Phosphodiesterase‐Iα/autotaxin (PD‐Iα/ATX): A multifunctional protein involved in central nervous system development and disease

Abstract

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.

Cellular function and molecular structure of ecto-nucleotidases

“…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].…”

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

“…ATX is detected in various biological fl uids and tissues, including plasma, placenta, ovary, small intestine ( 2 ), platelets ( 55 ), adipose tissue ( 56-59 ), nervous system ( 4,(60)(61)(62)(63), and cerebrospinal fl uid ( 64 ). In mice, both conditional gene knockout in adipose tissue and global Enpp2 heterozygosity result in a 50% decrease in ATX levels or activity in plasma ( 57 ), indicating that circulating ATX is predominately produced in adipose tissue, and further, that it is the primary enzyme responsible for maintaining circulating LPA levels.…”

Ectophosphodiesterase/nucleotide phosphohydrolase (Enpp) nucleotidases: cloning, conservation and developmental restriction

“…The expression in neural tissue is conserved during vertebrate evolution (Bächner et al, 1999;Ohuchi et al, 2007) suggesting that enpp2 is critical to both normal development and function of the nervous system. Human ENPP2 is involved in the secretion of cerebrospinal fluid, differentiation of oligodendrocytes but also in pathological conditions such as multiple sclerosis, neuropathic pain and Alzheimer-type dementia (ATD) (reviewed in Yuelling and Fuss, 2008;Dennis et al, 2005) Despite the importance of purine signalling in the nervous system, it seems that these neuronal functions are likely to be mediated by a novel domain located in the ENPP2 C-terminal region, the MORFO domain (Yuelling and Fuss, 2008). Mouse knock-outs for Enpp2 are embryonic lethal and therefore uninformative (Tanaka et al, 2006;van Meeteren et al, 2006) In Xenopus embryogenesis, enpp3 is strongly expressed during neurulation.…”