Autotaxin (lysoPLD/NPP2) protects fibroblasts from apoptosis through its enzymatic product, lysophosphatidic acid, utilizing albumin-bound substrate.
Autotaxin (ATX) was originally identified as a potent tumor cell motility-stimulating factor that displays multiple enzymatic activities including ATPase, Type I nucleotide pyrophosphatase/phosphodiesterase, and lysophospholipase D, depending on its substrates. We demonstrate herein that ATX is a key regulator of extracellular lysophosphatidic acid (LPA) that can act as survival factor, in addition to its mitogenic activity in mouse fibroblasts. Introduction of atx gene into NIH3T3 cells resulted in resistance to conditional apoptosis induced by serum-deprivation, and exogenous ATX protein prevented cells from death by starvation. Flow cytometric analysis showed that co-treatment of ATX with lysophosphatidylcholine as substrate rescued NIH3T3 cells from cellular apoptosis, and this survival activity of ATX was also demonstrated by caspase-3 degradation and PARP cleavage resulting from the enzymatic activity of extracellular ATX. Furthermore, the effect of ATX in preventing apoptosis appears to be mediated through the G-protein-coupled receptor pathway followed by the activation of phosphoinositide 3-kinase and Akt pathway leading to enhanced cell survival. These findings provide novel insights into understanding the functions of ATX as a key regulator of bioactive phospholipids and suggest interventions to correct dysfunction in conditions of tumor cell growth and metastasis.
Song
Jaehwi
J
Department of Pathology, College of Medicine and Microdissection Genomics Research Center, The Catholic University of Korea, Banpo-dong number 505, Seocho-gu, Seoul 137-701, Republic of Korea.
Clair
Timothy
T
Noh
Ji Heon
JH
Eun
Jung Woo
JW
Ryu
So Yeon
SY
Lee
Shi Nae
SN
Ahn
Young Min
YM
Kim
Su Young
SY
Lee
Sug Hyung
SH
Park
Won Sang
WS
Yoo
Nam Jin
NJ
Lee
Jung Young
JY
Nam
Suk Woo
SW
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000502:physiology; D008246:Lysophospholipids / Q000378:metabolism*; D051379:Mice; D009097:Multienzyme Complexes / Q000008:administration & dosage*; D041681:NIH 3T3 Cells; D043264:Phosphodiesterase I / Q000008:administration & dosage*; D010727:Phosphoric Diester Hydrolases / Q000187:drug effects* / Q000378:metabolism*; D011755:Pyrophosphatases / Q000008:administration & dosage*; D012709:Serum Albumin / Q000378:metabolism*; D013379:Substrate Specificity; D000099189:Lysophospholipase D
D008246:Lysophospholipids; D009097:Multienzyme Complexes; D043264:Phosphodiesterase I; D010727:Phosphoric Diester Hydrolases; D011755:Pyrophosphatases; D012709:Serum Albumin; D000099189:Lysophospholipase D; C032881:lysophosphatidic acid