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

Abstract

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...

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

“…One such mechanism that has received adequate attention in recent years is the autotaxin/lysophosphatidate (ATX/LPA) axis, because increasing evidence shows that the ATX/LPA axis plays critical roles in numerous processes central to tumorigenesis and progression, including proliferation, survival, migration, invasion, metastasis, cancer stem cell (CSC), tumor microenvironment, and treatment resistance. [4][5][6][7] Some promising studies are underway to access the therapeutic potential of ATX inhibitor and/or lysophosphatidate receptor (LPAR) antagonists. 8 Here, the authors review current studies, focusing on the impact of the ATX/LPA axis in pancreatic cancer and the potential use of targeting the ATX/LPA circuits on pancreatic cancer therapy.…”

Autotaxin signaling, purinergic receptors and lung damage

“…In further studies these questions will be addressed. The involvement of ATX in wound healing [4] and cell motility [7,19] suggests additional roles for ATX in the bronchial tissue remodeling seen in occupational asthma [20] . So also the remodeling should be studied in this connection.…”

“…Several studies indicate a role for the ATX-LPA axis in inflammatory conditions of the lung such as asthma [2] and idiopathic lung fibrosis [3] , but also in wound healing [4] , rheumatoid arthritis [5,6] and in linking inflammation and carcinogenesis in e.g. mammary cancer [7] .…”

“…A recent review by Mills and colleagues summarizes evidence indicating a role for increased ATX levels in carcinogenesis. For example, amplifications of the ATX gene, ENPP2, is a common genomic alteration in several human cancer types including mammary and lung adenocarcinoma, and transgenic overexpression of ATX or LPA receptors causes mammary cancer in mice [7] . We would like to highlight gender aspects of ATX expression in connection to its assumed role in human carcinogenesis.…”

Introduction to Thematic Review Series: Phospholipases: Central Role in Lipid Signaling and Disease

“…Gordon Mills and colleagues at the MD Anderson Cancer Center at the University of Texas in Houston have reviewed those PLD enzymes acting on lysophospholipids in their paper titled " Autotaxin, a lysophospholipase D with pleomorphic effects in oncogenesis and cancer progression " ( 17 ).…”