Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.4.1 (phosphodiesterase)
18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The exo-enzyme autotaxin/NPP2 (ATX/NPP2) is a potent stimulator of cell migration, invasion, metastasis, and angiogenesis. Recently, ATX/NPP2 was found to possess lysophospholipase D (lyso-LPD) activity, generating the bioactive mediator lysophosphatidic acid from precursors. In the present study, we used site-directed mutagenesis to delineate the active domain of lysophospholipid catalytic activity and to examine potential overlap with the nucleotide phosphodiesterase domain. We found four amino acid residues obligatory for the phosphodiesterase, lyso-PLD, and migration-stimulating activities of ATX/NPP2, suggesting that 5'-nucleotide phosphodiesterase (PDE) and lyso-PLD share a common reaction mechanism and inviting design of enzymatic inhibitors as therapeutic agents for neoplastic disease.
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PMID:Site-directed mutations in the tumor-associated cytokine, autotaxin, eliminate nucleotide phosphodiesterase, lysophospholipase D, and motogenic activities. 1272 17

The initial stages of central nervous system (CNS) myelination require complex interactions of oligodendrocytes with their surrounding extracellular environment. In the present study, we demonstrate that commencing with active myelination oligodendrocytes express phosphodiesterase-Ialpha/autotaxin [PD-Ialpha/ATX (NPP-2)] as a non-membrane-associated extracellular factor. As such a component of the extracellular environment, PD-Ialpha/ATX has the ability to antagonize the adhesive interactions between oligodendroglial cells and known extracellular matrix (ECM) molecules present in the developing CNS. This counteradhesion requires intracellular signaling through heterotrimeric G proteins on fibronectin substrates and thus represents an active cellular response. Similar counteradhesive effects in other systems have been attributed to the activity of matricellular proteins, which support intermediate stages of cell adhesion thought to facilitate cellular locomotion and remodeling. Thus, the release of PD-Ialpha/ATX may be critically involved in the regulation of the initial stages of myelination, i.e., oligodendrocyte remodeling, via modulation of oligodendrocyte-ECM interactions in a matricellular fashion.
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PMID:Phosphodiesterase-Ialpha/autotaxin: a counteradhesive protein expressed by oligodendrocytes during onset of myelination. 1283 32

Autotaxin (ATX/NPP2) is a tumor cell motility-stimulating factor that displays both a nucleotide pyrophosphatase/phosphodiesterase activity and a recently described lysophospholipase D (lysoPLD) activity. The precise function of ATX in tumor cells and the role of ATX in thyroid carcinoma remains unclear. We have quantified ATX mRNA expression in thyroid carcinoma cell lines and in tissues of patients with thyroid carcinomas. ATX gene activity was significantly higher in undifferentiated anaplastic thyroid carcinoma cell lines (UTC) and tumor tissues as compared to follicular thyroid carcinoma (FTC) cell lines, FTC tissues or goiter tissues that were used as a control. In the thyroid carcinoma cell line 1736, EGF and bFGF stimulated ATX mRNA expression, whereas the cytokines IL-4, IL-1beta and TGF-beta reduced ATX transcriptional levels. FTC-133 cells, stably transfected with an expression vector for ATX, showed a higher lysoPLD activity, a higher proliferation rate and an increased migratory behavior. In addition, ATX also displayed a paracrine stimulatory effect on the motility of different thyroid carcinoma cell lines. Overexpression of ATX in the stably transfected FTC-133 resulted in down-regulation of CD54/ intercellular adhesion molecule-1 (ICAM-1) gene expression and augmented gene activity of the pro-angiogenic chemokine IL-8. We conclude that ATX may be regarded as a new tissue marker for undifferentiated human thyroid carcinoma cells. ATX increases the proliferation and migration of thyroid carcinoma cell lines and may also affect the angiogenic potential of thyroid carcinoma cells. Further studies are needed to provide insight into the role of ATX in the normal and neoplastic thyroid gland.
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PMID:Expression, regulation and function of autotaxin in thyroid carcinomas. 1502 16

