Mechanism of Iyshosphatidic acid production.

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Autotaxin (ATX) is a tumor cell motility-stimulating factor, originally identified from melanoma cell supernatants. ATX also possesses 5^1-nucleotide pyrophosphatase and phosphodiesterase activities and the catalytic activity is a prerequisit for inducing cell motility. However, the ATX substrate essential for the activity has not been described. Here, we demonstrated that lysophospholipase D(lysoPLD) purified from fetal bovine serum catalyzing the production of the bioactive phospholipid mediator, lysophosphatidic acid (LPA), from lysophosphatidylcholine (LPC) is identical to ATX. The Km value for LPC was 25-fold higher than that for a synthetic substrate p-nitrophenyl-tri-monophosphate. LPA mediates multiple biological functions including cytoskeletal reorganization, chemotaxis and cell growth. Recombinant ATX, particularly in the presence of LPC, dramatically increased chemotaxis and proliferation of cancer cells. Moreover, we demonstrated that several cancer cells release significant amounts of LPC, a substrate for ATX into the culture medium. These data suggest the presence of ATX-mediated autocrine LPA production in certain cancer cells supporting their growth and motility.