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)

Autotaxin (ATX) was originally identified as a potent tumor cell motility-stimulating factor that displays multiple enzymatic activities including ATPase, Type I nucleotide pyrophosphatase/phosphodiesterase, and lysophospholipase D, depending on its substrates. We demonstrate herein that ATX is a key regulator of extracellular lysophosphatidic acid (LPA) that can act as survival factor, in addition to its mitogenic activity in mouse fibroblasts. Introduction of atx gene into NIH3T3 cells resulted in resistance to conditional apoptosis induced by serum-deprivation, and exogenous ATX protein prevented cells from death by starvation. Flow cytometric analysis showed that co-treatment of ATX with lysophosphatidylcholine as substrate rescued NIH3T3 cells from cellular apoptosis, and this survival activity of ATX was also demonstrated by caspase-3 degradation and PARP cleavage resulting from the enzymatic activity of extracellular ATX. Furthermore, the effect of ATX in preventing apoptosis appears to be mediated through the G-protein-coupled receptor pathway followed by the activation of phosphoinositide 3-kinase and Akt pathway leading to enhanced cell survival. These findings provide novel insights into understanding the functions of ATX as a key regulator of bioactive phospholipids and suggest interventions to correct dysfunction in conditions of tumor cell growth and metastasis.
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PMID:Autotaxin (lysoPLD/NPP2) protects fibroblasts from apoptosis through its enzymatic product, lysophosphatidic acid, utilizing albumin-bound substrate. 1621 96

Phosphodiesterase-Ialpha/autotaxin (PD-Ialpha/ATX) was originally identified as a cell-motility-stimulating factor secreted by a variety of tumor cells. Thus, studies related to its potential functional roles have traditionally focused on tumorigenesis. PD-Ialpha/ATX's catalytic activity, initially defined as nucleotide pyrophosphatase/phosphodiesterase, was soon recognized as being necessary for its tumor cell-motility-stimulating activity. However, only the discovery of PD-Ialpha/ATX's identity with lysophospholipase D, an extracellular enzyme that converts lysophosphatidylcholine into lysophosphatidic acid (LPA) and potentially sphingosylphosphoryl choline into sphingosine 1-phosphate (S1P), revealed the actual effectors responsible for PD-Ialpha/ATX's ascribed motogenic functions, i.e., its catalytic products. PD-Ialpha/ATX has also been detected during normal development in a number of tissues, in particular, the central nervous system (CNS), where expression levels are high. Similar to tumor cells, PD-Ialpha/ATX-expressing CNS cells secrete catalytically active PD-Ialpha/ATX into the extracellular environment. Thus, it appears reasonable to assume that PD-Ialpha/ATX's CNS-related functions are mediated via lysophospholipid, LPA and potentially S1P, signaling. However, recent studies identified PD-Ialpha/ATX as a matricellular protein involved in the modulation of oligodendrocyte-extracellular matrix interactions and oligodendrocyte remodeling. This property of PD-Ialpha/ATX was found to be independent of its catalytic activity and to be mediated by a novel functionally active domain. These findings, therefore, uncover PD-Ialpha/ATX, at least in the CNS, as a multifunctional protein able to induce complex signaling cascades via distinct structure-function domains. This Mini-Review describes PD-Ialpha/ATX's multifunctional roles in the CNS and discusses their potential contributions to CNS development and pathology.
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PMID:Phosphodiesterase-Ialpha/autotaxin (PD-Ialpha/ATX): a multifunctional protein involved in central nervous system development and disease. 1626 28

We searched for genes differentially expressed in the frontal cortices of Alzheimer-type dementia (ATD) patients compared with those of non-ATD controls using DNA microarray and quantitative reverse transcription-polymerase chain reaction (RT-PCR) analyses. Here we show that the expression level of the autotaxin (also called lysophospholipase D or ecto-nucleotide pyrophosphatase/phosphodiesterase 2) gene was significantly greater in ATD cortices than in non-ATD cortices. In both ATD and non-ATD groups, the expression levels were greater in patients with the apoE epsilon3/epsilon4 genotype than in patients with the apoE epsilon3/epsilon3 genotype, although the differences were not statistically significant. These observations suggest that expression of the autotaxin gene and cell signaling by lysophosphatidic acid may be involved in the pathology of ATD, and that this cell signaling pathway may be a potential target of treatments for ATD.
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PMID:Autotaxin expression is enhanced in frontal cortex of Alzheimer-type dementia patients. 1652 61

