas lipin-3 appears to be highly expressed in the intestine.22 3.1.1. Domain Structure of PAP Enzymes. The PAP activity of all mammalian lipins as well as the nonmammalian lipin orthologues depends on the catalytic DxDxT motif (where D and T represent aspartate and threonine, respectively, and x represents any amino acid),15a which is found within the CLIP region of the lipins (Figure 2).15b Mutation of either of the catalytic aspartate residues to glutamate results in the complete loss of PAP activity for lipin-1.21,35 The DxDxT motif is part of an evolutionarily conserved haloacid dehalogenase-like (HAD) domain, which constitutes the catalytic site for the hydrolysis reaction.24b,25 The NLIP (N-terminal lipin) domain is also essential for PAP activity.35a A point mutation of Gly84 to Arg in the NLIP domain of lipin-1 in the f ld2J mouse is associated with reduced PAP activity and increased lipodystrophy in these animals.35 On the basis of secondary structure comparisons to related members of the HAD-superfamily, four conserved HAD motifs are predicted to be important for PAP function.24b,25 Motif I consists of a β-strand followed by the DxDxT motif, while motif II consists of a β-sheet flanked by two α-helices (Figure 2). A 5124


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Figure 3. Different functions of lipin-1 in the nucleus. Lipin-1 associates with PPARα and PGC-1α in the nucleus of hepatocytes to promote PPARα target genes involved in FA oxidation. Lipin-1 can also act to repress cleaved SREBP (SREBPc) localization in the nucleus and prevent the induction of the genes regulated by SREBPc. Lipin-1 nuclear localization also promotes myocyte enhancer factor-2 (MEF2) signaling. In adipocytes, lipin-1 can inhibit the nuclear factor of activated T cells c4 (NFATc4), thus repressing cytokine signaling. PPARγ2 can also interact with lipin-1 to induce its target genes, e.g. phosphoenol pyruvate carboxykinase, which is involved in glyceroneogenesis. Abbreviations: DG, diacylglycerol; ER, endoplasmic reticulum; PA, phosphatidate; PPAR, peroxisome proliferator-activated receptor; PGC-1α, peroxisome proliferator-activated receptor gamma coactivator-1α; SREBP, sterol regulatory element binding protein; TG, triacylglycerol.

endoplasmic reticulum and translocates to the nucleus, where it acts as a transcriptional repressor of phospholipid biosynthesis when PA levels fall.53 As such, Pah1p acts as a transcriptional regulator of phospholipid synthesis, since its levels and activity dictate the amount of PA available for Opi1p binding. This mode of transcriptional regulation is different from that in mammals, since Opi1p is unique to fungi and is required to repress glycerophospholipid synthesis in response to inositol supplementation or lack of an essential nutrient, e.g. zinc.54 Also, the phosphorylation of Pah1p represses the transcription of genes encoding the enzymes required for phospholipid synthesis and nuclear membrane biogenesis.49 The role of Pah1p in regulating gene expression depends on its PAP activity, since mutation of the DxDxT catalytic PAP motif or even a conserved glycine residue abolishes this effect.15a,35b,41 Importantly, the mammalian lipins have a transcriptional coactivator function distinct from their catalytic PAP activity (discussed in section 3.2), which highlights an important difference between yeast and mammalian lipin orthologues. However, Santos-Rosa et al. did demonstrate that Pah1p associates with the promoters of genes encoding proteins involved in phospholipid synthesis although the mechanism by which this occurs is still unknown.49 These results indicate the importance of PAP activity in controlling phospholipid synthesis and nuclear homeostasis as well as sequestering FAs into TG storage. Similar studies in Caenorhabditis elegans demonstrate the role of its lipin orthologue in regulating endoplasmic reticulum membrane homeostasis as well as dictating the dynamic regulation of nuclear envelope assembly and disassembly.55 Furthermore, the lipin orthologues of Arabidopsis thaliana are essential for phospholipid remodeling to galactolipids, which is a mechanism designed to cope with phosphate starvation.56 While studies in S. cerevisiae and C. elegans show that their lipin

As indicated by work performed before the lipins were discovered, the sphingoid bases sphingosine and sphinganine, which are amphiphilic amines, inhibit the PAP activity of the lipins23a,44a and prevent interaction with membranes.7a Moreover, Zn2+ or Ca2+ salts of PA can also inhibit PAP activity.23a,46 In general, phosphorylation of mammalian lipin-1 does not affect the PAP activity as measured in vitro, but it does control subcellular localization and thus physiological activity,35a,47 as will be discussed below in section 3.5. 3.1.3. Roles of PAP Activity in Yeast, Worms, Flies, and Plants. Unlike mammalian lipins, there is only one lipin isoform in Saccharomyces cerevisiae. Pah1p (lipin yeast orthologue also known as Smp2) deficiency leads to aberrant changes in phospholipid species as well as decreased esterification of FA in the stationary phase, which leads to FA-induced cytotoxicity.48 Pah1p also regulates nuclear membrane growth in cell division, since loss of Pah1p leads to increased nuclear membrane size, whereas expression of nonphosphorylable Pah1p inhibited cell division.49 Lipid droplet formation is also regulated by Pah1p, since decreasing Pah1p expression leads to decreased lipid droplet biogenesis.50 Interestingly, neutral lipid levels were unchanged; instead, there was aberrant lipid accumulation at the endoplasmic reticulum. The authors also showed that this phenotype can be abrogated by knocking out DG kinase-1.50 The study concluded that DG formed by Pah1p activity is required for normal lipid droplet formation.50 Pah1p also regulates vacuole fusion, since deletion of the gene encoding Pah1p results in vacuole fragmentation. The catalytic activity of Pah1p is required for vacuole fusion, since an inactive mutant cannot rescue the phenotype.51 The regulation of PA levels in S. cerevisiae by the yeast lipin Pah1p also appears to control Opi1p-dependent and Opi1independent repression of genes encoding enzymes involved in phospholipid synthesis. 52 Opi1p binds to PA at the 5125


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survival and differentiation (Figure 3).59 MEF2 isoforms are also known to play roles in myogenesis, as well as muscle differentiation and growth, which will be discussed in section 3.8. Although lipin-1γ is enriched in the brain,23b it is unclear whether lipin-1 regulates neuronal growth and survival, since early studies detected no abnormalities in the central nervous system of lipin-1 deficient f ld mice.29a It is, however, possible that another lipin isoform could compensate for the absence of lipin-1, and further studies are required to examine this interaction with MEF2. Lipin-1 is also required to induce the expression of PPARγ during adipogenesis (Figure 3).60 Furthermore, lipin-1 directly binds to and activates PPARγ2 in mature adipocytes (Figure 3).61 Importantly, a recent study demonstrated that lipin-2 and -3 can induce adipogenesis in the absence of lipin-1 and that PAP activity is essential for this effect.45,62 The accumulation of PA in the absence of PAP activity in adipose tissue and cultured preadipocytes increases ERK signaling, which inhibits PPARγ activation and adipogenesis.62 Although lipins clearly act in the nucleus through their transcriptional coactivator motifs as well as through interaction with different transcriptional regulators, this study highlights the growing possibility that PAP activity could play an important role in regulating transcription by affecting the levels of PA and the consequent activation of signaling downstream of PA accumulation. The expressions of lipin-1α and -1β are differentially regulated during adipocyte differentiation. Lipin-1α is most prominently expressed in the early stages where it is required for activation of PPARγ, which is needed for adipocyte differentiation. Following this, lipin-1β expression is induced in the latter phases of adipocyte differentiation.31a Rosiglitazone, which is a PPARγ agonist, also increases lipin-1 expression in subcutaneous fat deposits and to a lesser extent in visceral fat.63 This preferential increase in lipin-1 expression could divert FA esterification and deposition to peripheral rather than visceral fat. Such an effect is compatible with the action of Rosiglitazone in promoting insulin sensitivity. However, Rosiglitazone does not significantly affect lipin-1 expression in brown adipose tissue.64 The requirement of lipin-1 for preadipocyte differentiation is demonstrated by the lack of mature adipose tissue in lipin-1 deficient (f ld) mice.26,28 Interestingly, lipin-1 deficient children do not develop lipodystrophy,65 as will be discussed below in section 3.9. The higher expression of lipin-2 mRNA levels in human adipose tissue could possibly mean that lipin-2 substitutes for the transcriptional functions of lipin-1.

orthologues are critically important in nuclear membrane maintenance and transcriptional regulation of phospholipid synthesis, there is less research investigating these processes in mammalian cells. One recent study did show that accumulation of lipin-1 in the nucleus of NIH 3T3 cells or mouse embryonic fibroblasts modified the shape of the nuclear membrane, and this was dependent on its PAP activity.47 It should also be noted that the PAP activities of mammalian lipins are important in regulating the activity of transcriptional regulators, and these two topics will be discussed in sections 3.2 and 3.5. Studies in Drosophila melanogaster have also demonstrated the potential role of lipin and Dullard (the nuclear-localized protein phosphatase known to dephosphorylate lipin) in regulating nuclear transport machinery and modulating bone morphogenetic protein (BMP) signaling.57 Abnormal wing vein morphology in Dullard hypomorphic mutants, similar to mutants with increased bone morphogenetic protein signaling, could be reversed by overexpressing lipin.57 Furthermore, target genes of the bone morphogenetic protein signaling pathway are negatively regulated by the expression of Dullard, which could be related to the mislocalization of the nuclear import machinery in Drosophila melanogaster, where Dullard is overexpressed.57 Thus, these authors postulate that Dullardregulated lipin is required to promote normal nuclear homeostasis and modulate bone morphogenetic protein signaling. Although phenotypes associated with nonmammalian orthologues can be dissimilar to the roles and regulation of the mammalian proteins, investigation in these eukaryotic systems can provide valuable insight in understanding common conserved functions and providing indicators as to why evolutionary adaptation occurred. As an example, the role of lipins in mammalian membrane homeostasis will be an important research question that has already been tackled in yeast, worms, and flies. 3.2. Lipins as Transcriptional Regulators

Mammalian lipins contain nuclear localization sequences, which enable them to translocate to the nucleus, where they promote the transcription of genes required for fatty acid uptake and oxidation.15a,25,45 In hepatocytes, lipin-1 acts in concert with peroxisome proliferator activated receptor-γ coactivator-1α (PGC-1α) to increase the expression of the peroxisome proliferator-activated receptor (PPARα) and its target genes (Figure 3).15a Lipin-1 appears to form a complex with PGC-1α and PPARα,31b which bind to PPARα response elements (PPRE) at the promoters of PPARα target genes such as carnitine palmitoyl transferase-1 (Cpt1) and acyl-CoA oxidase-1 (Aox1) (Figure 3).31b,41 Since lipin-1 contains no DNA-binding motifs, the association between lipin and the PPARα promoter is probably through the association of lipin-1 with the transcriptional activating complex.41 Lipin-1, -2, and -3 each contain a hydrophobic α-helical LxxIL motif in the conserved C-terminal lipin (CLIP) domain, which resembles a nuclear receptor interaction motif (Figure 2).31b,58 Experiments using sitedirected mutagenesis demonstrated that the LxxIL motif is required for lipin-1 to interact with PGC-1α and PPARα.31b Lipin-2 can also interact with PGC-1α and PPARα through its LxxIL motif as demonstrated in gene reporter assays.25 Lipin-1 localization to the nucleus is also required to promote the transcriptional activity of myocyte-enhancer factor 2 (MEF2), a transcription factor that regulates neuronal

