Phosphatidate Phosphohydrolase Catalyzes the Hydrolysis of Ceramide 1-Phosphate, Lysophosphatidate, and Sphingosine 1-Phosphate

Waggoner, David W.; Gómez-Muñoz, Antonio; Dewald, Jay; Brindley, David N.

doi:10.1074/jbc.271.28.16506

Cited by 138 publications

(108 citation statements)

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“…Although detailed kinetic analysis is needed, it is clear that the substrate specificities of the two PAPs cloned are distinct from each other and that dephosphorylation of sphingosine-1-phosphate by PAP-2a occurs to a negligible extent, if any. In this respect, the properties of PAP-2b are more similar to those of rat liver enzyme (17), which degrades all of these substrates at similar rates.…”

Section: Resultsmentioning

confidence: 62%

“…Waggoner et al (17) recently reported that the type 2 PAP purified from rat liver dephosphorylates lyso-PA, ceramide-1-phosphate, and sphingosine-1-phosphate in addition to PA. Furthermore, the same enzyme preparation was described as capable of dephosphorylating DG pyrophosphate (21).…”

Section: Resultsmentioning

confidence: 99%

“…The incubation with sphingosine-1-phosphate was continued for 20 min, and the reaction was stopped with 10 l of concentrated formic acid as described by Waggoner et al(17). In this case, the released 32 P i was separated by thin layer chromatography (17). All reaction rates were proportional to the amounts of enzyme protein and incubation time and were usually done in triplicates, the results of which differed Ͻ5%.…”

Section: Methodsmentioning

confidence: 99%

“…The enzyme purified from rat liver could hydrolyze ceramide-1-phosphate and sphingosine-1-phosphate in addition to PA and lyso-PA (17). Since ceramide, sphingosine, and their phosphorylated derivatives are known to serve as signaling molecules (18 -20), the type 2 PAP can be involved in the metabolic processing of lipid mediators derived from both glycerolipids and sphingolipids.…”

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confidence: 99%

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Cloning and Characterization of Two Human Isozymes of Mg2+-independent Phosphatidic Acid Phosphatase

Kai

Wada

Imai

et al. 1997

Journal of Biological Chemistry

175

211

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We obtained two human cDNA clones encoding phosphatidic acid phosphatase (PAP) isozymes named PAP-2a (M r ‫؍‬ 32,158) and -2b (M r ‫؍‬ 35, 119), both of which contained six putative transmembrane domains. Both enzymes were glycosylated and cleaved by N-glycanase and endo-␤-galactosidase, thus suggesting their post-Golgi localization. PAP-2a and -2b shared 47% identical sequence and were judged to be the human counterparts of the previously sequenced mouse 35-kDa PAP(83% identity) and rat Dri42 protein (94% identity), respectively. Furthermore, the sequences of both PAPs were 34 -39% identical to that of Drosophila Wunen protein. In view of the functions ascribed to Wunen and Dri42 in germ cell migration and epithelial differentiation, respectively, these findings unexpectedly suggest critical roles of PAP isoforms in cell growth and differentiation. Although the two PAPs hydrolyzed lysophosphatidate and ceramide-1-phosphate in addition to phosphatidate, the hydrolysis of sphingosine-1-phosphate was detected only for PAP-2b. PAP-2b was expressed almost ubiquitously in all human tissues examined, whereas the expression of PAP-2a was relatively variable, being extremely low in the placenta and thymus. In HeLa cells, the transcription of PAP-2a was not affected by different stimuli, whereas PAP-2b was induced (up to 3-fold) by epidermal growth factor. These findings indicate that despite structural similarities, the two PAP isozymes may play distinct functions through their different patterns of substrate utilization and transcriptional regulation.Phosphatidic acid phosphatase (PAP) 1 (EC 3.1.3.4) supplies diacylglycerol (DG) in glycerolipid biosynthesis by dephosphorylating phosphatidic acid (PA) (1). Since both DG (2) and PA (3) are potent signaling molecules, PAP plays an important role in cellular signal transduction in addition to lipid biosynthesis (4). In signaling systems mediated by phospholipase D (5), liberated PA is generally converted, albeit to different extents, to DG by the action of PAP (6 -8), thus suggesting that PAP contributes to the control of the relative balance of the two lipid second messengers.There exist two forms of mammalian PAP that can be distinguished with respect to subcellular localization and enzymologic properties (9). So far, distinct functions have been ascribed to the two forms of PAP. The type 1 PAP, a Mg 2ϩ -dependent and N-ethylmaleimide-sensitive enzyme, is considered to be primarily involved in lipid synthesis based on its translocation from the cytosol to microsomes upon stimulation of cellular triacylglycerol synthesis (10 -12). In this context, a recent work showed using a novel enzyme inhibitor that the type 1 PAP indeed participated in triacylglycerol synthesis in mouse macrophages (13). On the other hand, the type 2 PAP, a Mg 2ϩ -independent and N-ethylmaleimide-insensitive enzyme, has been postulated to participate in cellular signal transduction mediated by phospholipase D. The finding that the activities of the type 2 PAP and phospholipase D were decreased in a c...

