J. Biol. Chem., published online 13 November 2012, doi:10.1074/jbc.M112.358416

Credit: ANASTASSIS PERRAKIS

The secreted lysophospholipase autotaxin (ATX) is responsible for synthesizing lysophosphatidic acid (LPA), with numerous cellular outcomes. Most ATX research has focused on the β isoform, but three other isoforms are known to be produced, depending on which of the gene's 27 exons are translated. ATXα includes a polybasic 52-residue insert, thought to confer proteolytic instability to the protein. Houben et al. now demonstrate that although the insert is cleaved, most likely at a furin consensus site, this cleavage neither has an impact on protein stability nor affects enzyme activity. The authors also show that ATXα has similar kinetics to ATXβ and is equally sensitive to an ATX inhibitor, raising the question of why this inserted domain is present. Further inspection of the inserted sequence pointed to the presence of potential heparin-binding motifs; these were validated by the strong interaction of ATXα with unfractionated heparin, with an apparent Kd of 10 nM according to surface plasmon resonance, whereas ATXβ showed almost no binding. This effect was mirrored by the ability of ATXα, but not ATXβ, to bind the surface of glycosaminoglycan-expressing cells in a heparinase-sensitive manner. Surprisingly, heparin also increased ATXα activity by up to two-fold. Though ATX is known to be targeted to the cell membrane by integrin binding, these results point to a second, isoform-specific targeting mechanism that both localizes and activates ATXα to optimize LPA signaling.