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Published online 15 July 2002. doi:10.1083/jcb.200204026
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© The Rockefeller University Press, 0021-9525/2002/7/227 $5.00
The Journal of Cell Biology, Volume 158, Number 2, July 22, 2002 227-233

Report

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



Makiko Umezu-Goto1, Yasuhiro Kishi1, Akitsu Taira1, Kotaro Hama1, Naoshi Dohmae2, Koji Takio2, Takao Yamori3, Gordon B. Mills4, Keizo Inoue1, Junken Aoki1 and Hiroyuki Arai1

1 Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
2 Biomolecular Characterization Division, The Institute of Physical and Chemical Research, 2-1, Hirosawa, Wako, Saitama 351-0198, Japan
3 Division of Molecular Pharmacology, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Toshima-ku, Tokyo 170-8455, Japan
4 Department of Molecular Therapeutics, MD Anderson Cancer Center, Houston, TX 77030

Address correspondence to Junken Aoki, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033 Japan. Tel.: 81-3-5841-4723. Fax: 81-3-3818-3173. E-mail: jaoki{at}mol.f.u-tokyo.ac.jp

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.

Key Words: lysoPLD; EDG receptor; lysophosphatidylcholine; chemotaxis; cell proliferation


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