Autotaxin (ATX) is a multifunctional phosphodiesterase originally isolated from melanoma cells as a potent cell motility-stimulating factor. ATX is identical to lysophospholipase D, which produces a bioactive phospholipid, lysophosphatidic acid (LPA), from lysophosphatidylcholine (LPC). Although enhanced expression of ATX in various tumor tissues has been repeatedly demonstrated, and thus, ATX is implicated in progression of tumor, the precise role of ATX expressed by tumor cells was unclear. In this study, we found that ATX is highly expressed in glioblastoma multiforme (GBM), the most malignant glioma due to its high infiltration into the normal brain parenchyma, but not in tissues from other brain tumors. In addition, LPA1, an LPA receptor responsible for LPA-driven cell motility, is predominantly expressed in GBM. One of the glioblastomas that showed the highest ATX expression (SNB-78), as well as ATX-stable transfectants, showed LPA1-dependent cell migration in response to LPA in both Boyden chamber and wound healing assays. Interestingly these ATX-expressing cells also showed chemotactic response to LPC. In addition, knockdown of the ATX level using small interfering RNA technique in SNB-78 cells suppressed their migratory response to LPC. These results suggest that the autocrine production of LPA by cancer cell-derived ATX and exogenously supplied LPC contribute to the invasiveness of cancer cells and that LPA1, ATX, and LPC-producing enzymes are potential targets for cancer therapy, including GBM.
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PMID:Autotaxin is overexpressed in glioblastoma multiforme and contributes to cell motility of glioblastoma by converting lysophosphatidylcholine to lysophosphatidic acid. 1662 85

Autotaxin (ATX, nucleotide pyrophosphate/phosphodiesterase-2) is an autocrine motility factor initially characterized from A2058 melanoma cell-conditioned medium. ATX is known to contribute to cancer cell survival, growth, and invasion. Recently ATX was shown to be responsible for the lysophospholipase D activity that generates lysophosphatidic acid (LPA). Production of LPA is sufficient to explain the effects of ATX on tumor cells. Cyclic phosphatidic acid (cPA) is a naturally occurring analog of LPA in which the sn-2 hydroxy group forms a 5-membered ring with the sn-3 phosphate. Cellular responses to cPA generally oppose those of LPA despite activation of apparently overlapping receptor populations, suggesting that cPA also activates cellular targets distinct from LPA receptors. cPA has previously been shown to inhibit tumor cell invasion in vitro and cancer cell metastasis in vivo. However, the mechanism governing this effect remains unresolved. Here we show that 3-carba analogs of cPA lack significant agonist activity at LPA receptors yet are potent inhibitors of ATX activity, LPA production, and A2058 melanoma cell invasion in vitro and B16F10 melanoma cell metastasis in vivo.
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PMID:Carba analogs of cyclic phosphatidic acid are selective inhibitors of autotaxin and cancer cell invasion and metastasis. 1678 9

Autotaxin (ATX), or nucleotide pyrophosphatase-phosphodiesterase 2, is a secreted lysophospholipase D that promotes cell migration, metastasis, and angiogenesis. ATX generates lysophosphatidic acid (LPA), a lipid mitogen and motility factor that acts on several G protein-coupled receptors. Here we report that ATX-deficient mice die at embryonic day 9.5 (E9.5) with profound vascular defects in yolk sac and embryo resembling the Galpha13 knockout phenotype. Furthermore, at E8.5, ATX-deficient embryos showed allantois malformation, neural tube defects, and asymmetric headfolds. The onset of these abnormalities coincided with increased expression of ATX and LPA receptors in normal embryos. ATX heterozygous mice appear healthy but show half-normal ATX activity and plasma LPA levels. Our results reveal a critical role for ATX in vascular development, indicate that ATX is the major LPA-producing enzyme in vivo, and suggest that the vascular defects in ATX-deficient embryos may be explained by loss of LPA signaling through Galpha13.
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PMID:Autotaxin, a secreted lysophospholipase D, is essential for blood vessel formation during development. 1678 87

