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evolution
mouse and human enzymes show high structural homology
evolution
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the enzyme belongs to the ENPP family, but ATX/ENPP2 is a unique lysoPLD with no functional redundancy within the ENPP family, overview. The enzyme and its ENPP family members can be divided into two main subgroups, namely ENPP1-3 and ENPP4-7. ATX/ENPP2 and its closest relatives, ENPP1 and ENPP3, have two N-terminal somatomedin B (SMB)-like domains, a central phosphodiesterase (PDE) domain and a C-terminal nuclease (NUC)-like domain. The second subgroup (ENPP4-7) has only the PDE domain in common. ATX/NPP2 is a secreted protein, while the other ENPPs are transmembrane proteins, either type-I (ENPP4-7) or type-II (ENPP1-3)
malfunction
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down-regulation of endogenous autotaxin expression in 4T1 cells inhibits osteolytic bone metastasis formation independently of primary tumor growth in vivo
malfunction
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E9.5 ATX null mutants exhibit a failure of neural tube closure, most likely independent of the circulatory failure, which correlates with decreased cell proliferation and increased cell death, obligatory deletion results to embryonic lethality most likely due to aberrant vascular branching morphogenesis and chorio-allantoic fusion
malfunction
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in Enpp2 knockout mouse embryos, lysosomes in the visceral endoderm cells are fragmented
malfunction
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a recombinant ATX mutant, lacking lysoPLD activity, or heat-inactived ATX also induces lung epithelial cell migration
malfunction
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ATX SMB2 mutants with impaired binding to beta3 integrins display reduced LPA generating capacity. Mutation of a charged, surface-exposed residue at the N-terminus of the ATX SMB2 domain significantly reduces binding of ATX to platelet integrins. The effects of ATX on platelet and cell-associated LPA production, but not hydrolysis of small molecule or detergent-solubilized substrates, are attenuated by point mutations in the SMB2 that impair integrin binding
malfunction
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knockdown of ATX in zebrafish embryos causes abnormal blood vessel formation. In ATX morphant embryos, the segmental arteries sprouted normally from the dorsal aorta but stalled in the mid-course resulting in aberrant vascular connection around the horizontal myoseptum
malfunction
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adipocyte-specific knockout FATX-KO mice or mice treated with the lysophosphatidic acid receptor antagonist Ki16425 gain more weight and accumulate more adipose tissue than wild-type or control mice fed a high fat diet
malfunction
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ATX inhibitor bithionol remarkably decreases lymphocyte migration to the intestine and ameliorates both dextran sodium sulfate-induced colitis and CD4-induced ileocolitis, administration of bithionol or 1-bromo-3(s)-hydroxy-4-(palmitoyloxy) butylphosphonate significantly decreases transmigration of splenocytes through high-endothelial-like vessels induced by TNF-alpha
malfunction
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fasting decreases enzyme activity. Nutritional deficiency of 18 : 2- and 18 : 1-containing phosphatidylcholines causes selective reduction of corresponding unsaturated lysophosphatidylcholines relative to other species in the blood circulation. Prolonged fasting of rats causes a greater decrease in the level of lysophosphatidylcholine in the liver than that of phosphatidylethanolamine
malfunction
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ATX inhibitor bithionol remarkably decreases lymphocyte migration to the intestine and ameliorates both dextran sodium sulfate-induced colitis and CD4-induced ileocolitis, administration of bithionol or 1-bromo-3(s)-hydroxy-4-(palmitoyloxy) butylphosphonate significantly decreases transmigration of splenocytes through high-endothelial-like vessels induced by TNF-alpha
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malfunction
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fasting decreases enzyme activity. Nutritional deficiency of 18 : 2- and 18 : 1-containing phosphatidylcholines causes selective reduction of corresponding unsaturated lysophosphatidylcholines relative to other species in the blood circulation. Prolonged fasting of rats causes a greater decrease in the level of lysophosphatidylcholine in the liver than that of phosphatidylethanolamine
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malfunction
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knockdown of ATX in zebrafish embryos causes abnormal blood vessel formation. In ATX morphant embryos, the segmental arteries sprouted normally from the dorsal aorta but stalled in the mid-course resulting in aberrant vascular connection around the horizontal myoseptum
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metabolism
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in contrast to the decreased plasma enzyme activity in fasted rats, lysophosphatidic acid production from lysophosphatidylcholine by the enzyme activity progressively increases
metabolism
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in contrast to the decreased plasma enzyme activity in fasted rats, lysophosphatidic acid production from lysophosphatidylcholine by the enzyme activity progressively increases
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physiological function