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Section: Resultsmentioning

confidence: 62%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

Cloning and Characterization of Two Human Isozymes of Mg2+-independent Phosphatidic Acid Phosphatase

Kai

Wada

Imai

et al. 1997

Journal of Biological Chemistry

175

211

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“…LPA is rapidly dephosphorylated by a family of integral membrane proteins known as lipid phosphate phosphatases (LPPs) [16-18]. The LPP family (also known as PAP2) comprises four members (LPP 1 , LPP 2 , LPP 3 and a splice variant LPP 1a ) which dephosphorylate their lipid substrates, namely LPA, PA, sphingosine 1-phosphate (S1P), and ceramide 1-phosphate [19-21]. All the LPP subtypes are expressed in the brain [18,19,22] but very little is known about their functional roles.…”

Section: Introductionmentioning

confidence: 99%

Lipid phosphate phosphatase inhibitors locally amplify lysophosphatidic acid LPA1 receptor signalling in rat brain cryosections without affecting global LPA degradation

et al. 2012

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BackgroundLysophosphatidic acid (LPA) is a signalling phospholipid with multiple biological functions, mainly mediated through specific G protein-coupled receptors. Aberrant LPA signalling is being increasingly implicated in the pathology of common human diseases, such as arteriosclerosis and cancer. The lifetime of the signalling pool of LPA is controlled by the equilibrium between synthesizing and degradative enzymatic activity. In the current study, we have characterized these enzymatic pathways in rat brain by pharmacologically manipulating the enzymatic machinery required for LPA degradation.ResultsIn rat brain cryosections, the lifetime of bioactive LPA was found to be controlled by Mg2+-independent, N-ethylmaleimide-insensitive phosphatase activity, attributed to lipid phosphate phosphatases (LPPs). Pharmacological inhibition of this LPP activity amplified LPA1 receptor signalling, as revealed using functional autoradiography. Although two LPP inhibitors, sodium orthovanadate and propranolol, locally amplified receptor responses, they did not affect global brain LPA phosphatase activity (also attributed to Mg2+-independent, N-ethylmaleimide-insensitive phosphatases), as confirmed by Pi determination and by LC/MS/MS. Interestingly, the phosphate analog, aluminium fluoride (AlFx-) not only irreversibly inhibited LPP activity thereby potentiating LPA1 receptor responses, but also totally prevented LPA degradation, however this latter effect was not essential in order to observe AlFx--dependent potentiation of receptor signalling.ConclusionsWe conclude that vanadate- and propranolol-sensitive LPP activity locally guards the signalling pool of LPA whereas the majority of brain LPA phosphatase activity is attributed to LPP-like enzymatic activity which, like LPP activity, is sensitive to AlFx- but resistant to the LPP inhibitors, vanadate and propranolol.

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Sphingolipide – ihre Stoffwechselwege und die Pathobiochemie neurodegenerativer Erkrankungen

Kolter¹,

Sandhoff²

1999

Angewandte Chemie

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Phosphatidate Phosphohydrolase Catalyzes the Hydrolysis of Ceramide 1-Phosphate, Lysophosphatidate, and Sphingosine 1-Phosphate

Cited by 138 publications

References 50 publications

Cloning and Characterization of Two Human Isozymes of Mg2+-independent Phosphatidic Acid Phosphatase

Cloning and Characterization of Two Human Isozymes of Mg2+-independent Phosphatidic Acid Phosphatase

Lipid phosphate phosphatase inhibitors locally amplify lysophosphatidic acid LPA1 receptor signalling in rat brain cryosections without affecting global LPA degradation

Sphingolipide – ihre Stoffwechselwege und die Pathobiochemie neurodegenerativer Erkrankungen

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