3.3. Lipin-Deficient and Transgenic Overexpressing Models

Besides determining the functions of lipins in cell systems, the influence of lipins on metabolism has also been investigated using animal models that are either deficient in lipin expression or overexpress different lipin isoforms. Aberrant changes in the expression of lipins have been shown to be detrimental to glucose and fatty acid metabolism. For example, diurnal fuel utilization in lipin-1 deficient f ld mice is impaired compared to the case of control mice, probably as a result of lipodystrophy and insulin resistance in these mice.28,66 The lack of adipose tissue in f ld mice also impairs liver regeneration, since lipolysis from adipose tissue stores provides a major energy source during the regenerative process.67 Also, large increases in the expression of PAP activity, which presumably occur through the effect of glucocorticoids in increasing lipin-1 expression, 5126


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Figure 4. Regulation of the subcellular localization of lipins. Phosphorylation of lipins is stimulated by insulin signaling. One of the downstream kinases responsible for lipin-1 phosphorylation is mTORC1 (mTOR-raptor complex). Insulin-stimulated phosphorylation of lipin-1 also promotes 14−3−3 association to a serine-rich region downstream of the lipin-1 polybasic motif. Lipin-1 phosphorylation promotes its cytosolic localization and prevents its association to membranes. Lipins can exist in dimeric or tetrameric states in head-to-head, tail-to-tail conformations with each subunit able to catalyze its own independent phosphatidate phosphatase (PAP) activity. Lipin membrane localization is promoted by unsaturated fatty acids and also requires the presence of the polybasic nuclear localization motif (NLS). Sumoylation of lipin-1 stimulates its localization to the nucleus. Abbreviations: Ins, insulin; mTOR, mammalian target of rapamycin; PA, phosphatidate.

LPIN1 haplotype that increases the odds ratio of developing the Metabolic Syndrome by 1.6-fold.73 Some studies have also shown positive association of different metabolic measures with LPIN1 polymorphisms at other loci. For example, LPIN1 SNPs have been positively correlated to lower systolic and diastolic blood pressure in men.74 Furthermore, two LPIN1 haplotypes are associated with lower body mass index and waist circumference, and decreased frequency of the Metabolic Syndrome.73 On the other hand, it should also be noted that several studies found no correlation between LPIN1 SNPs and any metabolic parameters.75,76 LPIN1 gene expression levels have also been correlated to beneficial metabolic outcomes. Adipose LPIN1 expression in healthy individuals correlated positively to PPARα expression, insulin sensitivity, and maximal oxygen consumption during exercise.77 In contrast, adipose LPIN1 expression is decreased in obese individuals as well as women with the Metabolic Syndrome; weight reduction in obese patients resulted in increased LPIN1 expression in adipose tissue.78 These authors also showed an association of adipose LPIN1 mRNA levels with basal and insulin-stimulated glucose transport.78 Moreover, lipin-1 mRNA levels were increased in HIV patients without lipodystrophy compared to patients with lipodystrophy.79 The expression of inflammatory cytokines in the adipose tissue of these patients was also inversely correlated to lipin-1 expression in adipose tissue.79 On the other hand, the levels of adipose LPIN1 mRNA in a Chinese population study were negatively correlated with plasma TG and leptin levels as well as body fat composition.76 Overall, increased lipin-1 gene expression in adipose tissue appears to be linked to improved metabolic parameters. These studies correlate well with studies in transgenic mice with adipose-specific overexpression of lipin-1. These mice show increased adipose fat deposition, but they have improved

normally accompany liver regeneration and the marked accumulation of TG in the liver remnant.68 Interestingly, the specific overexpression of lipin-1 in skeletal muscle leads to TG accumulation in muscle and adipose tissue, and it produces insulin resistance.66b Adipose TG accumulation is also increased when lipin-1 is overexpressed in adipose tissue; however, in this case insulin sensitivity increases.66b This is probably caused by increased sequestration of FA in adipose tissue TG, which decreases FA-induced insulin resistance in other organs. Increased lipin-2 expression in the liver regulates hepatic insulin responses; for example, induction of lipin-2 expression by feeding mice a high-fat diet or by the use of agents that promote endoplasmic reticulum stress leads to decreased insulin-stimulated signaling.69 3.4. Lipin Expression and Gene Polymorphisms in Human Health and Disease

The importance of lipins in human health is highlighted by various studies, which examined gene polymorphisms and expression levels related to various disease phenotypes. Different lipin-1 gene polymorphisms have been linked to detrimental metabolic outcomes. LPIN1 single nucleotide polymorphisms (SNPs) in patients with polycystic ovary syndrome are associated with significant differences in measurements of HOMA-IR (homeostatic model assessment of insulin resistance), plasma TG, and LDL-cholesterol as well as response to oral glucose tolerance tests.70 A study of FrenchCanadians in Québec demonstrated the significant association of LPIN1 SNPs to resting metabolic rate and plasma insulin levels; however, significance was only achieved by comparison across generations.71 A similar study in Finland established a correlation of LPIN1 SNPs to serum insulin and body mass index.72 Linkage disequilibrium studies also demonstrated a 5127


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100, or by titrating in albumin to complex the oleate.89b It was suggested that this inhibitory effect of oleate on PAP could inhibit TG synthesis during starvation and metabolic stress in order to divert FA into β-oxidation. However, increasing FA supply stimulates both TG synthesis and β-oxidation, which are now considered to be companion rather than antagonistic pathways.90 In support of the concept that FAs are stimulators of PAP activity, Hopewell et al. demonstrated that the effect of albumin-bound oleate on soluble PAP was to induce translocation onto membranes as measured by density centrifugation and colocalization with the activity of an endoplasmic reticulum marker.7b Control experiments were performed in the absence of added membranes, and nonspecific aggregation was not observed. Furthermore, numerous studies show that addition of FAs does not change total PAP activities in experiments that determined PAP translocation to membranes in in vitro systems as well as in intact hepatocytes.7,8,88 In fact, Cascales et al. showed that high concentrations of oleate (up to 2 mM) stimulated the total PAP activity in rat hepatocytes.8 The hypothesis that electrostatic interactions between the polybasic motifs on lipins govern binding to negatively charged membrane surfaces is supported by the effect of introducing negative charges through lipin phosphorylation on the subcellular localization of the lipins.35a,47,87b,91 Phosphorylation of lipin-1 at a serine-rich region downstream of the polybasic motif also promotes interaction of 14−3−3 proteins at this site (Figure 4).91 This interaction with 14−3−3 favors lipin-1 localization in the cytosol (Figure 4). The mammalian target of rapamycin complex 1 (mTORC1) is responsible for phosphorylating some of the serine residues on lipin-1 (Figure 4).35a,47,92 As previously mentioned, phosphorylation of lipin-1 at most of the sites identified does not affect PAP activity, but rather changes its subcellular localization.35a,47,87b Phosphorylation of mammalian lipin-1 and -2 on CDK1 recognition motifs does appear to affect PAP activity;85 however, the specific Ser/Thr residues have only been identified in yeast.52,87a The dephosphorylation of lipin-1 is regulated in part by the Dullard phosphatase.49,87b,93 The mammalian Dullard phosphatase can only dephosphorylate the lipins when its regulatory subunit, nuclear envelope phosphatase-1 regulatory subunit 1, is present,94 just like the analogous complex in yeast.87b Importantly, Han et al. had discovered the identity of the mammalian orthologue of the Dullard regulatory subunit, which was previously named transmembrane protein 188 (TMEM188).94 One additional component regulating the membrane association of lipins is the presence of an evolutionarily conserved amphipathic α-helix at the N-termini of the lipins.87b This α-helix is required to anchor the yeast lipin orthologue onto the nuclear/endoplasmic reticulum membrane after lipin dephosphorylation by the yeast orthologues of Dullard phosphatase and its regulatory subunit, Nem1pSpo1p.87b A recent study showed that inhibition of the mammalian target of rapamycin complex 1 (mTORC1) phosphorylation on lipin-1 promotes the nuclear localization of lipin-1, where it inhibits sterol regulatory element binding protein (SREBP) signaling.47 The localization of lipin-1 in the nucleus also governs the shape of the nucleus; inhibition of mTORC1 signaling promotes the nuclear localization of lipin-1, and this causes an elongation of the nucleus.47 Significantly, the nuclearlocalized lipin-1 is only able to affect nuclear shape if its catalytic PAP activity is intact.47 This result demonstrates the

insulin sensitivity, possibly by sequestering excess FAs in the adipose tissue as opposed to excessive fat deposition in the liver and muscle.66b Furthermore, lipin-1 plays an important role in inflammatory signaling in adipocytes, since increased expression of lipin-1 in adipocytes decreases the expression of proinflammatory cytokines and vice versa.80 Therefore, the beneficial effects of increased adipose lipin-1 expression in humans could be linked to decreases in inflammatory signaling and the prevention of nonadipose lipid accumulation. Finally, PAP activities and lipin-1 expression are decreased in the hearts,81 adipose tissue,82 and livers83 of Type 2 diabetic patients as well as patients with heart failure.84 It is likely that these changes occur as a result of the disease phenotypes, but it is still unclear whether decreased lipin expression by itself could exacerbate disease progression or symptoms. In summary, lipin gene polymorphisms and the levels of lipin expression are linked to both positive and negative outcomes in different disease phenotypes. Further work is needed to improve the feasibility of using these gene polymorphisms as diagnostic indicators. 3.5. Regulation of Lipin Compartmentalization

The importance of lipins in regulating cellular metabolism and signaling is highlighted by the dynamic regulation of their subcellular localization as well as gene expression. The subcellular localization of the lipin-1 and -2 is important for regulating the participation of the lipins in glycerolipid synthesis and transcriptional regulation. Lipin-1 and -2 are present in the cytosol, and they translocate to the endoplasmic reticulum and the nucleus.15a,25,35a,85 The subcellular localization of lipins is dynamically regulated by post-translational modifications as well as changes in electrostatic interactions, which enables an active response to rapid changes in cellular signaling and nutrient status. As predicted from early studies, the association of PAP with membranes is regulated by phosphorylation of the enzyme.86 It is now known that this association with membranes is governed by the state of phosphorylation of the lipin and by the presence of an evolutionarily conserved polybasic motif near the Nterminus (Figure 2), which can also function as a nuclear localization sequence.35a,45,87 Lipin-1 has at least 17 serine/ threonine residues, which are phosphorylated (Figure 2).35a,87a From sequence homology analysis of these 17 residues, 8 homologous residues in lipin-2 and 11 residues in lipin-3 are predicted to be phosphorylation sites.35a Insulin stimulates the hyperphosphorylation of lipin-1, which increases its cytosolic localization (Figure 4).35a Conversely, it was shown before the genes encoding the PAP enzymes had been identified that the association of unsaturated fatty acids, their acyl-CoA esters, and phosphatidate with membranes promotes the association of PAP.8,25,35a,45,88 It was hypothesized from this work that membrane association is dictated by electrostatic interactions between negatively charged regions in the membrane interacting with PAP. The polybasic motifs of the lipins now provide such a binding domain. Additional evidence supporting this hypothesis is provided by the action of amphiphilic cationic compounds, which prevent the membrane-association of PAP activity.7b In contrast, other studies claimed that the apparent association of PAP activity with membranes is an artifact.89 These authors showed that unsaturated FAs, such as oleate, aggregate and inhibit PAP activity in an in vitro system. This effect can be reversed by the simultaneous addition of Triton X5128