Autotaxin is a secreted cell motility-stimulating exo-phosphodiesterase with lysophospholipase D activity that generates bioactive lysophosphatidic acid. Lysophosphatidic acid has been implicated in various neural cell functions such as neurite remodeling, demyelination, survival and inhibition of axon growth. Here, we report on the in vivo expression of autotaxin in the brain during development and following neurotrauma. We found that autotaxin is expressed in the proliferating subventricular and choroid plexus epithelium during embryonic development. After birth, autotaxin is mainly found in white matter areas in the central nervous system. In the adult brain, autotaxin is solely expressed in leptomeningeal cells and oligodendrocyte precursor cells. Following neurotrauma, autotaxin is strongly up-regulated in reactive astrocytes adjacent to the lesion. The present study revealed the cellular distribution of autotaxin in the developing and lesioned brain and implies a function of autotaxin in oligodendrocyte precursor cells and brain injuries.
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PMID:Autotaxin (NPP-2) in the brain: cell type-specific expression and regulation during development and after neurotrauma. 1719 9

Autotaxin (ATX) is an autocrine motility factor that promotes cancer cell invasion, cell migration, and angiogenesis. ATX, originally discovered as a nucleotide phosphodiesterase, is known now to be responsible for the lysophospholipid-preferring phospholipase D activity in plasma. As such, it catalyzes the production of lysophosphatidic acid (LPA) from lysophophatidylcholine (LPC). ATX is thus an attractive drug target; small molecular inhibitors might be efficacious in slowing the spread of cancers. With this study we have generated a series of beta-keto and beta-hydroxy phosphonate derivatives of LPA, some of which are potent ATX inhibitors.
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PMID:Synthesis and biological evaluation of phosphonate derivatives as autotaxin (ATX) inhibitors. 1725 36

Autotaxin (ATX), or nucleotide pyrophosphatase-phosphodiesterase 2, is a secreted lysophospholipase D that generates bioactive phospholipids that act on G protein-coupled receptors. Here we show the expression patterns of the ATX gene in mouse and chicken embryos. ATX has a dynamic spatial and temporal expression pattern in both species and the expression domains during neural development are quite distinct from each other. Murine ATX (mATX) is expressed immediately rostral to the midbrain-hindbrain boundary, whereas chicken ATX (cATX) is expressed in the diencephalon and later in the parencephalon-synencephalon boundary. In the neural tube, cATX is expressed in the alar plate in contrast to mATX in the floor plate. ATX is also expressed in the hindbrain and various organ primordia such as face anlagen and skin appendages of the mouse and chicken. These results suggest conserved and non-conserved roles for ATX during neural development and organogenesis in these species.
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PMID:Diversified expression patterns of autotaxin, a gene for phospholipid-generating enzyme during mouse and chicken development. 1736 25

Autotaxin (ATX), or nucleotide pyrophosphatase/phosphodiesterase 2 (NPP2), is an exo-enzyme originally identified as a tumor cell autocrine motility factor. ATX is unique among the NPPs in that it primarily functions as a lysophospholipase D, converting lysophosphatidylcholine into the lipid mediator lysophosphatidic acid (LPA). LPA acts on specific G protein-coupled receptors to elicit a wide range of cellular responses, ranging from cell proliferation and migration to neurite remodeling and cytokine production. While LPA signaling has been studied extensively over the last decade, we are only now beginning to explore the properties and biological importance of ATX as the major LPA-producing phospholipase. In this review, we highlight recent advances in our understanding of the ATX-LPA axis, giving first an update on LPA action and then focusing on ATX, in particular its regulation, its link to cancer and its vital role in vascular development.
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PMID:Regulation and biological activities of the autotaxin-LPA axis. 1745 84


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