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ATX expression and lysophosphatidic acid signalling are vital for the development of the nervous system, ATX and lysophosphatidic acid are necessary for embryonic HIF-1a expression
physiological function
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ATX promotes the migrations of THP-1 and Jurkat cells via Gi-signaling pathway
physiological function
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autotoxin promotes metastasis and tumor growth
physiological function
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constitutive activationof the Rho-ROCK-LIM kinase pathway by extracellular production of lysophosphatidic acid by the action of autotaxin is required to maintain the large size of lysosomes in visceral endoderm cells
physiological function
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expression of autotaxin by cancer cells controls osteolytic bone metastasis formation
physiological function
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expression of autotaxin by cancer cells controls osteolytic bone metastasis formation
physiological function
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the autotaxin-lysophosphatidic acid receptor axis plays a causal role in breast tumorigenesis and cancer-related inflammation
physiological function
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the enzyme controls the blood concentration of lysophosphatidic acid
physiological function
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ATX moderately facilitates platelet adhesion to fibrinogen, synergistic effect of platelet activation and ATX on LPA generation. ATX binding to platelet integrins enables agonist-stimulated LPA production. The lysophospholipase D generates the bioactive lipid mediator lysophosphatidic acid. Integrin-bound ATX can access cell surface substrates and deliver LPA to cell surface receptors
physiological function
ATX promotes localized LPA signaling
physiological function
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ATX stimulates tumour-cell migration, angiogenesis and metastasis
physiological function
autotaxin exhibits lysophospholipase D activity, hydrolyzing lysophosphatidylcholine to the signalling lipid lysophosphatidic acid
physiological function
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autotaxin is a catalytic protein, which possesses lysophospholipase D activity producing lysophosphatidic acid, and is involved in cellular membrane lipid metabolism and remodeling. It acts as a culprit protein for cancer, which potently stimulates cancer cell proliferation and tumor cell motility, augments the tumorigenicity and induces angiogenic responses. Lysophosphatidic acid is a potent mitogen, which facilitates cell proliferation and migration, neurite retraction, platelet aggregation, smooth muscle contraction, actin stress formation and cytokine and chemokine secretion. ATX also catalyzes the formation of cyclic phosphatidic acid, which have antitumor role by antimitogenic regulation of cell cycle, inhibition of cancer invasion and metastasis
physiological function
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autotaxin is a multifunctional ecto-type phosphodiesterase that converts lysophospholipids such as lysophosphatidylcholine to lysophosphatidic acid by its lysophospholipase D activity. ATX has an essential role in embryonic blood vessel formation. Autotaxin is required for the development of intersegmental arteries in zebrafish
physiological function
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autotaxin is a secreted lysophospholipase D that hydrolyzes lysophosphatidylcholine into lysophosphatidic acid, initiating signaling cascades leading to cancer metastasis, wound healing, and angiogenesis
physiological function
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autotaxin is a secreted lysophospholipase D that hydrolyzes lysophosphatidylcholine to generate lysophosphatidic acid, a lipid mediator that activates G protein-coupled receptors to evoke various cellular responses. The produced LPAs are delivered from the active site to cognate G protein-coupled receptors through a hydrophobic channel
physiological function
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autotaxin is a secreted soluble enzyme that generates lysophosphatidic acid through its lysophospholipase D activity
physiological function
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autotaxin is an enzyme present in the blood and responsible for biosynthesis of lysophosphatidic acid
physiological function
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GDE1 has a weak activity to generate N-palmitoylethanolamine from its corresponding 1-alkenyl-2-hydroxy-glycero-3-phospho(N-acyl)ethanolamines, suggesting that this enzyme is at least in part responsible for the lysophospholipase D activity in mouse brain
physiological function
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lysophospholipase D hydrolyzes lysophosphatidylcholine to form the bioactive lipid lysophosphatidic acid
physiological function
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secreted autotaxin, which exhibits lysophospholipase D activity, stimulates lung epithelial cell migration through lysophosphatidic acid generation-dependent and -independent pathways lung cell migration is a crucial step for re-epithelialization that in turn is essential for remodelling and repair after lung injury, overview. Extracellular ATX stimulates cell migration through G?i-coupled LPA receptors, cytoskeleton rearrangement, phosphorylation of PKC delta and cortactin at the leading edge of migrating cells. Cortactin regulates ATX-V5-induced cell migration
