Autotaxin has lysophospholipase D activity leading to tumor cell growth and motility by lysophosphatidic acid production

Abstract

Autotaxin (ATX) is a tumor cell motility–stimulating factor, originally isolated from melanoma cell supernatants. ATX had been proposed to mediate its effects through 5′-nucleotide pyrophosphatase and phosphodiesterase activities. However, the ATX substrate mediating the increase in cellular motility remains to be identified. Here, we demonstrated that lysophospholipase D (lysoPLD) purified from fetal bovine serum, which catalyzes the production of the bioactive phospholipid mediator, lysophosphatidic acid (LPA), from lysophosphatidylcholine (LPC), is identical to ATX. The Km value of ATX for LPC was 25-fold lower than that for the synthetic nucleoside substrate, p-nitrophenyl-tri-monophosphate. LPA mediates multiple biological functions including cytoskeletal reorganization, chemotaxis, and cell growth through activation of specific G protein–coupled receptors. Recombinant ATX, particularly in the presence of LPC, dramatically increased chemotaxis and proliferation of multiple different cell lines. Moreover, we demonstrate that several cancer cell lines release significant amounts of LPC, a substrate for ATX, into the culture medium. The demonstration that ATX and lysoPLD are identical suggests that autocrine or paracrine production of LPA contributes to tumor cell motility, survival, and proliferation. It also provides potential novel targets for therapy of pathophysiological states including cancer.

Cellular function and molecular structure of ecto-nucleotidases

“…An important step forward in understanding the functional role of NPP2 (autotaxin) was the discovery of its identity with lysophospholipase D in serum [374,375]. It converts extracellular LPC to lysophosphatidic acid (Fig.…”

Autotaxin–lysophosphatidic acid– LPA 3 signaling at the embryo‐epithelial boundary controls decidualization pathways

“…So far, six LPA‐specific GPCRs named LPA 1 ‐LPA 6 have been identified (Aikawa et al , 2015; Sheng et al , 2015). LPA is mainly synthesized from lysophospholipids such as lysophosphatidylcholine (LPC) by a secretory enzyme autotaxin (ATX; Umezu‐Goto et al , 2002). Studies of knock‐out (KO) mice and human genetic diseases of these LPA‐related genes have shown that LPA has various pathophysiological roles including angiogenesis (Yukiura et al , 2011), hair follicle formation (Inoue et al , 2011; Hayashi et al , 2015), bone development (Nishioka et al , 2016), and neural development (Yung et al , 2015).…”

Potential involvement of adipocyte insulin resistance in obesity-associated up-regulation of adipocyte lysophospholipase D/autotaxin expression

“…Autotaxin catalyses a lysophospholipase D-activity [2,4,5] leading to the hydrolysis of lysophosphatidylcholine (LPC) into lysophosphatidic acid (LPA), a bioactive phospholipid known to control several cellular events via activation of specific G-protein-coupled receptors [6].…”