TY - JOUR
T1 - Autotaxin induces lung epithelial cell migration through lysoPLD activity-dependent and -independent pathways
AU - Zhao, Jing
AU - He, Donghong
AU - Berdyshev, Evgeny
AU - Zhong, Mintao
AU - Salgia, Ravi
AU - Morris, Andrew J.
AU - Smyth, Susan S.
AU - Natarajan, Viswanathan
AU - Zhao, Yutong
PY - 2011/10/1
Y1 - 2011/10/1
N2 - Lung cell migration is a crucial step for re-epithelialization that in turn is essential for remodelling and repair after lung injury. In the present paper we hypothesize that secreted ATX (autotaxin), which exhibits lysoPLD (lysophospholipase D) activity, stimulates lung epithelial cell migration through LPA (lysophosphatidic acid) generation-dependent and -independent pathways. Release of endogenous ATX protein and activity was detected in lung epithelial cell culture medium. ATX with V5 tag overexpressed conditional medium had higher LPA levels compared with control medium and stimulated cell migration through G αi-coupled LPA receptors, cytoskeleton rearrangement, phosphorylation of PKC (protein kinase C) δ and cortactin at the leading edge of migrating cells. Inhibition of PKCδ attenuatedATX-V5 overexpressed conditionalmedium-mediated phosphorylation of cortactin. In addition, a recombinant ATX mutant, lacking lysoPLD activity, or heat-inactived ATX also induced lung epithelial cellmigration. Extracelluar ATX bound to the LPA receptor and integrin β4 complex on A549 cell surface. Finally, intratracheal administration of LPS (lipopolysaccharide) into the mouse airway induced ATX release and LPA production in BAL (bronchoalveolar lavage) fluid. These results suggested a significant role for ATX in lung epithelial cell migration and remodelling through its ability to induce LPA productionmediated phosphorylation of PKCδ and cortactin. In addition we also demonstrated assocation of ATX with the epithelial cellsurface LPA receptor and integrin β4.
AB - Lung cell migration is a crucial step for re-epithelialization that in turn is essential for remodelling and repair after lung injury. In the present paper we hypothesize that secreted ATX (autotaxin), which exhibits lysoPLD (lysophospholipase D) activity, stimulates lung epithelial cell migration through LPA (lysophosphatidic acid) generation-dependent and -independent pathways. Release of endogenous ATX protein and activity was detected in lung epithelial cell culture medium. ATX with V5 tag overexpressed conditional medium had higher LPA levels compared with control medium and stimulated cell migration through G αi-coupled LPA receptors, cytoskeleton rearrangement, phosphorylation of PKC (protein kinase C) δ and cortactin at the leading edge of migrating cells. Inhibition of PKCδ attenuatedATX-V5 overexpressed conditionalmedium-mediated phosphorylation of cortactin. In addition, a recombinant ATX mutant, lacking lysoPLD activity, or heat-inactived ATX also induced lung epithelial cellmigration. Extracelluar ATX bound to the LPA receptor and integrin β4 complex on A549 cell surface. Finally, intratracheal administration of LPS (lipopolysaccharide) into the mouse airway induced ATX release and LPA production in BAL (bronchoalveolar lavage) fluid. These results suggested a significant role for ATX in lung epithelial cell migration and remodelling through its ability to induce LPA productionmediated phosphorylation of PKCδ and cortactin. In addition we also demonstrated assocation of ATX with the epithelial cellsurface LPA receptor and integrin β4.
KW - Autotaxin (ATX)
KW - Cell migration
KW - Lysophosphatidic acid (LPA)
KW - Lysophospholipase D (lysoPLD)
KW - Signal transduction
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U2 - 10.1042/BJ20110274
DO - 10.1042/BJ20110274
M3 - Article
C2 - 21696367
AN - SCOPUS:80052693188
SN - 0264-6021
VL - 439
SP - 45
EP - 55
JO - Biochemical Journal
JF - Biochemical Journal
IS - 1
ER -