The nucleotide pyrophosphatases/phosphodiesterases NPP1 and NPP2/autotaxin are structurally related eukaryotic ecto-enzymes, but display a very different substrate specificity. NPP1 releases nucleoside 5'-monophosphates from various nucleotides, whereas NPP2 mainly functions as a lysophospholipase D. We have used a domain-swapping approach to map substrate-specifying determinants of NPP1 and NPP2. The catalytic domain of NPP1 fused to the N- and C-terminal domains of NPP2 was hyperactive as a nucleotide phosphodiesterase, but did not show any lysophospholipase D activity. In contrast, chimaeras of the catalytic domain of NPP2 and the N- and/or C-terminal domains of NPP1 were completely inactive. These data indicate that the catalytic domain as well as both extremities of NPP2 contain lysophospholipid-specifying sequences. Within the catalytic domain of NPP1 and NPP2, we have mapped residues close to the catalytic site that determine the activities towards nucleotides and lysophospholipids. We also show that the conserved Gly/Phe-Xaa-Gly-Xaa-Xaa-Gly (G/FXGXXG) motif near the catalytic site is required for metal binding, but is not involved in substrate-specification. Our data suggest that the distinct activities of NPP1 and NPP2 stem from multiple differences throughout the polypeptide chain.
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PMID:Substrate-specifying determinants of the nucleotide pyrophosphatases/phosphodiesterases NPP1 and NPP2. 2924 84

Lysophosphatidic acid (LPA) is an important lipid mediator that binds to G-protein-coupled receptors of the Edg family, inducing proliferation and migration in many cell lines. Much has been learned about pathways involved in LPA signaling, but the pathways responsible for LPA production remain to be fully resolved. Several potential routes have been proposed for LPA production. One involves the sequential actions of phopholipase D (PLD) and phospholipase A(2) (PLA(2)). Another route involves the sequential actions of PLA(2) and lysophospholipase D (lysoPLD). LysoPLD is defined as an enzyme which hydrolyzes lysophospholipids to produce LPA. Two major forms of lysoPLD, microsomal and extracellular forms, have been reported. A microsomal lysoPLD plays an important role in the metabolism of platelet-activating factor (PAF) because of its preference for alkyl-phospholipids. The extracellular form of lysoPLD coexists with its substrate, lysophosphatidylcholine (LPC), in the extracellular compartment. LysoPLDs purified from the extracellular space have recently been shown to be molecularly identical to autotaxin (ATX). ATX, an enzyme previously known to possess 5'-nucleotide pyrophosphatase and phosphodiesterase (PDE) activities, was subsequently shown to have lysoPLD activity. The unexpected linkage of the extracellular lysoPLD with ATX has raised many interesting questions. The characterization and purification of lysoPLDs are reviewed here.
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PMID:Lysophospholipase D and its role in LPA production. 1521 58

Two-dimensional gel electrophoresis and peptide mass fingerprinting were used to identify proteins in cerebrospinal fluid (CSF) pooled from three patients with multiple sclerosis (MS) and in CSF pooled from three patients with non-MS inflammatory central nervous system (CNS) disorders. Resolution of CSF proteins on three pH gradients (3-10, 4-7 and 6-11) enabled identification of a total of 430 spots in the MS CSF proteome that represented 61 distinct proteins. The gels containing MS CSF revealed 103 protein spots that were not seen on control gels. All but four of these 103 spots were proteins known to be present in normal human CSF. The four exceptions were: CRTAC-IB (cartilage acidic protein), tetranectin (a plasminogen-binding protein), SPARC-like protein (a calcium binding cell signalling glycoprotein), and autotaxin t (a phosphodiesterase). It remains unknown whether these four proteins are related to the cause and pathogenesis of MS.
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PMID:Proteomic analysis of multiple sclerosis cerebrospinal fluid. 1522 87

Lysophosphatidic acid (LPA) is a lipid mediator with a wide variety of biological actions, particularly as an inducer of cell proliferation, migration and survival. LPA binds to specific G-protein-coupled receptors and thereby activates multiple signal transduction pathways, including those initiated by the small GTPases Ras, Rho, and Rac. LPA signaling has been implicated in such diverse processes as wound healing, brain development, vascular remodeling and tumor progression. Knowledge of precisely how and where LPA is produced has long proved elusive. Excitingly, it has recently been discovered that LPA is generated from precursors by 'autotaxin', a once enigmatic exo-phosphodiesterase implicated in tumor cell motility. Exogenous phospholipases D can also produce LPA, which may contribute to their toxicity. Here we review recent progress in our understanding of LPA bioactivity, signaling and synthesis.
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PMID:The ins and outs of lysophosphatidic acid signaling. 1527 89

