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

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.