physiological function
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Heminecrolysin induces erythrocyte hemolysis via lysophospholipase D activity. Heminecrolysin efficiently binds to erythrocyte's membrane and provokes phosphatidylserine translocation without cleavage of glycophorin A, suggesting that, unlike spider's phospholipase D, complement is activated only via the classical pathway. Heminecrolysin induces pro-inflammatory cytokine release and causes necrosis in the vascular tissue
physiological function
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in a dextran sodium sulfate mouse model, the enzyme expression level is considerably higher in colonic mucosa of chronically developed colitis than in colonic mucosa of acute colitis. The enzyme is required for lymphocyte transmigration, but not for surface expression of b7-integrin and CD11beta on splenocytes that migrated through epithelial cells. The role of the ATX-LPA axis in leukocyte transendothelial migration through induced high endothelial venule-like vessels has no tropism for surface expression of adhesion molecules on leukocytes
physiological function
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the enzyme and its reaction product lysophosphatidic acid have a critical role in lymphocyte migration to secondary lymphoid organs, involvement of the enzyme in inflammatory bowel disease patients, the enzyme/lysophosphatidic acid has a role in the migration of lymphocytes to the inflamed intestine
physiological function
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the enzyme is constitutively released from corneal tissues and/or ciliary body into the aqueous humor, with no injury-induced increase in release following freeze-wounding. Wound-induced increases in lysophosphatidic acid-like biological activity are due to linoleoyl species-rich molecular composition in aqueous humor from wounded eyes, possible mechanisms, overview
physiological function
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the enzyme is involved in synthesis of lysophosphatidic acid, a phospholipid growth factor acting via lysophosphatidic acid-specific receptors (LPA1R to LPA6R) and involved in several pathologies including obesity. Enzyme expression is up-regulated in obese patients and mice in relationship with insulin resistance and impaired glucose tolerance. Lysophosphatidic acid-specific receptor LPA1R is the most abundant receptor subtype in adipose tissue. Its expression is higher in non-adipocyte cells than in adipocytes and is not altered in obesity. The enzyme increases and receptor LPA1R decreases while preadipocytes differentiate into adipocytes (adipogenesis). Lysophosphatidic acid inhibits adipogenesis through down-regulation of the pro-adipogenic transcription factor PPARgamma2. ATX/LPA signaling impairs glucose homeostasis, regulation of obesity involves the enzyme, overview
physiological function
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the enzyme is involved in synthesis of lysophosphatidic acid, a phospholipid growth factor acting via specific receptors (LPA1R to LPA6R) and involved in several pathologies including obesity. ATX/LPA signaling impairs glucose homeostasis, regulation of obesity involves the enzyme, overview
physiological function
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the enzyme is involved in the formation of blood vessel networks in fertilized hen egg white through several lysophosphatidic acid receptors on various extraembryonic membranes, including the yolk sac membrane and chorioallantoic membrane
physiological function
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the enzyme is the major lysophosphatidic acid-producing enzyme being involved in a great diversity of (patho)physiological processes. Enzyme-produced lysophosphatidic acid acts on distinct G protein-coupled receptors thereby activating multiple signaling cascades and cellular responses. The ATX-LPA signaling axis is implicated in a remarkably wide variety of physiological and pathological processes, ranging from vascular and neural development to lymphocyte homing, fibrosis and cancer
physiological function
the enzyme is the predominant contributor to lysophosphatidic acid production in the human body, especially in the blood, and therefore has important roles in various physiological functions, including development of vasculature and lymphocyte trafficking
physiological function
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the enzyme is the primary lysophosphatidic acid-producing phospholipase. Enzyme-lysophosphatidic acid signaling is essential for development and has been implicated in a great diversity of (patho)physiological processes, ranging from lymphocyte homing to tumor progression. Isozyme ATX alpha but not ATX beta binds abundantly to cultured mammalian cells in a manner strictly dependent on heparan sulfate. By mediating bindings to heparan sulfate proteoglycans, the isozyme ATXalpha insertion loop likely serves to target LPA production close to the lysophosphatidic acid receptors
physiological function
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the enzyme is the primary lysophosphatidic acid-producing phospholipase. Enzyme-lysophosphatidic acid, ATX-LPA, signaling is essential for development and has been implicated in a great diversity of (patho)physiological processes, ranging from lymphocyte homing to tumor progression. Isozyme ATX alpha but not ATX beta binds abundantly to cultured mammalian cells in a manner strictly dependent on heparan sulfate. By mediating bindings to heparan sulfate proteoglycans, the isozyme ATXalpha insertion loop likely serves to target LPA production close to the lysophosphatidic acid receptors