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stress as well as high fat feeding, and this increase is linked to hepatic insulin resistance.69 Significantly, knocking down lipin-2 in diet-induced obese mice with adenovirus encoding shRNA against lipin-2 improves their performance in glucose tolerance tests, and the opposite is true if lipin-2 is overexpressed.69 Although cAMP does not increase Lpin1 transcription in hepatocytes by itself, β2-adrenergic receptor signaling can induce the upregulation of lipin-1 gene expression by activating nuclear orphan receptor-1 signaling.98 TORC2 (transducer of regulated CREB activity) in conjunction with cAMP response element binding protein (CREB) increases Lpin1 expression in hepatocytes.99 TORC2 activation and localization to the nucleus is induced by dephosphorylation of Ser171.100 Glucagon and fasting promote the dephosphorylation of Ser171, whereas insulin and feeding cause its phosphorylation.100,101 Therefore, TORC2 appears to be a major player in the cAMP- and insulin-dependent regulation of Lpin1 transcription, at least in the liver. Lipin-1 expression might also be regulated by miRNA-200b or miRNA-429,102 as well as miR217.103 Transcription of the Lpin1 gene also depends on PGC-1α and estrogen-related receptors-α and -γ (ERRα and γ), which bind to their respective response elements in the first intron.31b,84 Interestingly, gene expression of PGC-1α is increased in hepatocytes by cAMP and this action is synergized by glucocorticoids.96a These changes in PGC-1α mRNA levels coincided with rather than preceded the increase in Lpin1 mRNA that is stimulated by glucocorticoids and cAMP. Moreover, glucocorticoids induce PPARα gene expression 1− 2 h after the induction of Lpin1 expression.96a These observations support the findings by Finck et al., who showed the role of lipin-1 as a transcriptional coactivator with PGC-1α in regulating PPARα levels in the liver.31b It should also be noted that insulin does not antagonize the transcriptional upregulation of the genes encoding PGC-1α or PPARα.96a SREBP-1 is also involved in the induction of LPIN1 gene expression in Huh7 hepatocarcinoma cells.104 Interestingly, ethanol induces hepatic PAP activity through the action of glucocorticoids,105 and this was related to the development of the ethanol-induced fatty liver.106,107 A recent study showed that SREBP also regulates the ethanol-induced upregulation of Lpin1 expression.108 On the other hand, activation of AMPactivated protein kinase (AMPK) appears to inhibit the effects of ethanol on Lpin1 expression. As mentioned previously, the localization of lipin-1 to the nucleus that is induced by mTORC1 inhibition leads to a decrease in SREBP signaling by decreasing the amount of nuclear SREBP.47 The combination of these findings suggests that the induction of lipin-1 by SREBP-1 followed by lipin-1 nuclear localization could act as a negative feedback mechanism to fine-tune SREBP signaling. A recent study also showed that lipin-1 gene expression can be increased by hypoxia, and this increase is mediated by hypoxia inducible factor 1 (HIF1) binding to the hypoxia response element on the LPIN1 promoter and inducing transcriptional upregulation of the LPIN1 gene.109 A hypoxiainduced increase in PAP activities from rat livers had already been previously demonstrated.110 Other cellular stresses that induce reactive oxygen species production and p53 activation, such as glucose deprivation and DNA damage, also induce LPIN1 gene expression in C2C12 myotubes and human fibroblasts.111 These authors showed that p53 binds to the first intron of the Lpin1 gene in the mouse DP16.1 p53/ts cell line with a temperature-sensitive activation of p53 at 32 °C.

importance of the regulation of PA levels in nuclear membrane homeostasis in mammalian cells. Furthermore, the authors showed that nuclear localization of lipin-1 is required to inhibit SREBP signaling but inhibition only occurs if the catalytic PAP motif is present. Other studies have also shown that lipin-1 localization in the nucleus or on microsomal membranes is prevented by its phosphorylation downstream of insulin signaling.35a,45,91 As mentioned previously, the dephosphorylation of lipin-1 is mediated by Dullard phosphatase, and a recent study demonstrated that lipin-1 nuclear localization in HeLa cells is increased when Dullard phosphatase and its regulatory subunit, nuclear envelope phosphatase 1-regulatory subunit 1 (NEP1-R1), are coexpressed in these cells.94 Lipin-1 localization to the nucleus is also promoted by sumoylation (Figure 4).59 Sumoylation motifs consisting of a φKXE sequence (where φ represents any hydrophobic amino acid and X represents any amino acid) have been identified in lipin-1α, lipin-1β, and lipin-2 (Figure 2).59 Only lipin-1α and -1β have been positively demonstrated to be sumoylated.59 Ultimately, the effects of lipin-1 in regulating the activity of other transcriptional regulators such as SREBP, PPARγ, PGC1α, and NFATc4 are dependent on its ability to localize to nuclei. Lipin-1 can also translocate to mitochondrial membranes of NIH 3T3 cells and bind to PA formed through the action of mitochondria-localized phospholipase D (mitoPLD).95 Interestingly, these authors found that the interaction of lipin with PA was through a polybasic PA-binding domain different from the nuclear localization sequence, which stretched from amino acid 417 to 426 of lipin-1β.95 Lipin-1 could also be recruited to the plasma membrane by binding to plasma membranelocalized PA formed by PLD2. Thus, the recruitment of lipin1 to the mitochondria in combination with the regulation of mitochondria-localized PLD determine the balance between the mitochondrial levels of PA and DG, which promote mitochondrial fusion and fission, respectively.95 In conclusion, the regulation of lipin subcellular localization by phosphorylation and other post-translational modifications as well as interactions with PA facilitates the involvement of lipins in glycerolipid synthesis and mitochondrial membrane dynamics as well as transcriptional regulation in the nucleus. 3.6. Transcriptional Regulation of the Lipins

The gene expressions of lipin-1 and -2 are tightly regulated by the differential action of various hormones in the feed/fast cycle. Glucocorticoids, which are elevated in the plasma during stress, during starvation, during diabetes, and after feeding ethanol or fructose,6 stimulate the transcriptional upregulation of lipin-1 gene expression. This depends on the interaction of the activated glucocorticoid receptor with the glucocorticoid receptor response element upstream of the Lpin1 promoter.96 This induction by glucocorticoids is synergized by the action of glucagon through cAMP, and it is antagonized by insulin.96a These effects mirror the changes in the gene expression level for lipin-1 in the liver during fasting, diabetes, and ethanol feeding.96a Adipose expression of lipin-1 is also negatively affected by signaling downstream of pro-inflammatory cytokines, which will be discussed in section 3.8. Lipin-2 levels are also increased by fasting,34,96a,97 and this appears to depend on PPARβ/δ activation and binding to a peroxisome proliferator response element 1300 base pairs downstream of the Lpin2 transcriptional start site.97 Additionally, lipin-2 expression is also increased by acute endoplasmic reticulum 5129


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complexity to understanding how hepatic metabolism could be regulated by differential expression of lipin-1 and lipin-2.

The results in this section demonstrate the mechanisms by which the transcriptional regulation of the genes encoding the lipins are controlled by the changes in hormonal levels during the feed/fast cycle as well as by cellular stresses.

3.8. Lipins and Inflammatory Signaling

Besides the role of lipins of sequestering fatty acids into TG and regulating phospholipid synthesis, the involvement of lipins in glycerolipid synthesis also appears to play an important role in modulating inflammatory signaling in macrophages. Depletion of lipin-1 in human macrophages decreases the number of intracellular lipid droplets and prevents an increase in lipid droplet size when treated with oleate.118 Lipin-1 depletion also abrogates the activation of cytosolic group IVA phospholipase A2 and the mobilization of arachidonate, which is involved in eicosanoid synthesis.118 These authors postulated that this effect on phospholipase A2 could be due to the lipin-1 mediated formation of DG and its role in activating protein kinase C upstream of phospholipase A2119 or due to direct stimulation of the phospholipase A2 activity.118 Additionally, the latter authors also suggested that the effect of lipin-1 on lipid droplet morphology could also affect phospholipase A2 activity, since this enzyme can translocate onto lipid droplets.118 Valdearcos et al. also demonstrated that lipin-2 plays an important role in regulating inflammatory signaling activated by palmitate in RAW 264.7 and human macrophages.120 Depletion of lipin-2 decreases palmitate incorporation into TG and increases palmitate-induced pro-inflammatory signaling downstream of JNK activation.120 Therefore, lipin-2 appears to repress palmitate-induced inflammatory signaling in macrophages by promoting the sequestration of palmitate into TG. As a transcriptional regulator acting in the nucleus, lipin-1 can also inhibit the transcriptional activity of the nuclear factor of activated T cells (NFATc4) in adipocytes (Figure 3). Lipin-1 directly interacts with NFATc4 and recruits histone deacetylases to the promoter region.80a This repression appears to be required for inhibition of the expression of adipokines, cytokines, and other inflammatory factors.80a Conversely, the expression of lipin-1 is decreased in mouse adipose tissue and 3T3-L1 adipocytes within 16 h of treatment with lipopolysaccharide and proinflammatory cytokines,80c which would increase pro-inflammatory signaling in adipocytes due to derepression of NFAT transcriptional activity. Similarly, suppression of lipin-1 in 3T3-L1 adipocytes increases the expression of monocyte chemoattractant protein-1, which can promote monocyte chemotaxis.80b Inflammatory signaling induced by acute pathogenic insult often leads to increased plasma FA levels as a means of providing energy as well as assisting in tissue repair.121 Therefore, Lu et al. proposed that decreased lipin-1 expression downstream of inflammatory signaling is part of a coordinated transcriptional response to increase plasma FA levels during the acute response to pathogens by decreasing adipose FA sequestration into TG and promoting adipose tissue lipolysis.80c,122 Thus, the regulation of lipin levels plays an important role in the inflammatory response, which is vital in the body’s response against foreign antigens. However, it is clear that chronic upregulation of inflammatory signaling can become maladaptive and detrimental to human health. Overall, lipins appear to be important in regulating inflammatory signaling in macrophages as well as adipocytes. Lipin-1 can repress inflammatory signaling in adipocytes, and its expression is required for the proper function of macrophages in producing eicosanoids. Lipin-2 can prevent palmitateinduced inflammatory signaling in macrophages by increasing

