The Autotaxin–LPA Axis Emerges as a Novel Regulator of Lymphocyte Homing and Inflammation

Knowlden, Sara A.; Georas, Steve N.

doi:10.4049/jimmunol.1302831

Cited by 153 publications

(157 citation statements)

References 80 publications

(104 reference statements)

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“…Many studies have established ATX as a key regulator of infl ammatory response at multiple levels that is required for proper maintenance of immune system homeostasis (129)(130)(131). For example, ATX binding to chemokine-activated lymphocytes is associated with increased immune cell homing to lymphoid vessels, and intravenous injection of enzymatically inactive ATX attenuates this process ( 132 ).…”

Section: Role In Physiology and Cancer Pathophysiologymentioning

confidence: 99%

Thematic Review Series: Phospholipases: Central Role in Lipid Signaling and Disease Autotaxin, a lysophospholipase D with pleomorphic effects in oncogenesis and cancer progression

Federico

Jeong

Vellano

et al. 2016

Journal of Lipid Research

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a 125 kDa glycoprotein composed of 915 amino acids ( 1 ). Because it promoted chemotaxis on melanoma cells in an autocrine fashion, the protein was aptly named auto-taxin. Four years after the discovery of the fi rst variant, now commonly referred to as ATX ␣ , or melanoma ATX, a second isoform was cloned by the same team from the teratocarcinoma cell line, Ntera2D1. This polypeptide shared 94% identity with the melanoma protein and was immediately recognized as the alternatively spliced product of the same gene ( 2 ).The initial characterization of the fi rst isoform revealed that ATX biological activity was sensitive to pertussis toxin treatment. Furthermore, not only did the polypeptide share close homology with the murine pyrophosphatase/ type I phosphodiesterase (PDE) PC-1, including a threonine residue crucial for PDE enzymatic activity, but it was also able to hydrolyze PDE substrates in vitro ( 3 ). The confi rmation that ATX was an enzyme came when a new PDE, the PDE1/nucleotide pyrophosphatase (PD-1 ␣ /PDNP 2), was cloned from a cDNA library of human retina and found to be identical to the sequence of melanoma ATX ␣ with the exception of a missing stretch of 52 amino acids encoded by exon 12 in the central region of the open reading frame. The transcript of this variant, now frequently referred to as ATX ␤ , or teratoma ATX, produced a 863 amino acid polypeptide chain with a mass of 99,034 Da ( 4 ), and was independently isolated a few years later in mouse tissues ( 5 ). The third ATX isoform was detected for the fi rst time in rat brain, but was originally designated as PD-I ␣ , a brain-specifi c PDE I/nucleotide pyrophosphatase ( 6 ). Further research showed that PD-I ␣ was identical to ATX ␤ teratoma protein, except for the presence of an additional stretch of 25 amino acids encoded by an alternatively Abstract The ectonucleotide pyrophosphatase/phosphodiesterase type 2, more commonly known as autotaxin (ATX), is an ecto-lysophospholipase D encoded by the human ENNP2 gene. ATX is expressed in multiple tissues and participates in numerous key physiologic and pathologic processes, including neural development, obesity, infl ammation, and oncogenesis, through the generation of the bioactive lipid, lysophosphatidic acid. Overwhelming evidence indicates that altered ATX activity leads to oncogenesis and cancer progression through the modulation of multiple hallmarks of cancer pathobiology. Here, we review the structural and catalytic characteristics of the ectoenzyme, how its expression and maturation processes are regulated, and how the systemic integration of its pleomorphic effects on cells and tissues may contribute to cancer initiation, progression, and therapy. Additionally, the up-to-date spectrum of the most frequent ATX genomic alterations from The Cancer Genome Atlas project is reported for a subset of cancers. ( Fig. 1 ). In 1992, the fi rst alternatively spliced isoform was cloned from the melanoma cell line, A2058, and characterized as STRUCTURE AND ENZYMATIC ACTIVITY ATX belongs to the nuc...

