title: Autotaxin (lysoPLD/NPP2) protects fibroblasts from apoptosis through its enzymatic product, lysophosphatidic acid, utilizing albumin-bound substrate.
abstract: 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.
authors.affiliation: 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.
authors.forename: Jaehwi
authors.initials: J
authors.lastname: Song
authors.forename: Timothy
authors.initials: T
authors.lastname: Clair
authors.forename: Ji Heon
authors.initials: JH
authors.lastname: Noh
authors.forename: Jung Woo
authors.initials: JW
authors.lastname: Eun
authors.forename: So Yeon
authors.initials: SY
authors.lastname: Ryu
authors.forename: Shi Nae
authors.initials: SN
authors.lastname: Lee
authors.forename: Young Min
authors.initials: YM
authors.lastname: Ahn
authors.forename: Su Young
authors.initials: SY
authors.lastname: Kim
authors.forename: Sug Hyung
authors.initials: SH
authors.lastname: Lee
authors.forename: Won Sang
authors.initials: WS
authors.lastname: Park
authors.forename: Nam Jin
authors.initials: NJ
authors.lastname: Yoo
authors.forename: Jung Young
authors.initials: JY
authors.lastname: Lee
authors.forename: Suk Woo
authors.initials: SW
authors.lastname: Nam
mesh_terms: 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
chemical_list: D008246:Lysophospholipids; D009097:Multienzyme Complexes; D043264:Phosphodiesterase I; D010727:Phosphoric Diester Hydrolases; D011755:Pyrophosphatases; D012709:Serum Albumin; D000099189:Lysophospholipase D; C032881:lysophosphatidic acid