3.7. Lipins and the Regulation of Hepatic Lipoprotein Secretion

During fasting or starvation, the action of glucagon and glucocorticoids in the presence of low insulin signaling leads to an increase in lipin-1 expression. Lipin-1 localization in the nucleus and increased transcription of genes involved in FA oxidation occurs simultaneously with increased lipin-1 expression and association with the endoplasmic reticulum due to increased plasma FA supply from adipose lipolysis. These combined actions allow concurrent increases in glycerolipid synthesis and FA oxidation. Classically, these two pathways were considered to be mutually antagonistic, since they compete for acyl-CoA esters; however, recent evidence shows that TG synthesis and FA oxidation are complementary processes. In fact, the extent of fatty acid oxidation can be reliant upon lipolysis from TG stores.90,112 The secretion of very low density lipoproteins (VLDL) is also thought to be regulated by lipin expression, especially in diabetes and insulin resistance. This can be explained since VLDL secretion is stimulated strongly by glucocorticoids and insulin attenuates VLDL secretion.113,114 The effect of glucocorticoids on VLDL secretion depends on the dynamics and location of TG synthesis and turnover, but it can also be partly attributed to the stabilization of apolipoprotein B expression for VLDL packaging.114b The mutually competitive effects of glucocorticoids and insulin on VLDL secretion are also reminiscent of the regulation of Lpin1 expression. In fact, increasing lipin-1 expression in McA7777 cells increases VLDL secretion.115,58 Contrary to this evidence, it has also been observed that neonatal fld mice, which are lipin-1 deficient, have increased plasma TG levels.27 Furthermore, adenoviral overexpression of lipin-1 in the livers of these mice decreases circulating TG levels.31b These results suggest that the effects of lipin-1 are more complex. Modifying lipin-1 expression in hepatocytes isolated from f ld mice indicates that lipin-1 expression does not determine the rate of TG synthesis, but it does influence the rates of TG secretion in VLDL-sized particles that contained apoB48.116 Hepatocytes from f ld mice had increased VLDLTG secretion and very high expression of stearoyl-CoA desaturase-1 (Scd1),116 which is a major regulator of VLDL secretion.117 Adenoviral overexpression of lipin-1β did not affect TG synthesis rates, but it suppressed VLDL secretion and Scd1 expression without affecting the expression levels of microsomal triglyceride transfer protein and apoB.116 These authors demonstrated by expressing mutant forms of lipin-1 that this effect requires lipin-1 transcriptional coactivator function but not PAP activity. At present, it is unclear what transcriptional targets are important in mediating this effect. These results with f ld mice also provide strong evidence for the participation of lipin-2 or -3 in promoting high levels of VLDL secretion.116 In fact, lipin-2 could be important in regulating hepatic TG synthesis during conditions of high FA availability, which suggests that lipin-2 is the major isoform responsible for facilitating VLDL secretion.34 It is also interesting to note that lipin-1 and -2 expression can be reciprocally regulated, albeit during adipocyte differentiation.85 This adds another layer of 5130


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work could result from the use of [2-3H]glycerol rather than [3H]oleate to measure TG synthesis.124 Lipin-1 and lipin-2 appear to play indispensable roles, e.g. during adipogenesis. Lipin-2 expression is inhibited during adipogenesis whereas lipin-1 expression is required for adipocyte differentiation.16a,85,96b This result is compatible with the observation that lipin-1 deficient f ld mice are devoid of mature adipose tissue. However, rare cases of lipin-1 deficiency have been reported in children, and this condition is associated with rhabdomyolysis and myoglobinuria, suggesting a unique role in skeletal muscle maintenance.65 The involvement of lipin-1 in regulating mitochondrial homeostasis through the modulation of PA and DG levels, as described in section 3.5, could explain the rhabdomyolysis in lipin-1 deficient patients, especially since rhabdomyolysis frequently occurs as a result of defects in mitochondrial function.65,126 Importantly, current studies have not linked any mutations in LPIN2 or LPIN3 with this phenotype.126b Interestingly, these children do not show deficits in adipose tissue formation, unlike the lipodystrophic f ld mice.65 Lipin-2 is expressed at significant levels in human adipose tissue, and it is possible that lipin-2 may be able to compensate for the loss of lipin-1 in human adipose tissue.16b,22 Zhang et al. did demonstrate that adipogenesis can be induced by the PAP activity of any lipin isoform and that the accumulation of PA in lipin-1 deficient adipose tissue and the subsequent activation of ERK were responsible for inhibiting PPARγ activation and adipogenesis.62 On the other hand, studies of lipin-2 deficient Majeed Syndrome patients, who present a severe disease phenotype including congenital dyserythropoietic anemia, extensive osteomyelitis, and recurrent high fever, demonstrate that lipin-1 and lipin-3 do not compensate completely for loss of lipin-2 activity in some tissues.16a

the sequestration of palmitate into TG. Further investigation regarding the roles and regulation of lipins and the effects on inflammation are warranted, given the increasing importance of deciphering inflammatory signaling in diseases such as diabetes and cancer. 3.9. Lipins: Redundancy, Compensation, and Selective Functions

The lipin isoforms show redundancy and overlapping functions in some tissues. Depletion of lipin-1 by siRNA in human monocyte-derived macrophages does not decrease the formation of TG, although the composition of TG in lipid droplets is altered.118 The core of lipid droplets is formed mainly from TG synthesized through the Kennedy pathway.123 In liver, depletion of lipin-1 does not affect TG synthesis because of the high expression of lipin-2.116 Similarly, lipin-3 expression has been demonstrated to compensate for the loss of lipin-1 in the liver of f ld mice.22 PAP activity in hepatoma cells was not reduced when lipin-1 was knocked down, and this effect is likely due to the expression of lipin-2 and lipin-3 in these cells.115 Recent studies show that hearts from lipin-1 deficient f ld mice have at least an 80% decrease in PAP activity, but there is no obvious defect in the synthesis of TG, PC, and PE, or in FA oxidation in the perfused working hearts.124 There do appear to be subtle differences in the accumulation of acidic phospholipids, e.g. PA and phosphatidylinositol, which indicates a unique role for lipin-1 in regulating a specific subcellular pool of PA. 124 This PA was proposed to activate mTORC1 (mammalian target of rapamycin complex 1) signaling and endoplasmic reticulum stress. Although mTORC1 signaling was increased, the f ld hearts were not hypertrophic but instead became smaller, which is probably related to the increase in endoplasmic reticulum stress.124 The effect on heart size could also be linked to the interaction of lipin-1 with myocyte enhancer factor-2 (MEF2) isoforms and their subsequent activation,59 which is critical for cardiac development, growth, and hypertrophy.125 Future studies should determine whether lipin-1 interaction with MEF2 is important in the development of compensatory cardiac hypertrophy. In unpublished work, we also measured glycerolipid synthesis in neonatal rat ventricular myocytes by using [3H]oleate as a substrate and E600 (100 μM) to block TG hydrolysis. Knocking down lipin-1 by 50% with adenovirus expressing shRNA against Lpin1 did not significantly decrease the incorporation of oleate into TG. These results with cultured cardiomyocytes confirm those from the perfused working heart system, which is more physiologically relevant. It is concluded that partial or complete depletion of lipin-1 does not significantly decrease the capacity of the heart to synthesize TG and that the residual lipin-2 and lipin-3 activities possess sufficient capacity to maintain the levels of FA esterification and oxidation.124 It was also concluded by Mitra et al. that f ld hearts contain more PA than the controls.84 However, in this work, knockdown of lipin-1 in neonatal rat ventricular myocytes did decrease the incorporation of [2-3H]glycerol into TG, but only when this was stimulated by oleate. These authors concluded that PAP activity is not rate-limiting during basal TG synthesis but that it does become rate-limiting when TG synthesis is stimulated with high levels of FA. Some of the discrepancies between these studies with rat ventricular myocytes and our

3.10. Known and Putative Roles of Lipins in Lipid Signaling

Lipin-1 plays a role in lipid signaling during myelination in Schwann cells.29b Fld mice containing a null mutation in Lpin1 exhibit progressive peripheral neuropathy in addition to lipodystrophy and insulin resistance.26 PA accumulates in the endoneurium of Schwann cells from these mice as a result of the loss of lipin-1.29b This accumulation of PA leads to the aberrant activation of mitogen-activated protein kinase/ extracellular signal-regulated kinase kinase (MEK) and extracelluar signal-regulated kinase 1/2 (ERK1/2), which was shown to be associated with demyelination of the Schwann cells.29b Treatment of myelinated ganglia cultured from rat embryos with PA caused demyelination, whereas treatment with MEK-ERK1/2 inhibitors PD98059 or U0126 restored myelination of ganglia.29b Thus, lipin-1 appears to dephosphorylate the specific pool of PA that acts as a bioactive signal to activate the MEK-ERK1/2 pathway. Loss of lipin-1 thereby leads to the inhibition of myelination signaling pathways in Schwann cells.16b,29b As discussed previously, PA accumulation in f ld adipose tissue also increases ERK activation and inhibits PPARγ-dependent adipogenesis.62 The hearts of f ld mice also exhibit increased accumulation of PA as described above, and this was associated with increased mTORC1 signaling, S6 phosphorylation, and endoplasmic reticulum stress.124 In human tissues, lipin-1 may also play a role in regulating the cellular levels of the bioactive lipids PA and DG, since an accumulation of PA was reported as a result of lipin-1 deficiency in skeletal muscle, but this was from only one patient.65 5131


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Figure 5. Sequence alignment of conserved residues and catalytic motifs in mouse lipid phosphate phosphatases (LPPs) 1, 2, and 3. Numbers indicate residue number. The FDKTRL and YY motifs important in determining apical versus basolateral localization in polarized cells are shown. The glycosylation site is highlighted in red, and the integrin binding motif in LPP3 is highlighted in purple. LPP1 and -2 do not have the conserved RGD-like domain. Conserved residues in catalytic motifs C1, C2, and C3 are described, and the residues involved in catalysis are shown in red.

degrade the PA produced by PLD. It has been hypothesized that the lipins may play this role,16b although there is little clear direct evidence to support this hypothesis at present.

Other evidence that the lipins could be involved in receptormediated signal transduction emerged from early studies on signaling through the epidermal growth factor receptor (EGFR).127 PAP activity was proposed to be regulated by association with EGF signaling in A431 cells, since PAP activity was coimmunoprecipitated with the EGFR.128 Treatment with EGF decreased the association of PAP activity with the EGFR and simultaneously increased association with protein kinase C ε (PKCε).128 Second, DG is a bioactive lipid and plays a role in inflammatory signaling in immune cells.119 PAP has been proposed to play a role in immune signaling through DG production.119 Stimulation of the inflammatory response in RAW 264.7 and U937 macrophages with lipopolysaccharide leads to a transient increase in cellular DG levels with a concomitant decrease in cytosolic PAP activity.119 This result suggested that PAP activity translocates onto membranes and catalyzes the hydrolysis of PA (produced by the action of phospholipase D) to form DG, which can then activate PKC and downstream inflammatory signaling involving group IVA phospholipase A2 and increased COX-2 (cyclooxygenase-2) gene expression.119 Third, treatment of adipocytes with the dual PLD1/PLD2 inhibitor, FIPI, caused lipin-1 to translocate to the nucleus, which suggests that PA produced through PLD activation could regulate the subcellular localization of lipin-1.45 Collectively, these studies provide evidence that the lipins are involved in regulating signal transduction pathways. It remains unclear whether the lipins can degrade PA produced through the action of PLD1 and PLD2.16b Earlier studies suggested that the LPPs are downstream of PLD activation and PA formation.129 However, studies on the membrane topology of the LPPs revealed that the active sites of the LPPs are on the extracellular side of the plasma membrane and the lumenal leaflets of organellar membranes,130 whereas the majority of PA should be produced on the cytosolic leaflet of the membrane bilayer. Moreover, there is no conclusive evidence that PA can rapidly traverse the lipid bilayer to a significant extent. Thus, it is uncertain how the LPPs could

3.11. Concluding Remarks for the Lipins

The role of lipins in regulating metabolism and signaling has been studied extensively in both cellular and animal models. The action of lipins as PAP enzymes regulates the branch-point that controls the relative formation of acidic phospholipids versus TG, PC, and PE (Figure 1). The lipins could also modulate the signaling effects of PA and DG. It is also clear that regulation of the subcellular localization of the lipins from the cytosolic compartment to different organelles is essential for fulfilling their roles in modulating signaling pathways, regulating glycerolipid synthesis, and serving as cotranscriptional regulators. In the case of glycerolipid synthesis, PA is formed on membranes of the endoplasmic reticulum, and therefore, the cytosolic lipins have to attach to these membranes to access this substrate. So far, most of our knowledge comes from studies of lipin-1, and further work on the regulation and actions of lipin2 and -3 is needed to understand of how each lipin contributes both redundant and unique functions in different tissues. The work will be helped greatly by studying mouse knockout models for the different lipins and particularly by using conditional models where the expressions of the lipins can be selectively controlled in different tisssues.

