Serum Lysophosphatidic Acid Is Produced through Diverse Phospholipase Pathways

Aoki, Junken; Taira, Akitsu; Takanezawa, Yasukazu; Kishi, Yasuhiro; Hama, Kotaro; Kishimoto, Tatsuya; Mizuno, Koji; Saku, Keijiro; Taguchi, Ryo; Arai, Hiroyuki

doi:10.1074/jbc.m206812200

Cited by 390 publications

(355 citation statements)

References 52 publications

(53 reference statements)

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“…The scheme is based on data presented in the following papers-NPP1: [351,353,412,453,625]; NPP2: [351,353,377,380,403,406]; NPP3: [351]; NPP6: [388]; NPP7: [389,626]. GPC glycerophosphorylcholine, LPC lysophosphatidylcholine, pNPPC p-nitrophenyl phosphorylcholine, SPC sphingosylphosphorylcholine substrate [354][355][356][357].…”

Section: General Properties and Functional Rolementioning

confidence: 99%

“…It was hypothesized that sequences in all three domains together form a lysophospholipid-binding site [376]. In addition, ATX has the capacity to hydrolyze several other lysophospholipids to produce lysophosphatidic acid (LPA), including lysophosphatidylserine, lysophosphatidylethanolamine, and lysophosphatidylinositol [377]. LPA in turn acts on at least six distinct G protein-coupled receptors (LPA1-6) and elicits a large variety of both short-term and long-term cellular responses, including promotion of cell proliferation, survival, and motility of cells [343].…”

Section: General Properties and Functional Rolementioning

confidence: 99%

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Cellular function and molecular structure of ecto-nucleotidases

Zimmermann

Zebisch

Sträter

2012

Purinergic Signalling

854

922

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Ecto-nucleotidases play a pivotal role in purinergic signal transmission. They hydrolyze extracellular nucleotides and thus can control their availability at purinergic P2 receptors. They generate extracellular nucleosides for cellular reuptake and salvage via nucleoside transporters of the plasma membrane. The extracellular adenosine formed acts as an agonist of purinergic P1 receptors. They also can produce and hydrolyze extracellular inorganic pyrophosphate that is of major relevance in the control of bone mineralization. This review discusses and compares four major groups of ectonucleotidases: the ecto-nucleoside triphosphate diphosphohydrolases, ecto-5′-nucleotidase, ecto-nucleotide pyrophosphatase/phosphodiesterases, and alkaline phosphatases. Only recently and based on crystal structures, detailed information regarding the spatial structures and catalytic mechanisms has become available for members of these four ecto-nucleotidase families. This permits detailed predictions of their catalytic mechanisms and a comparison between the individual enzyme groups. The review focuses on the principal biochemical, cell biological, catalytic, and structural properties of the enzymes and provides brief reference to tissue distribution, and physiological and pathophysiological functions.

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Section: General Properties and Functional Rolementioning

confidence: 99%

Section: General Properties and Functional Rolementioning

confidence: 99%

Cellular function and molecular structure of ecto-nucleotidases

Zimmermann

Zebisch

Sträter

2012

Purinergic Signalling

854

922

View full text Add to dashboard Cite

show abstract

“…The total amount of LPA in plasma is in the low nanomolar range [70][71][72][73][74], and the portion derived from isolated platelets remains only a fraction of that generated ex vivo during blood clotting [70].In the course of blood clotting, large amounts of LPA are generated, reaching concentrations as high as 5-10 µM [70,71,75,76], and the molecular species are dominated by the 18:2 and 20:4 unsaturated acyl species (20% and 34% of total LPA, respectively) [70]. LPA 20:4 is a more potent activator of platelets than other saturated or mono-unsaturated acyl species [77][78][79].…”

Section: Discussionmentioning

confidence: 99%

The early- and late stages in phenotypic modulation of vascular smooth muscle cells: Differential roles for lysophosphatidic acid

