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2014 ; 55
(6
): 1010-8
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Autotaxin: structure-function and signaling
#MMPMID24548887
Perrakis A
; Moolenaar WH
J Lipid Res
2014[Jun]; 55
(6
): 1010-8
PMID24548887
show ga
Autotaxin (ATX), or ecto-nucleotide pyrophosphatase/phosphodiesterase-2, is a
secreted lysophospholipase D (lysoPLD) that hydrolyzes extracellular
lysophospholipids into the lipid mediator lysophosphatidic acid (LPA), a ligand
for specific G protein-coupled receptors. ATX-LPA signaling is essential for
development and has been implicated in a great diversity of (patho)physiological
processes, ranging from lymphocyte homing to tumor progression. Structural and
functional studies have revealed what makes ATX a unique lysoPLD, and how
secreted ATX binds to its target cells. The ATX catalytic domain shows a
characteristic bimetallic active site followed by a shallow binding groove that
can accommodate nucleotides as well as the glycerol moiety of lysophospholipids,
and by a deep lipid-binding pocket. In addition, the catalytic domain has an open
tunnel of unknown function adjacent to the active site. Here, we discuss our
current understanding of ATX structure-function relationships and signaling
mechanisms, and how ATX isoforms use distinct mechanisms to target LPA production
to the plasma membrane, notably binding to integrins and heparan sulfate
proteoglycans. We also briefly discuss the development of drug-like inhibitors of
ATX.
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