4. LIPID PHOSPHATE PHOSPHATASES Like the lipin family, the LPPs consist of three related proteins named LPP1, LPP1a (a splice variant), LPP2, and LPP3. In contrast to PAP enzymes, LPPs are not specific for their substrates, and they can dephosphorylate many phosphate esters in vitro in addition to PA, provided that they are lipids. These substrates include lysophosphatidate (LPA), sphingosine 1-phosphate (S1P), and ceramide 1-phosphate (C1P),131 diacylglycerol pyrophosphate,132 and N-oleoyl ethanolamine phosphatidic acid.133 Mammalian LPPs can be differentiated 5132


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Figure 6. Catalytic reaction of lipid phosphate phosphatases (LPPs) on lipid substrates. (i) The C3 histidine acts as a nucleophile on the phosphate group with the C3 Asp acting as an electron-pair donor. (ii) A phosphohistidine intermediate is formed and the phosphate ester bond is broken by interaction with the C2 histidine. (iii) The dephosphorylated lipid substrate leaves the active site and the phosphohistidine intermediate is hydrolyzed. (iv) The phosphate molecule is released, and the catalytic site is available for the next reaction.

when the LPPs are localized on the plasma membrane.131,144 The functional significance of this orientation at the plasma membrane was established in cultured cells, since the LPPs exhibit ecto-activity against several extracellular lipid phosphates.131 The importance of this ecto-activity in vivo was subsequently demonstrated in LPP1 hypomorph mice (Ppap2atr/tr) mice, which have low LPP1 expression in most organs with the exception of the brain.145 These mice have higher concentrations of circulating LPA than the controls, and the half-life of this LPA is increased from 3 min in wild-type mice to about 12 min.145 The biological significance of this observation will be discussed below in section 4.3.1 with regard to LPA signaling. The regulation of the plasma membrane localization of LPPs can be further refined by novel sorting motifs.146 Jia et al. showed that a FDKTRL motif on the N-terminus of LPP1 (Figure 5) targets its localization to the apical surface membrane in MDCK cells. Furthermore, a dityrosine motif on the second cytoplasmic loop between α-helices II and III of LPP3 (Figure 5) directs LPP3 toward the basolateral membrane. There is also some evidence to suggest that LPP1 and LPP3 are present in lipid rafts or caveolae.129,147 Besides localization to the plasma membrane, LPPs are also found in the endoplasmic reticulum,144,144 the Golgi network,148 and endosomal compartments.149 The location of the catalytic site of the LPPs on the outside of the cell or facing the lumenal side of organellar membranes130 should preclude their direct involvement in the Kennedy pathway of glycerolipid synthesis since newly synthesized PA is produced on the cytosolic surface of organelles.

from PAP by not requiring Mg2+ for activity and by their insensitivities to inhibition by N-ethylmaleimide.4 Furthermore, LPPs are integral membrane proteins, unlike the cytosolic lipins. As mentioned above, the LPPs are not primarily localized to the endoplasmic reticulum; instead, they are located at the plasma membrane4 with the catalytic site facing the extracellular space.131,134 This topology suggested that LPPs could be acting as regulators of cellular signaling by catalyzing the dephosphorylation of extracellular bioactive lipids such as LPA and S1P. 4.1. Structure of the LPPs and Related Proteins

4.1.1. Structure of the LPPs. LPP1, LPP2, and LPP3 are encoded by three separate genes PPAP2A, PPAP2C, and PPAP2B, respectively, which unfortunately were given the PAP2 nomenclature. PPAP2A is located on chromosome 5q11, whereas PPAP2C and PPAP2B are present at chromosome 19p13 and 1p32.2, respectively. These genes encode proteins approximately 300 amino acids in length with 40% identity in the primary amino acid sequence. Most of the conserved amino acids are found in the three catalytic domains of the LPPs termed C1, C2, and C3 (Figure 5).135 On the basis of these conserved catalytic domains, the LPPs belong to a phosphatase superfamily,136 which includes bacterial acid phosphatases,137 bacterial and yeast diacylglycerol pyrophosphatases,138 fungal chloroperoxidase,139 yeast dihydrosphingosine/phytosphingosine phosphate phosphatase,140 two specific mammalian sphingosine 1-phosphate phosphatases,141 presqualene diphosphate phosphatase,142 and mammalian glucose 6-phosphatase.143 All three LPPs contain six transmembrane α-helices (Figure 5) with the C- and N-terminus facing the cytoplasmic side 5133


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Figure 7. Noncatalytic and intracellular functions of LPPs (lipid phosphate phosphatases). The RGD motif on hLPP3 and the RGE on mLPP3 can bind to integrins and dictate cell-to-cell interaction. LPP1 and 3 can both block the intracellular activation of phospholipase D (PLD) and decrease intracellular phosphatidate (PA) to diacylglycerol (DG) levels, thus negatively affecting downstream targets of PLD, e.g. extracellular signal-regulated kinases (ERK). Intracellular LPP2 regulates cell cycle progression by regulating cyclin A expression. Abbreviations: PC, phosphatidylcholine; TM, transmembrane domain.

LPPs can form homo- and hetero-oligomers with each subunit capable of functioning independently of the others in catalyzing dephosphorylation reactions.150 These results are corroborated by work in Drosophila melanogaster, which showed dimerization of Wunen, the homologue of mammalian LPP3, but this is not a requirement for biological function.151 Furthermore, different combinations of oligomeric states can regulate subcellular localization.150 The first two conserved sequences of the catalytic domain C1 and C2 are localized near the start and end of the second extracellular loop, respectively, between transmembrane helices III and IV.130 There is an N-glycosylation site between these two conserved sequences (Figure 5). The third conserved sequence, C3, is between helices V and VI (Figure 5). C1 is probably responsible for substrate recognition, whereas C2 and C3 contain the amino acids required for the phosphotransferase reaction (Figure 5).149 The catalytic mechanism has been postulated and described through a combination of computational modeling and the crystallographic X-ray structure of a related enzyme, chloroperoxidase.149,152 The conserved histidine on C3 serves as the nucleophile acting on the phosphate group to form a phospho-histidine intermediate (Figure 6).149 The C2 histidine is involved in breaking the phosphate bond to release the dephosphorylated lipid substrate (Figure 6). The conserved lysine and arginine residues on C1 as well as the arginine on C3 help coordinate the substrate in the active site (Figure 6).136b

Other lipid phosphate phosphatases have been described, including DPPL1/PPAPDC1B and DPPL2/PPAPDC1A. These are diacylgylcerolpyrophosphate-like phosphatases, which are mammalian homologues of yeast diacylglycerol phosphate phosphatases.153 They do not require Mg2+ for activity, but unlike the LPPs they are sensitive to inhibition by N-ethylmaleimide. The preferred substrate for these enzymes is diacylglycerol pyrophosphate over LPA and PA. DPPL1 mRNA seems to be ubiquitously expressed, whereas DPPL2 mRNA is restricted to several tissues, including the brain, kidney, and testis, and it is preferentially expressed in endothelial cells.153 Studies in yeast have shown the existence of a lipid phosphate phosphatase with its active site facing cytosol.154 This lead to a search for such a phosphatase in mammalian cells, since this enzyme could control pools of lipid phosphates present on the cytosolic side of membranes. PPAPDC2/PDP1 was initially identified as a phosphatase in neutrophils, which preferentially converts presqualene disphosphate to the monophosphate compared to its actions on farnesylpyrophosphate and PA.142 Later, PPAPDC2/PDP1 was shown to be present in the ER and nuclear envelope and was predicted to possess a cytosolic-facing active site.155 The authors showed that PPAPDC2 has a relatively higher affinity for farnesylpyrophosphate and geranylgeranylpyrophosphate over LPA, PA, and S1P. This substrate specificity, together with the observation that overexpression of PPAPDC2 decreases protein isoprenylation resulting in defects in cell growth and cytoskeletal 5134


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Figure 8. Lipid phosphate phosphatases (LPPs) can modulate lysophosphatidate (LPA) and sphingosine 1-phosphate (S1P) signaling. LPA, formed by the action of autotaxin (ATX) on lysophosphatidylcholine (LPC) can signal through its G-protein coupled receptors (LPA1−8) to regulate cell survival and proliferation pathways. S1P can also bind to its own G-protein coupled receptors (S1P1−5) to induce similar signaling cascades. LPPs decrease LPA and S1P signaling by reducing circulating LPA and S1P levels. The monoacylglycerol (MG) and sphingosine formed can readily enter the cell. Intracellular LPA and S1P are re-formed by kinases and induce intracellular signals, e.g. peroxisome proliferator-activated receptor γ (PPARγ) and nuclear factor κB (NFκB) signaling. Abbreviations: ER, endoplasmic reticulum; ERK, extracellular signal regulated kinase; PI3K, phosphoinositide 3-kinase; SPP, sphingosine phosphate phosphatase; TRAF2, TNF (tumor necrosis factor) receptor-associated factor 2.

activities of the LPPs.149,159 As such, the LPR/PRGs cannot dephosphorylate lipid phosphates using the catalytic mechanism that has been described for the LPPs and other related proteins.160 Despite this, PRGs have been shown to be involved in facilitating axonal outgrowth during development and regenerative sprouting and filopodia formation.161

organization associated with dysregulation of Rho family GTPases, shows that these enzymes function as isoprenoid phosphatases.155 PPAPDC3/NET39 is the third member of this family.156 While it has no enzymatic activity, it is highly expressed in muscle tissues, where it negatively regulates myogenesis. Interestingly, NET39 interacts with mTOR and negatively regulates mTOR activity.156 Since PLD activation can increase mTOR signaling, it would be interesting to see how NET39 affects PLD activation or PA-mTOR interactions. 4.1.2. Structure and Functions of the Sphingomyelin Synthases. Other proteins that are structurally related to the LPPs have been described. These include the sphingomyelin synthases,157 which act as transferases to transfer phosphocholine from phosphatidylcholine onto ceramide and generate diacylglycerol and sphingomyelin. The two mammalian sphingomyelin synthases (SMS1 and SMS2) contain the C2 and C3 catalytic motifs found in the LPPs. These motifs in SMS1 and -2 are likely to mediate the phosphotransferase step of catalysis.149 The C1 motif of the LPPs is absent, and it is replaced by unique SMS-specific sequence motifs that are likely to be responsible for substrate recognition and orientation in the active site. 4.1.3. Structure and Functions of the LPP-Related Proteins or Plasticity Related Genes (LPR/PRGs). LPPrelated proteins (LPRs) or plasticity related genes (PRGs) are structurally similar to the LPP family with predicted six transmembrane domains. There are five members in this family (PRG1−5).149,158 PRG1 and -2 have long hydrophobic Cterminal tails, which is unique to them and may contribute to their biological function.149 Despite their similarity to the LPPs, the LPR/PRGs lack some conserved amino acids in the phosphatase active site that are essential for the phosphatase