Myelination within the central nervous system (CNS) involves substantial morphogenesis of oligodendrocytes requiring plastic changes in oligodendrocyte-extracellular matrix (ECM) interactions, that is, adhesion. Our previous studies indicated that a regulator of such adhesive plasticity is oligodendrocyte-released phosphodiesterase-I alpha/autotaxin (PD-I alpha/ATX). We report here, that PD-I alpha/ATX's adhesion antagonism is mediated by a protein fragment different from the one that stimulates tumor cell motility. Furthermore, PD-I alpha/ATX's adhesion-antagonizing fragment causes a reorganized distribution of the focal adhesion components vinculin and paxillin and an integrin-dependent reduction in focal adhesion kinase (FAK) phosphorylation at tyrosine residue 925 (pFAK-925). In vivo, a similar reduction in pFAK-925 occurs at the onset of myelination when PD-I alpha/ATX expression is significantly upregulated. Most importantly, it can also be induced by the application of exogenous PD-I alpha/ATX. Our data, therefore, suggest that PD-I alpha/ATX participates in the regulation of myelination via a novel signaling pathway leading to changes in integrin-dependent focal adhesion assembly and consequently oligodendrocyte-ECM interactions.
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PMID:Phosphodiesterase-I alpha/autotaxin controls cytoskeletal organization and FAK phosphorylation during myelination. 1548 70

Autotaxin (ATX) or nucleotide pyrophosphatase/phosphodiesterase 2 (NPP2) is an NPP family member that promotes tumor cell motility, experimental metastasis, and angiogenesis. ATX primarily functions as a lysophospholipase D, generating the lipid mediator lysophosphatidic acid (LPA) from lysophosphatidylcholine. ATX uses a single catalytic site for the hydrolysis of both lipid and non-lipid phosphodiesters, but its regulation is not well understood. Using a new fluorescence resonance energy transfer-based phosphodiesterase sensor that reports ATX activity with high sensitivity, we show here that ATX is potently and specifically inhibited by LPA and sphingosine 1-phosphate (S1P) in a mixed-type manner (Ki approximately 10(-7) M). The homologous ecto-phosphodiesterase NPP1, which lacks lysophospholipase D activity, is insensitive to LPA and S1P. Our results suggest that, by repressing ATX activity, LPA can regulate its own biosynthesis in the extracellular environment, and they reveal a novel role for S1P as an inhibitor of ATX, in addition to its well established role as a receptor ligand.
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PMID:Inhibition of autotaxin by lysophosphatidic acid and sphingosine 1-phosphate. 1576 51

Autotaxin (NPP2) is an extracellular protein that is upregulated in various malignancies, including breast and lung cancer. It potently stimulates cell proliferation, cell motility and angiogenesis, which is accounted for by its intrinsic lysophospholipase-D activity that generates the lipid mediators lysophosphatidic acid and sphingosine-1-phosphate. Based on its structural similarities with the better characterized nucleotide pyrophosphatase/phosphodiesterase NPP1, it has always been assumed that NPP2 is also synthesized as a type-II integral membrane protein and that extracellular NPP2 is generated from this membrane precursor. We show here, however, using domain swapping and mutagenesis experiments as well as N-terminal protein sequencing, that NPP2 is actually synthesized as a pre-pro-enzyme and that the proteolytically processed protein is secreted. Following the removal of a 27-residue signal peptide by the signal peptidase, NPP2 is subsequently cleaved by proprotein convertases (PCs). The removal of an N-terminal octapeptide by PCs is associated with an enhanced activity of NPP2 as a lysophospholipase D. These novel insights in the maturation of NPP2 have also implications for the development of NPP2 inhibitors as potential anti-cancer agents.
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PMID:Proteolytic maturation and activation of autotaxin (NPP2), a secreted metastasis-enhancing lysophospholipase D. 1598 67


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