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

Phosphodiesterase‐Iα/autotaxin (PD‐Iα/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‐Iα/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‐Iα/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‐Iα/ATX's ascribed motogenic functions, i.e., its catalytic products. PD‐Iα/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‐Iα/ATX‐expressing CNS cells secrete catalytically active PD‐Iα/ATX into the extracellular environment. Thus, it appears reasonable to assume that PD‐Iα/ATX's CNS‐related functions are mediated via lysophospholipid, LPA and potentially S1P, signaling. However, recent studies identified PD‐Iα/ATX as a matricellular protein involved in the modulation of oligodendrocyte–extracellular matrix interactions and oligodendrocyte remodeling. This property of PD‐Iα/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‐Iα/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‐Iα/ATX's multifunctional roles in the CNS and discusses their potential contributions to CNS development and pathology. © 2005 Wiley‐Liss, Inc.