Autotaxin (ATX): A multi-functional and multi-modular protein possessing enzymatic lysoPLD activity and matricellular properties

Yuelling, Larra M.; Fuss, Babette

doi:10.1016/j.bbalip.2008.04.009

Cited by 72 publications

(60 citation statements)

References 94 publications

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“…A brainspecific variant (PD-Iα/ATXγ) is found almost exclusively on the myelin forming oligodendrocytes of the brain [346]. It acts in the modulation of oligodendrocyte extracellular matrix interactions and oligodendrocyte remodeling, a property independent of its catalytic activity [347,348].…”

Section: General Properties and Functional Rolementioning

confidence: 99%

“…Three different isoforms have been characterized that differ in length and tissue distribution [344,406]. The nomenclature of the isoforms varies between authors [343,344,348,406]. The largest isoform (ATXm, ATXα), the human melanomaderived autotaxin [403], comprises 915 aa and contains a highly basic insertion in the catalytic domain.…”

Section: General Molecular Propertiesmentioning

confidence: 99%

“…Process outgrowth was found to be mediated in part via the EF hand-like motif located at the far C-terminal end of the MORFO domain. It is hypothesized that the MORFO-EF site binds to a cell surface receptor [348,434].…”

Section: Protein Interactionsmentioning

confidence: 99%

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Cellular function and molecular structure of ecto-nucleotidases

Zimmermann

Zebisch

Sträter

2012

Purinergic Signalling

888

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 Molecular Propertiesmentioning

confidence: 99%

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Cellular function and molecular structure of ecto-nucleotidases

Zimmermann

Zebisch

Sträter

2012

Purinergic Signalling

888

922

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“…Enpp2, also designated autotaxin, phosphodiesterase I a/autotaxin, and nucleotide pyrophosphatase/phosphodiesterase 2, was originally discovered as an autocrine motility-stimulating factor released from cancer cells (3). ENPP2 catalyzes the conversion of lysophosphatidylcholine to lysophosphatidic acid (LPA), which exerts a variety of biological effects, in part via G-protein-coupled receptors (3,4).…”

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confidence: 99%

ENPP2 Contributes to Adipose Tissue Expansion and Insulin Resistance in Diet-Induced Obesity

et al. 2014

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Body weight is tightly regulated by food intake and energy dissipation, and obesity is related to decreased energy expenditure (EE). Herein, we show that nucleotide pyrophosphatase/phosphodiesterase 2 (ENPP2, autotaxin) is an adipose-derived, secreted enzyme that controls adipose expansion, brown adipose tissue (BAT) function, and EE. In mice, Enpp2 was highly expressed in visceral white adipose tissue and BAT and is downregulated in hypertrophied adipocytes/adipose tissue. Enpp2 +/2 mice and adipocyte-specific Enpp2 knockout mice fed a highfat diet showed smaller body weight gains and less insulin resistance than control mice fed the same diet. BAT was functionally more active and EE was increased in Enpp2-deficient mice. In humans, ENPP2 expression in subcutaneous fat and ENPP2 levels in serum were reduced in obese subjects. Taken together, our results establish ENPP2 as an adipose-derived, secreted enzyme that regulates adipose obesity and systemic metabolism. They also suggest ENPP2 could be a useful therapeutic target for the treatment of metabolic disease.Until recently, adipose tissue was viewed as a passive energy storage organ, but with the discovery of leptin and the adipose-derived humoral factors now known as "adipokines," it has become apparent that adipose tissue is an active endocrine organ that is essential for energy homeostasis (1). Moreover, obese adipose tissue secretes various inflammatory cytokines, including interleukin-6 (IL-6) and tumor necrosis factor-a (TNF-a), whose activities are known to contribute to the development of metabolic and cardiovascular diseases (2).Enpp2, also designated autotaxin, phosphodiesterase I a/autotaxin, and nucleotide pyrophosphatase/phosphodiesterase 2, was originally discovered as an autocrine motility-stimulating factor released from cancer cells (3). ENPP2 catalyzes the conversion of lysophosphatidylcholine to lysophosphatidic acid (LPA), which exerts a variety of biological effects, in part via G-protein-coupled receptors (3,4). In addition, the COOH-terminal noncatalytic domain of ENPP2 also has biological effects independent of LPA (3). Homozygous Enpp2-deficient mice die in utero due to profound vascular defects, but heterozygous Enpp2-deficient (Enpp2 +/2 ) mice are apparently healthy, with plasma LPA levels about half those in wild-type (WT) mice (5). Enpp2 is reportedly expressed in mouse adipose tissue and 3T3-F442A preadipocytes, and medium conditioned by Enpp2-expressing COS7 cells increased proliferation of 3T3-F442A cells. Recently, Dusaulcy et al. (6) reported that adipocytespecific Enpp2 knockout (KO) mice fed a high-fat diet showed greater adiposity and less systemic insulin resistance

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“…[99][100][101][102] A functionally active, non-catalytic domain of ATX mediates the matricellular and anti-adhesive role of this glycoprotein, which possesses heparin-binding properties. 103 The crystal structure of ATX has been elucidated, and its catalytic activity domain is well characterized. 79,98,100,104 Based on the elevated levels of ATX in various pathological conditions, this protein has been considered a promising therapeutic target for inflammation, fibrosis, and cancer.…”

Section: Lysophospholipids In Regulation Of Ah Outflow and Iopmentioning

confidence: 99%

Bioactive Lysophospholipids: Role in Regulation of Aqueous Humor Outflow and Intraocular Pressure in the Context of Pathobiology and Therapy of Glaucoma

Rao

2014

Journal of Ocular Pharmacology and Therapeutics

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Homeostasis of aqueous humor (AH) outflow and intraocular pressure (IOP) is essential for normal vision. Impaired AH outflow through the trabecular meshwork (TM) and a resultant elevation in IOP are common changes in primary open-angle glaucoma (POAG), which is the most prevalent form of glaucoma. Although elevated IOP has been recognized as a definitive risk factor for POAG and lowering elevated IOP remains a mainstay for glaucoma treatment, little is known about the molecular mechanisms, especially external cues and intracellular pathways, involved in the regulation of AH outflow in both normal and glaucomatous eyes. In addition, despite the recognition that increased resistance to AH outflow via the conventional pathway consisting of TM and Schlemm's canal is the main cause for elevated IOP, there are no clinically approved drugs that target the conventional pathway to lower IOP in glaucoma patients. The aim of this article is to briefly review published work on the importance of bioactive lysophospholipids (eg, lysophosphatidic acid and sphingosine-1-phosphate), their receptors, metabolism, signaling, and role in the regulation of AH outflow via the TM and IOP, and to discuss pharmacological targeting of key proteins in the lysophospholipid signaling pathways to lower IOP in glaucoma patients.

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Autotaxin (ATX): A multi-functional and multi-modular protein possessing enzymatic lysoPLD activity and matricellular properties

Cited by 72 publications

References 94 publications

Cellular function and molecular structure of ecto-nucleotidases

Cellular function and molecular structure of ecto-nucleotidases

ENPP2 Contributes to Adipose Tissue Expansion and Insulin Resistance in Diet-Induced Obesity

Bioactive Lysophospholipids: Role in Regulation of Aqueous Humor Outflow and Intraocular Pressure in the Context of Pathobiology and Therapy of Glaucoma

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