4.2. Role of Lipid Phosphate Phosphatases in Cell Signaling

LPPs regulate cell signaling, since they help to control the relative concentrations of bioactive lipid phosphates versus that of their dephosphorylated products, which themselves are often signaling molecules (Figure 7). For example, PA is a lipid signaling molecule and its conversion by the LPPs to DG produces a potential stimulator of conventional and novel PKC isoforms. The effects of the LPPs on signaling are mediated at the cell surface through the ecto-activities of the LPPs and through noncatalytic interactions with surface integrins. The LPPs also affect signaling inside the cell through the metabolism of lipid phosphates formed downstream of the activation of surface receptors (Figure 8). 4.2.1. LPPs and the Regulation of LPA Signaling through their Ecto-activities. Lysophosphatidate (LPA) is a circulatory bioactive lipid that activates cells through at least eight G-protein coupled receptors.162 LPA is present at concentrations of 100 nM to 2 μM in extracellular fluids; this concentration can rise to as high as 10 μM in the tumor microenvironment.163 Extracellular LPA formation occurs mainly through the hydrolysis of lysophosphatidylcholine (LPC) by autotaxin (ATX), which is a secreted enzyme with lysophospholipase D activity (Figure 7). LPC concentrations in the blood are about 200 μM.163a A large proportion of circulatory LPC is polyunsaturated, and this can be secreted by cells such as hepatocytes.164 LPC is also derived from the action of lecithin/cholesterol acyltransferase on phosphatidylcholine 5135


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in high density lipoproteins;159 therefore, LPC derived from this source is mainly saturated. It should be noted that ATX activity preferentially catalyzes the hydrolysis of polyunsaturated LPC.165−167 Saturated LPA can also be produced through the actions of secretory phospholipase A2 on PA in microvesicles that shed from activated hematopoietic cells during inflammation.168 Moreover, LPA generated from group VIA phospholipase A2 (Ca2+-independent) has been shown to be involved in tumorigenesis.169 The effects of high circulatory levels of LPA in tumor biology have been studied extensively. For example, elevated LPA concentrations in the ascites fluid and plasma of patients with ovarian cancer are implicated in the formation and metastases of tumors.170 Furthermore, ATX expression promotes tumor progression, metastasis, angiogenesis, and resistance from apoptosis.159 These effects are most probably mediated by the formation of LPA through ATX activity on circulatory LPC.171 LPA signaling is also essential in wound repair and tissue development.159,172 The involvement of LPA in these processes is not surprising, since signaling through LPA receptors promotes cell growth, proliferation, survival, differentiation, and motility (Figure 8).159,170 The effectors of LPA signaling downstream of its G-protein coupled receptors include activation of phosphatidylinositol 3-kinase, phospholipase D (PLD), the extracelluar signal-regulated kinase (ERK) pathway, and small G-proteins such as Rho, Rac, and Ras (Figure 8).173 These signals stimulate cell division, migration, and angiogenesis, which are involved in embryogenesis and wound repair. It appears that these signaling processes become dysfunctional in cancer. Ecto-LPP activity on the plasma membrane can modulate the levels of extracellular LPA (Figure 8). Therefore, the balance of LPA formation versus hydrolysis will determine the concentration of LPA in circulation as well as in the tumor microenvironment. As mentioned above, the ecto-activity of the LPPs was first shown by overexpression of LPP1 in fibroblasts, which led to an increase in the dephosphorylation of extracellular LPA, PA, and C1P.131 The apparent Km for degradation of exogenous LPA was calculated to be approximately 36 μM, which is higher than physiological concentrations of LPA (high nM to low μM range), but this is comparable to the elevated LPA levels in cancer (approximately 10 μM). This indicates that the LPPs can increase the dephosphorylation of lipid phosphates in proportion to their concentration in extracellular fluids. The physiological action of LPP1 is shown by experiments in LPP1 hypomorph mice (Ppap2atr/tr),145 which have increased plasma LPA concentrations and a longer half-life for circulating LPA compared to the control mice as described above. In light of these results, it was surprising that circulating LPA concentrations were not significantly decreased in transgenic mice with LPP1 overexpression.163b These mice were relatively infertile and had smaller body sizes and birth weights; there were also defects in hair structure and fur growth.163b In contrast to the results with circulating LPA levels, fibroblasts from these transgenic mice responded less to LPA-stimulated migration than control fibroblasts.174 Furthermore, DG accumulation increased in these fibroblasts after stimulation of PA production with phorbol ester.163b Although this study did not find significant changes in ERK activation downstream of LPA, S1P, EGF, or PDGF signaling, a later study demonstrated that ERK activation was lower in LPP1 overexpressing fibroblasts treated with LPA, S1P, and

PDGF.174a This discrepancy can be explained by the magnitude of LPP1 overexpression in the studies; the latter study used fibroblasts expressing 20 copies of the LPP1 gene compared to the control cells. Overall, the accumulated body of evidence suggests that LPP1 is one of the enzymes responsible for catalyzing the rapid degradation of LPA in the circulation. This rapid turnover of plasma LPA levels in mice was confirmed in experiments where mice were injected intravenously with a specific boronic acidmodified thiazolidinedione-based inhibitor of ATX activity.175 Moreover, these results illustrate the importance of ATX and LPPs in modulating plasma LPA through their respective capacities for generating and hydrolyzing plasma LPA. Evidence for the role of the ecto-activity of LPPs being a regulator of cell signaling was obtained from experiments where LPP1 was overexpressed in fibroblasts. This attenuated the activation of PLD and ERK1/2 by LPA and led to a reduction in cell division.131 Conversely, LPP1 expression is decreased in the majority of ovarian cancers as well as in ovarian cancer cell lines.176 This same study showed that increasing LPP1 expression in these cell lines caused an increase in LPA hydrolysis, which the authors linked to increased apoptosis, and decreased cell proliferation and colony formation. Furthermore, another study linked the importance of LPPs in treating ovarian carcinomas by demonstrating that the antiproliferative actions of gonadotropin-releasing hormone on ovarian cancer cells can be attributed to an increase in ecto-LPP activity.177 LPP3 overexpression can also decrease the proliferation, survival, and colony-forming ability of cultured ovarian cancer cells as well as decrease tumor growth in vivo.178 Importantly, the authors showed that these observations depend on the ecto-activity of LPP3, since there was increased LPA hydrolysis in the medium of LPP3-overexpressing cells. Also, the decrease in colony formation caused by LPP3 overexpression was reversed by using a nonhydrolyzable LPA analogue instead of LPA. This observation demonstrates the importance of the LPPs in degrading extracellular LPA. The overall evidence suggests that elevated LPA levels in the microenvironment of ovarian cancers due to increased ATX activity and decreased LPP1 and 3 ectoactivities contribute to tumor proliferation and metastases. In contrast, LPP2 expression and its intracellular LPP activity are positively correlated to cancer cell growth, and this will be discussed in section 4.4. Therefore, inhibiting ATX activity or inducing LPP1 and LPP3 ecto-activities could serve as viable drug targets in cancer treatment. Besides regulating LPA signaling in cancer cell growth and survival, LPPs (more specifically LPP1) can also regulate the effects of LPA on platelet aggregation and shape changes.179 In this study, Smyth et al. showed that exogenously added LPA induced the localization of LPP1 to the plasma membrane. Inhibition of LPP activity by a sn-3-substituted difluoromethylenephosphonate analogue of PA potentiated Rho-dependent actin reorganization, which induced platelet spreading and aggregation. Ecto-LPP activities also modulate preadipocyte proliferation and extracellular LPA levels in the medium.180 The hydrolysis of LPA by LPPs results in the formation of monoacylglycerol (MG), which in most instances terminates extracellular signaling since MG is normally not bioactive. The exception to this is 2-arachidonoylglycerol (2-AG), which activates cannabinoid receptors (CB1 and CB2) (Figure 7).181 A significant proportion of circulating LPC contains arachidonate in the sn-2 position,164 and this can be hydrolyzed by ATX to form sn-2-arachidonoyl-LPA, which could then be 5136


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the LPPs. However, these S1P phosphatases are expressed mainly on the endoplasmic reticulum rather than on the plasma membrane.197 This means that the LPPs should be a major regulator of external S1P signaling. Studies on FTY720 also indicate a role for the LPPs as ectoenzymes. FTY720 is an analogue of sphingosine that is used as an immunomodulatory drug for treating multiple sclerosis. FTY720 is converted to FTY720-P by sphingosine kinase-2.198 Lysates from cells that overexpressed LPP1, -2, and -3 showed that only LPP3 dephosphorylated FTY720-P. LPP3 acted as an ecto-phosphatase in intact cells, to control the equilibrium between FTY720 and FTY720-P that was observed in vivo.198 This result is surprising compared to the broad substrate preference of the LPPs for lipid phosphates.149,159 Other studies showed that LPP1a had the highest activity and affinity for FTY720-P.199 These results suggested that the first extracellular loop, which is different in LPP1a compared to LPP1, is involved in substrate recognition. Further work would seem to be required to explain these discrepancies. 4.2.3. Hydrolysis of Other Extracellular Lipid Phosphates by LPPs. In addition to using extracellular LPA and S1P as substrates, LPPs can also degrade extracellular PA and C1P.131 However, both PA and C1P are very hydrophobic and they are not transported to a significant extent by binding to albumin and other proteins in circulation, unlike the less lipophilic S1P and LPA. PA is released in microvesicles from hematopoietic cells during inflammatory responses.168 Furthermore, PA in the plasma membrane of neutrophils can increase endothelial membrane permeability through the induction of intracellular tyrosine kinases;200 this process is antagonized by LPPs, which can hydrolyze the extracellular PA. Exogenously added C1P increases the intracellular concentrations of C1P.192 This can be partially attributed to the phosphatase action of LPPs on extracellular C1P in combination with the uptake and phosphorylation of the ceramide product to form intracellular C1P. This lipid phosphate activates cytosolic PLA2 activity, which leads to arachidonate production and increased prostaglandin E2 synthesis in human alveolar epithelial cells.192