Guo

Makarova

Cheng

et al. 2008

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

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Lysophosphatidic acid (LPA) has been implicated as causative in phenotypic modulation (PM) of cultured vascular smooth muscle cells (VSMC) in their transition to the dedifferentiated phenotype. We evaluated the contribution of the three major LPA receptors, LPA 1 and LPA 2 GPCR and PPARγ, on PM of VSMC. Expression of differentiated VSMC-specific marker genes, including smooth muscle α-actin, smooth muscle myosin heavy chain, calponin, SM-22α, and hcaldesmon, was measured by quantitative real-time PCR in VSMC cultures and aortic rings kept in serum-free chemically defined medium or serum-or LPA-containing medium using wild-type C57BL/6, LPA 1 , LPA 2 , and LPA 1&2 receptor knockout mice. Within hours after cells were deprived of physiological cues, the expression of VSMC marker genes, regardless of genotype, rapidly decreased. This early PM was neither prevented by IGF-I, inhibitors of p38, ERK1/2, or PPARγ nor significantly accelerated by LPA or serum. To elucidate the mechanism of PM in vivo, carotid artery ligation with/without replacement of blood with Krebs solution was used to evaluate contributions of blood flow and pressure. Early PM in the common carotid was induced by depressurization regardless of the presence/absence of blood, but eliminating blood flow while maintaining blood pressure or after sham surgery elicited no early PM. The present results indicate that LPA, serum, dissociation of VSMC, IGF-I, p38, ERK1/2, LPA 1 , and LPA 2 are not causative factors of early PM of VSMC. Tensile stress generated by blood pressure may be the fundamental signal maintaining the fully differentiated phenotype of VSMC.

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“…[46] Inhibition of ATX Recent evidence shows that LPA is produced extracellularly from LPC by the lysoPLD activity of ATX. [47] The local production of LPA by ATX/lysoPLD could support the invasion of tumor cells, promoting metastasis. [7] The mechanisms of enhanced tumor cell invasion by LPA include two important molecular mechanisms.…”

Section: Receptor Activation Assaysmentioning

confidence: 99%

α‐Substituted Phosphonate Analogues of Lysophosphatidic Acid (LPA) Selectively Inhibit Production and Action of LPA

Jiang

Fujiwara

et al. 2007

ChemMedChem

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Isoform-selective agonists and antagonists of the lysophosphatidic acid (LPA) G-protein-coupled receptors (GPCRs) have important potential applications in cell biology and therapy. LPA GPCRs regulate cancer cell proliferation, invasion, angiogenesis, and biochemical resistance to chemotherapy-and radiotherapy-induced apoptosis. LPA and its analogues are also feedback inhibitors of the enzyme lysophospholipase D (lysoPLD, also known as autotaxin), a central regulator of invasion and metastasis. For cancer therapy, the ideal therapeutic profile would be a metabolically stabilized pan-LPA receptor antagonist that also inhibits lysoPLD. Herein we describe the synthesis of a series of novel α-substituted methylene phosphonate analogues of LPA. Each of these analogues contains a hydrolysis-resistant phosphonate mimic of the labile monophosphate of natural LPA. The pharmacological properties of these phosphono-LPA analogues were characterized in terms of LPA receptor subtype-specific agonist and antagonist activity using Ca 2+ mobilization assays in RH7777 and CHO cells expressing the individual LPA GPCRs. In particular, the methylene phosphonate LPA analogue is a selective LPA 2 agonist, whereas the corresponding α-hydroxymethylene phosphonate is a selective LPA 3 agonist. Most importantly, the α-bromomethylene and α-chloromethylene phosphonates show pan-LPA receptor subtype antagonist activity. The α-bromomethylene phosphonates are the first reported antagonists for the LPA 4 GPCR. Each of the α-substituted methylene phosphonates inhibits lysoPLD, with the unsubstituted methylene phosphonate showing the most potent inhibition. Finally, unlike many LPA analogues, none of these compounds activate the intracellular LPA receptor PPARγ.

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Serum Lysophosphatidic Acid Is Produced through Diverse Phospholipase Pathways

Cited by 390 publications

References 52 publications

Cellular function and molecular structure of ecto-nucleotidases

Cellular function and molecular structure of ecto-nucleotidases

The early- and late stages in phenotypic modulation of vascular smooth muscle cells: Differential roles for lysophosphatidic acid

α‐Substituted Phosphonate Analogues of Lysophosphatidic Acid (LPA) Selectively Inhibit Production and Action of LPA

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