TY - JOUR
T1 - Autotaxin has lysophospholipase D activity leading to tumor cell growth and motility by lysophosphatidic acid production
AU - Umezu-Goto, Makiko
AU - Kishi, Yasuhiro
AU - Taira, Akitsu
AU - Hama, Kotaro
AU - Dohmae, Naoshi
AU - Takio, Koji
AU - Yamori, Takao
AU - Mills, Gordon B.
AU - Inoue, Keizo
AU - Aoki, Junken
AU - Arai, Hiroyuki
PY - 2002/7/22
Y1 - 2002/7/22
N2 - 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, ρ-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.
AB - 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, ρ-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.
KW - Cell proliferation
KW - Chemotaxis
KW - EDG receptor
KW - LysoPLD
KW - Lysophosphatidylcholine
UR - http://www.scopus.com/inward/record.url?scp=1542359873&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=1542359873&partnerID=8YFLogxK
U2 - 10.1083/jcb.200204026
DO - 10.1083/jcb.200204026
M3 - Article
C2 - 12119361
AN - SCOPUS:1542359873
SN - 0021-9525
VL - 158
SP - 227
EP - 233
JO - Journal of Cell Biology
JF - Journal of Cell Biology
IS - 2
ER -