converted to 2-AG by LPP activities. 2-AG itself can be further processed by phospholipase A2 activity to form arachidonate, which is the precursor for eicosanoid production.182 Although it is tempting to speculate about the role of LPPs in cannabinoid signaling, there is no direct evidence linking LPPs with 2-AG formation or cannabinoid receptor activation. It should be noted that MG produced from ecto-LPP activities can be taken up by the cell and phosphorylated by acylglycerol kinases to form intracellular LPA (Figure 8).183 Intracellular LPA can then initiate signaling through the activation of nuclear LPA1184 and PPARγ receptors.185 Although there are numerous studies showing the effect of LPPs on modulating signaling, it should be noted that the importance of the LPPs in controlling cell activation has been questioned. This was because the LPPs act on many lipid phosphates with relatively high K m values for their substrates.163a However, the studies describing LPP activity and substrate preference were performed in vitro, which could underestimate the specificity and activity of LPPs in vivo. For example, the assays employed to measure LPP activities use an artificial means of presenting lipid substrates, which could overcome the limitations of substrate accessibility in the cell. Moreover, the LPPs are not preserved in a contiguous plasma membrane under the in vitro assay conditions. It should also be noted that LPPs in vivo can be enriched in detergent-resistance lipid rafts,149 for which the physical properties might not be reproduced in cell-free assay systems. The study showing that LPP1 hydrolyses LPA in proportion to its circulating concentrations under physiopathological conditions would be expected of an enzyme that evolved to control LPA and S1P turnover, as will be discussed below.131 4.2.2. Effect of LPPs on S1P Signaling. Sphingosine 1phosphate (S1P) is a sphingolipid analogue of LPA, and it signals through its five G-protein coupled receptors (Figure 8).186 S1P is present in the circulation at concentrations in the range of 100 nM to 1 μM.187 Circulatory S1P is often bound to albumin or lipoprotein particles, and it can also be carried by erythrocytes.187 S1P is released from platelets to initiate tissue repair and angiogenesis.186 Alternatively, S1P is secreted from various cell types, e.g. astrocytes, through the action of ATPbinding cassette (ABC) transporters ABCC1, ABCG2, and ABCA1.187,188 Exogenously added S1P is cleared from blood in 15−30 min, and this process depends on a cellular phosphatase activity (presumably LPP activity) and not on S1P-lyase.189 Overexpression of LPP1 in human pulmonary artery endothelial cells leads to an increased hydrolysis of extracellular S1P.190 The sphingosine formed is taken up by the cells and is acted upon by sphingosine kinase-1 to form intracellular S1P. Formation of S1P inside the cell can activate signaling involved in Ca2+ mobilization,191 ERK activation,187 eicosanoid synthesis,192 TRAF2 E3 ubiquitin ligase activity,193 and stress fiber formation.194 LPP3 expression in Bergmann glia is required for proper cerebellar development through modulation of S1P signaling and metabolism.195 Furthermore, LPP3 is required for hydrolyzing thymic S1P, thus promoting the egress of mature T cells from the thymus.196 Beyond these two studies that highlight the importance of LPP3 in cell migration and development in the thymus and cerebellum respectively, the contribution of LPPs to the regulation of S1P signaling in vivo has yet to be elucidated. Intracellular S1P is dephosphorylated by two specific S1P phosphatases141 in addition to any effect of

4.3. Noncatalytic Functions of LPPs

In addition to its ecto-activity, human LPP3 also possesses a noncatalytic function that is mediated outside the cell. This depends on an arginine-glycine-aspartate (RGD) recognition motif on the second extracellular loop between transmembrane domains III and IV (Figure 5). This motif dictates interactions with integrins at the plasma membrane, particularly the αvβ3 and α5β1 integrins to promote endothelial cell-to-cell adhesion (Figure 7).201 This interaction does not depend on the catalytic LPP activity. Interestingly, murine and rat LPP3 contain arginine-glycine-glutamate (RGE) motifs, instead of RGD motifs, and the murine LPP3 was found to interact with αvβ3 and α5β1 integrins.202 However, when the RGD motif of human LPP3 was mutated to RGE, the mutant LPP3 could no longer associate with the integrins.201 This discrepancy could be due to the inability to accommodate the larger glutamate residue compared to aspartate in that position of human LPP3, compared to mouse LPP3. LPP1, which has arginine-glycineasparagine (RGN) instead of RGD, is not able to perform in a similar manner. LPP3 expression is also increased in endothelial cells by the actions of basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF).203 Furthermore, LPP3 5137


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motifs presumably facing the lumenal side of these organelle membranes. As such, intracellular LPPs could potentially regulate the levels of intracellular lipid phosphates as well as the dephosphorylated substrates, which could also influence signaling themselves.159 The first convincing evidence that the LPPs control intracellular signaling came from studies which showed that they regulate ERK activation downstream of thrombin signaling.208 Since thrombin is not a substrate of LPPs, the ecto-LPP activity cannot affect signaling extracellularly; instead, LPP activity could be affecting G-protein coupled receptor signaling directly or the LPPs could act on intracellular lipid phosphate signaling downstream of receptor activation (Figure 7). Evidence showing that overexpression of LPP1 and LPP2 decreases intracellular PA/DG ratios indicates that these LPPs could control ERK activation by decreasing PA levels (Figure 7).209 Subsequent work also demonstrated that LPP1 overexpression in mouse embryonic fibroblasts decreased PDGFstimulated, ERK-dependent cell migration.174a The authors attributed this result to increases in intracellular DG concentrations in the LPP1 overexpressing cells. Sustained intracellular DG levels are known to downregulate protein kinase C (PKC) isoforms in cells, and it was shown that LPP1 overexpression led to decreased expression of classical PKC isoforms, which are required for PDGF-induced migration.174a Furthermore, Long et al. showed that LPP2 and LPP3 can affect cell survival by regulating the intracellular levels of PA and S1P, respectively.210 Increased expression of LPP1 also abrogated cell migration that was stimulated by LPA and a phosphonate LPA analogue.174b This LPA analogue can activate LPA1/3 receptors, but it cannot be hydrolyzed by LPP1. Therefore, its signaling cannot be attenuated by the ecto-activities of the LPPs. Additionally, high LPA concentrations were chosen in these experiments such that the degradation of some of the extracellular LPA during the incubation would not be sufficient to decrease LPA-induced cell migration.174b Instead, the authors demonstrated that the catalytic action of LPP1 decreased PLD activation, and thus PA accumulation, downstream of LPA receptor signaling. This attenuated the effects of LPA and the LPA analogue on cell migration. In addition to PLD activation, LPP1 overexpression also decreased the activation of ERK and Rho, which are two other important proteins involved in LPA-induced fibroblast migration. On the other hand, PDGF-induced migration in LPP1 overexpressing fibroblasts was not affected and there was no effect on PDGFstimulated ERK activation. Conversely, PLD activation by PDGF was decreased by LPP1 overexpression; however, PLD activation is not required for PDGF to induced cell migration. Several other studies have also shown the effect of LPPs in regulating intracellular PA levels.211,212,209,210,163b In the case of LPP3, there was increased conversion of PA, formed by PLD activation, to DG when LPP3 was overexpressed in either Swiss 3T3 or HEK 293 cells.129 The authors also showed that this process could be facilitated by the colocalization of LPP3 with PLD2 in lipid rafts and caveolin-enriched regions of the plasma membrane. LPP2 has been postulated to hydrolyze PA formed from PLD1 stimulation, which would reduce PA-induced recruitment of sphingosine kinase-1 to perinuclear membranes.213 Also, Ras-transformed fibroblasts have low LPP activities and the PA to DG ratio in these cells after stimulation of PLD activity was increased compared to the case of control fibroblasts.214 Basal levels of PA also increased with time in

appears to mediate the stimulatory effects of bFGF and VEGF on the capillary morphogenesis of these endothelial cells, since an anti-LPP3 antibody raised against the RGD motif is able to antagonize these effects.203 Subsequent studies showed that LPP3 can induce endothelial cell migration by increasing fibronectin expression through β-catenin/lymphoid enhancer binding factor-1 (LEF-1) signaling in a phosphatase and tensin homologue (PTEN)-dependent manner. This effect of LPP3 occurs only in subconfluent endothelial cells, since LPP3 associated with p120-catenin at its C-terminal cytoplasmic domain in confluent cells. This association blocked the induction of β-catenin/LEF-1 signaling. Overall, the noncatalytic function of LPP3, mediated through the RGD motif, seems to play an important role in endothelial cell-to-cell adhesion as well as in migration. The effect of LPP3 on β-catenin/LEF-1 signaling indicates that LPP3 could be involved in the Wnt signaling pathway. This observation is supported by studies in LPP3 deficient mice. LPP3 deficient embryos are not viable due to failed formation of the chorio-allantoic placenta and defects in yolk sac vasculature.204 Investigation of LPP3 gene expression in embryos reveals differential and dynamic LPP3 expression in the ectoderm, endoderm, and allantois after 6.5−9.5 days of embryonic development.204 Since LPP3 deficient embryos die around E9.5, Escalante-Alcalde et al. generated mice with Ppap2b null β-galactosidase reporter alleles and determined LPP3 expression in heterozygous embryos from E8.5 to E13.5.205 They found that gene expression for LPP3 was again highly dynamic, especially in the gut endoderm, limb buds, mesenchyme, and pericardial−endocardial regions. As mentioned previously, one proposed mechanism by which LPP3 deficiency affects embryonic development is the effect of LPP3 on Wnt signaling. The anterior−posterior axes in a subset of LPP3 deficient embryos were shortened, which is a phenotype similar to that found in axin deficiency.204 Axin is an inhibitor of Wnt signaling,206 and it was found, as in axin deficient embryos, that Wnt signaling is hyperactivated in LPP3 deficient embryos. LPP3 was shown to negatively regulate βcatenin-mediated TCF signaling.204 It should be noted that the TCF/LEF transcription factor was not identified in this study. These results appear to conflict with the results from subconfluent endothelial cells showing that LPP3 induces βcatenin/LEF-1 signaling. This could be explained by differential regulation through interactions of LPP3 with uncharacterized proteins depending on the cellular process involved, i.e. embryonic development versus cell migration. The role of LPP3 in cell migration was further examined in Drosophila melanogaster embryos. The Wunen proteins (wun and wun2) of D. melanogaster are homologous to mammalian LPP3.149,207 The Wunens act redundantly in germ cells to produce signals that dictate germ cell−germ cell repulsion. Somatic tissues expressing Wunens can also guide germ cell migration through repulsion.207 Moreover, proper expression of the Wunens is required for maintaining the survival and integrity of the germ cells. It was proposed that the repulsion caused by wun and wun2 is dictated by spatially restricted hydrolysis of unknown lipid factors. Interestingly, there does not appear to be any expression of receptors for lipid phosphates in D. melanogaster.149 4.4. Intracellular Roles of LPPs

As discussed above, LPPs are also present in the endoplasmic reticulum144,144 and the Golgi network,148 with the catalytic 5138