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Section: Role In Physiology and Cancer Pathophysiologymentioning

confidence: 99%

Thematic Review Series: Phospholipases: Central Role in Lipid Signaling and Disease Autotaxin, a lysophospholipase D with pleomorphic effects in oncogenesis and cancer progression

Federico

Jeong

Vellano

et al. 2016

Journal of Lipid Research

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“…36,37 Emerging data indicate that the ATX/LPA axis is implicated in fueling many inflammatory diseases, including asthma, pulmonary fibrosis, rheumatoid arthritis, obesity, atherosclerosis, neuropathic pain, hepatitis, and inflammatory bowel disease. 37,51 It was generally acknowledged that neoplastic diseases often arise at sites of persistent inflammation and several inflammatory conditions, and overwhelming evidence indicates that altered ATX/LPA axis leads to tumorigenesis and progression through the modulation of multiple hallmarks of cancer pathobiology. [4][5][6][7][27][28][29]37,52 This section will focus on the roles of the ATX/LPA axis in cancer pathophysiology (Figure 1).…”

Section: Atx/lpa Axismentioning

confidence: 99%

“…It seems apparent that the ATX/LPA axis emerges as a novel regulator of lymphocyte homing and inflammation. 37,51 Role of ATX/LPA axis in cancer pathophysiology. Aberrant ATX/LPA axis has been associated with multiple signaling pathways including inflammation and carcinogenesis.…”

Section: Atx/lpa Axismentioning

confidence: 99%

The critical role and potential target of the autotaxin/lysophosphatidate axis in pancreatic cancer

et al. 2017

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Autotaxin, an ecto-lysophospholipase D encoded by the human ENNP2 gene, is expressed in multiple tissues, and participates in numerous critical physiologic and pathologic processes including inflammation, pain, obesity, embryo development, and cancer via the generation of the bioactive lipid lysophosphatidate. Overwhelming evidences indicate that the autotaxin/lysophosphatidate signaling axis serves key roles in the numerous processes central to tumorigenesis and progression, including proliferation, survival, migration, invasion, metastasis, cancer stem cell, tumor microenvironment, and treatment resistance by interacting with a series of at least six G-protein-coupled receptors (LPAR1-6). This review provides an overview of the autotaxin/lysophosphatidate axis and collates current knowledge regarding its specific role in pancreatic cancer. With a deeper understanding of the critical role of the autotaxin/lysophosphatidate axis in pancreatic cancer, targeting autotaxin or lysophosphatidate receptor may be a potential and promising strategy for cancer therapy.

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“…LPAs are extracellular and intracellular molecules that are synthesized from their corresponding lysophosphatidylcholine (LPC) precursors by a secreted lysophospholipase D ( 24 ) known as autotaxin ( 23,25 ). The relationship between LPAs and TSGs is poorly understood, except for the interaction of p53 and LPA in the regulation of hypoxia-inducible factor 1 ␣ ( 26 ).…”

Section: Untargeted Metabolomics and Lipidomics And Targeted Quantitamentioning

confidence: 99%

Disruption of tumor suppressor gene Hint1 leads to remodeling of the lipid metabolic phenotype of mouse liver

Beyoğlu

Krausz

Martin

et al. 2014

Journal of Lipid Research

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The Autotaxin–LPA Axis Emerges as a Novel Regulator of Lymphocyte Homing and Inflammation

Cited by 153 publications

References 80 publications

Thematic Review Series: Phospholipases: Central Role in Lipid Signaling and Disease Autotaxin, a lysophospholipase D with pleomorphic effects in oncogenesis and cancer progression

Thematic Review Series: Phospholipases: Central Role in Lipid Signaling and Disease Autotaxin, a lysophospholipase D with pleomorphic effects in oncogenesis and cancer progression

The critical role and potential target of the autotaxin/lysophosphatidate axis in pancreatic cancer

Disruption of tumor suppressor gene Hint1 leads to remodeling of the lipid metabolic phenotype of mouse liver

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