physiological function
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the enzyme promotes MDA-MB-231 breast cancer cell and mouse aortic vascular smooth muscle cell migration in lysophosphatidic acid-dependent and -independent ways, overview. The enzyme binds to integrin adhesion receptors required for cell migration. Integrin-mediated cell surface binding results in enzyme uptake and intracellular trafficking, critical for the ability of the enzyme to promote rapid directionally persistent MDA-MB-231 cell migration
physiological function
GDE4 functions as an N-acylethanolamine-generating lysophospholipase D in living cells. The expression of GDE4 increases the levels of most species of lysophosphatidic acid in the cell
physiological function
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in a dextran sodium sulfate mouse model, the enzyme expression level is considerably higher in colonic mucosa of chronically developed colitis than in colonic mucosa of acute colitis. The enzyme is required for lymphocyte transmigration, but not for surface expression of b7-integrin and CD11beta on splenocytes that migrated through epithelial cells. The role of the ATX-LPA axis in leukocyte transendothelial migration through induced high endothelial venule-like vessels has no tropism for surface expression of adhesion molecules on leukocytes
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physiological function
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GDE1 has a weak activity to generate N-palmitoylethanolamine from its corresponding 1-alkenyl-2-hydroxy-glycero-3-phospho(N-acyl)ethanolamines, suggesting that this enzyme is at least in part responsible for the lysophospholipase D activity in mouse brain
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physiological function
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autotaxin is a multifunctional ecto-type phosphodiesterase that converts lysophospholipids such as lysophosphatidylcholine to lysophosphatidic acid by its lysophospholipase D activity. ATX has an essential role in embryonic blood vessel formation. Autotaxin is required for the development of intersegmental arteries in zebrafish
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additional information
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a loop region in the catalytic domain is a major determinant for the substrate specificity of the Enpp family enzymes, Asn230 is critical for the recognition of the common phosphate moieties, structure of the ATX active site in the free-form and with bound Zn2+, overview
additional information
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ATX interacts with integrins, possible role for the solvent-exposed surface of the N-terminal tandem somatomedin B-like domains in binding to platelet integrin alphaIIbbeta3. The opposite face of the somatomedin B-like domain interacts with the catalytic phosphodiesterase domain to form a hydrophobic channel through which lysophospholipid substrates enter and leave the active site. Integrin binding therefore localizes ATX activity to the cell surface, providing a mechanism to generate LPA in the vicinity of its receptors
additional information
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extracelluar ATX binds to the LPA receptor and integrin beta4 complex on A-549 cell surface
additional information
structural basis of substrate discrimination and integrin binding by autotaxin, ATX, that interacts with cell-surface integrins via its N-terminal somatomedin-B-like domains, using an atypical mechanism, overview
additional information
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the ability of ATX to drive cell migration is enhanced by the presence of the ATX substrate lysophosphocholine
additional information
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the predicted nucleotide phosphate and Mg2+ binding sites of the protein are important for lysoPLD enzymatic activity
additional information
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Thr210 coordinates one of the two catalytic zinc ions and hydrogen bonds with the phosphate or sulfate in the active site. Kinetics of ATX depend strongly on the substrate identity, suggesting that ATX could display different kinetic profiles for the various in vivo substrates
additional information
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enzyme crystal structure analysis, phosphodiesterase domain and substrate binding pocket, overview, the enzyme structure is a tunnel that spans from the active site location to the opposite side of ATX. It is formed from the interaction between the SMB1 and the PDE domain. The tunnel may function as an lysophosphatidic acid binding site and, by inference, a product release site
additional information
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Heminecrolysin does not affect glycophorin A expression
additional information
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the catalytic domain shows shallow groove and a deep hydrophobic pocket, and an open tunnel, which forms a sort of T-junction with the shallow groove, substrate binding structure, overview. The enzyme contains a SMB domain that mediates the binding to cell surface integrins
additional information
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the tripartite catalytic domain shows shallow groove and a deep hydrophobic pocket, and an open tunnel, which forms a sort of T-junction with the shallow groove, substrate binding structure, overview. The enzyme contains a SMB domain that mediates the binding to cell surface integrins