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culture in these fibroblasts.215 The general conclusion from these experiments is that the decrease in PA concentrations depended on the direct action of the LPPs in converting PA to DG. However, the attenuation of PLD activation downstream of the activation of a G-protein coupled receptor or a receptor tyrosine kinase could also contribute to the observed decrease in PA accumulation following increased LPP expression.174b It should also be noted that PLD acts on PC to form PA on the cytosolic surface of membranes. PA formed in this manner would not be readily accessible to the active sites of LPPs, which face the extracellular space or the lumenal side of membranes. Instead, lipins could be the enzymes responsible for catalyzing the hydrolysis of PA formed from PLD activation. Lipins readily translocate from the cytosol to membranes when PA is formed.16b The actions of the LPPs in controlling the net accumulation of PA could have a profound affect on cell signaling. First, PA activates numerous downstream targets, including protein kinase C-ζ, mTORC1, Sos, Raf, phospholipase C-γ, sphingosine kinase-1, ERK, and NADPH oxidase.173,216 The LPPs could control DG formation, which could alter the activation of protein kinase C. Second, DG can theoretically activate classical and novel protein kinase Cs (PKCs) as well as RasGRP. However, a previous study has also shown that PKCs are activated by polyunsaturated DGs, e.g. those produced when phosphatidylinositol-4,5-bisphosphate is hydrolyzed by phospholipase C rather than by PLD activation.217 The fatty acid compositions of PC, which is converted to PA and then to DG by phospholipase D and LPP activity, respectively, do not appear to be favorable for PKC activation.217 LPP2 has also been shown to be important in regulating the cell cycle (Figure 7).218 More specifically, knocking down LPP2 in fibroblasts delayed cyclin A accumulation and entry into the S-phase. Conversely, overexpressing LPP2 resulted in premature entry into the S-phase due to premature cyclin A accumulation. This effect depended on the catalytic activity of LPP2, since the inactive mutant form did not affect S-phase entry. The lipid phosphate substrate of LPP2 that is involved in this phenotype is still unknown.218 The specific role of LPP2 in regulating the cell cycle is demonstrated by the observation that overexpressing LPP1 and LPP3 does not regulate entry into the S-phase. This result demonstrates the unique role of LPP2 in regulating cell cycle progression and growth, which contrasts with the antiproliferative actions of LPP1 and -3 ecto-activities on the hydrolysis of extracellular LPA and the resulting attenuation of LPA downstream signaling in cancer cells (section 4.2.1). LPP2 overexpressing fibroblasts eventually arrest in the G2/ M transition after 15 to 35 passages. Moreover, the cells exhibit a senescent phenotype when they finally exit the cell cycle.218 This is reminiscent of oncogenes such as Ras and BRAF, which stimulate cell proliferation followed by premature senescence, probably as a means of preventing malignancy.219 Interestingly, LPP2 knockout mice are fertile and exhibit no obvious phenotype.220 However, LPP2 is not essential for cell cycle progression; instead, it regulates the timing of entry into the Sphase. Other proteins that regulate entry into the S-phase or late G1 phase, e.g. cyclins D1, D2, E1, and E2 in addition to CDK2, 4, and 6, have been knocked out in mice, and these mice, as is the case for the LPP2 knockout mice, also show no obvious phenotype.218 Subsequent work identified LPP2 (PPAP2C) by gene microarray as one of three potentially novel targets, which are

up-regulated in transformed compared to nontransformed human adult mesenchymal stem cells.221 These authors also demonstrated the increased expression of LPP2 in transformed fibroblasts and the cancer cell lines MCF7, SK-LMS1, MG63, and U2OS. Knockdown of LPP2 impaired anchorage-dependent growth of the cancer cell lines and also decreased the growth of primary mesenchymal stem cells, but not of differentiated human fibroblasts. These authors confirmed previous work showing that knockdown of LPP2 delayed entry into the S-phase of the cell cycle,218 and furthermore, they demonstrated the regulation of the transcription of PPAP2C is partly controlled by p53.221 This work established that inhibiting the activity of LPP2, rather than the activities of LPP1 and 3, is a putative therapeutic target in treating cancer. The LPPs potentially control the accumulation of several bioactive lipid phosphates in addition to PA. Formation of intracellular LPA could occur through the action of phospholipase A1 or A2 on PA. Intracellular LPA can bind to nuclear LPA1 receptors to modulate pro-inflammatory signaling184 and can also induce PPARγ signaling.185a,222 LPPs could theoretically affect the levels of intracellular LPA, although this has not yet been demonstrated. LPPs can also degrade both C1P and S1P.223 S1P can also be dephosphorylated by S1Pspecific phosphatases.141 C1P and S1P are both involved in inflammatory signaling. C1P promotes the activation of PLA2 to produce arachidonate, and S1P induces cyclooxygenase 2 (COX2), which converts arachidonate to prostaglandin E2.192 The LPPs could determine the balance of intracellular signals that dictate various cellular processes, such as inflammation, by modulating the levels of C1P and S1P compared to those of their products, ceramide and sphingosine. Another example is the counter-balance of signaling between ceramide and S1P in the regulation of apoptotic signaling versus cell proliferation.224 The LPPs regulate important cell processes such as cell survival, proliferation, and migration. As mentioned above, LPP activity appears to be decreased in several cancer cell lines. This could make cancer cells hypersensitive to the survival and migratory signals in two ways.216 First, the ability of the cancer cell to degrade extracellular LPA and S1P would be attenuated, thus enabling these extracellular messengers to have a greater effect in stimulating cell division, survival, migration, and angiogenesis. Second, low expression of LPP activity would increase the responses to agonists that activate G-protein coupled receptors (e.g., LPA and S1P) and receptor tyrosine kinases (e.g., EGF, PDGF) by favoring intracellular signaling by lipid phosphates formed downstream of the activation of these receptors. 4.5. Regulation of LPP Expression

Although the LPPs are clearly important in regulating cell signaling, relatively little is known about the control of their expressions. LPP1 was identified as an androgen regulated gene in prostate cancer cells.225 It was observed that Dri42, which is equivalent to rat LPP3, is increased during differentiation of epithelial cells.144 Subsequent microarray analysis identified Dri42 as being upregulated in prostate cancer by synthetic androgen226 and by a transcription factor, Kruppel-like factor-5, which is essential for cancer proliferation.227 EGF increases the expression of mRNA for LPP3 but not LPP1.148 Studies in human endothelial cells demonstrated that the LPP3/VCIP gene was responsive to VEGF.228 LPP3 expression is also increased in endothelial cells by the action of basic fibroblast growth factor.203 5139


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4.6. Concluding Remarks for the LPPs

Author Contributions

The LPPs have important roles in regulating cell signaling through extracellular LPA and S1P. The LPPs also regulate intracellular signaling by dephosphorylating lipids formed downstream of the activation of both G-protein coupled receptors and receptor tyrosine kinases. A major outstanding problem in LPP research is to identify the physiological lipid phosphate targets of the different LPPs and understand the mechanisms of how each family member contributes to the control of signal transduction.

‡

These authors contributed equally.

Notes

5. CONCLUSIONS Research on the lipins and the lipid phosphate phosphatases developed together, since both of these enzyme families exhibited PA phosphatase activity and these enzymes were originally classified as PAP-1 and PAP-2, respectively. It became obvious that PAP-1 and PAP-2 played very different roles: PAP1 is involved in regulating glycerolipid synthesis, whereas PAP-2 appeared to function in controlling cell signaling. The major advances in understanding the roles of the two types of PA phosphatases came when the genes encoding these two families of enzymes were identified. The three PAP-2 enzymes are integral membrane proteins that play important functions in regulating the division, survival, and migration of cells through their actions in degrading several bioactive lipid phosphates. Because of this broad substrate specificity, they were renamed lipid phosphate phosphatases (LPPs). The PAP-1 family of enzymes are now called lipins, since this was the name given to these proteins before they were identified as PAPs. The three mammalian lipins are all Mg2+-dependent, NEM-sensitive PAPs, which is used to define their catalytic activities. As predicted, the lipins are cytosolic proteins that translocate to membranes and play a key role in providing DG for the synthesis of PC, PE, and TG. Additionally, they also have multiple functions in regulating cell signaling and transcriptional coregulation that controls the development of adipose tissue as well as the expression of proteins involved in fatty acid oxidation. In contrast, the LPPs appear to control the extracellular concentrations of various lipid phosphates, e.g. LPA and S1P, thereby attenuating downstream signaling in survival and proliferation pathways. LPPs also appear to play important roles in modulating intracellular levels of lipid phosphates. Besides this catalytic function, LPPs can regulate other important processes, such as cell−cell interactions, thymic egress, embryogenesis, and the timing of cell cycle progression. In conclusion, research on these two protein families has diverged over recent years, and it is clear that the lipins and LPPs have distinct and important roles in cell survival and metabolism.

The authors declare no competing financial interest.

Biographies

Bernard Kok is currently completing his doctoral thesis with Dr. David N. Brindley at the University of Alberta and hopes to be finished by June 2012. He graduated with a B.Sc. Specialization in Biochemistry from the University of Alberta in April 2006. His work focuses on the role and regulation of lipins, particularly lipin-1, in controlling cardiac metabolism and function.

ASSOCIATED CONTENT Special Issue Paper †

Part of the thematic issue “Lipid Biochemistry, Metabolism, and Signaling”.

Ganesh Venkatraman ([email protected]) was born in Chennai, India. He obtained his Bachelor’s degree in Biotechnology (B.Tech.) from SRM University, India, in 2008. Currently, he is a doctoral candidate in the Department of Biochemistry at University of Alberta, Canada. His work in Dr. Brindley’s lab focuses on the role of lysophospholipids and lipid phosphate phosphatases in breast cancer progression and metastasis.

AUTHOR INFORMATION Corresponding Author

*Tel, (780) 492-2078; fax, (310) 492-3383; e-mail, david. [email protected]. 5140


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Studentship from the Women and Children’s Health Research Institute, both from the University of Alberta.

ABBREVIATIONS ABC ATP-binding cassettes ATX autotaxin C1P ceramide 1-phosphate DG diacylglycerol EGFR epidermal growth factor receptor ERK extracellular signal-regulated kinase FA fatty acid f ld fatty liver dystrophy HAD haloacid dehalogenase LPA lysophosphatidate LPC lysophosphatidylcholine LPP lipid phosphate phosphatase MEF2 myocyte enhancer factor-2 MG monoacylglycerol mTORC1 mammalian target of rapamycin complex 1 NFAT nuclear factor of activated T cells PA phosphatidate PAP phosphatidate phosphatase PC phosphatidylcholine PDGF platelet-derived growth factor PE phosphatidylethanolamine PKC protein kinase C PLA phospholipase A PLD phospholipase D PGC-1α peroxisome proliferator-activated receptor gamma coactivator-1α PPAR peroxisome proliferator-activated receptor S1P sphingosine 1-phosphate SREBP sterol regulatory element binding protein TG triacylglycerol VEGF vascular endothelial growth factor VLDL very low density lipoprotein particle

Dora Capatos is completing her Master of Science degree under the supervision of Dr. David Brindley at the University of Alberta. She obtained a B.Sc. in Biochemistry from the University of Lethbridge. Her project is to investigate a role for the lipins in signal transduction in cancer cells.

David Brindley received his Ph.D. and performed a one-year fellowship under the supervision of Prof. Georg Hübscher at the University of Birmingham, England, and worked on glycerolipid synthesis. He then took a position as a Research Fellow with Prof. Konrad Bloch at Harvard University, Cambridge, MA, USA, to work on the fatty acid synthases of Mycobacterium phlei. After that, he returned to England to the Department of Biochemistry, Nottingham University, where he obtained a faculty position and started his independent research. He also received his D.Sc. from the University of Birmingham. He later joined the Department of Biochemistry at the University of Alberta, Edmonton, Canada. His work concentrates on the regulation of phosphatidate phosphatase and the hormonal control of triacylglycerol synthesis and lipoprotein metabolism, especially in diabetes and obesity. Phosphatidate phosphatase activity was recently discovered to be catalyzed by a family of lipin proteins that control fatty acid oxidation as well as triacylglycerol synthesis. He also studies a second family of phosphatidate phosphatases, the lipid phosphate phosphatases. These enzymes have broad specificity and dephosphorylate many bioactive lipid phosphates. This latter work developed into the study of lipid mediators in regulating signal transduction in wound healing and cancer.

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ACKNOWLEDGMENTS This work was supported by grants from the Canadian Institutes of Health Research, the Heart and Stroke Foundation of Alberta, and the Canadian Breast Cancer Foundation. B.P.C.K. holds a 75th Anniversary Award, and G.V. received a 5141


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