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Exosomes bind to autotaxin and act as a physiological delivery mechanism to stimulate LPA receptor signalling in cells

Jethwa, Susanna A.; Leah, Emma J.; Zhang, Qifeng; Bright, Nicholas A.; Oxley, David; Bootman, Martin D.; Rudge, Simon A. and Wakelam, Michael J. O. (2016). Exosomes bind to autotaxin and act as a physiological delivery mechanism to stimulate LPA receptor signalling in cells. Journal of Cell Science, 129(20) pp. 3948–3957.

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Autotaxin (ATX; also known as ENPP2), the lysophospholipase responsible for generating the lipid receptor agonist lysophosphatidic acid (LPA), is a secreted enzyme. Here we show that, once secreted, ATX can bind to the surface of cell-secreted exosomes. Exosome-bound ATX is catalytically active and carries generated LPA. Once bound to a cell, through specific integrin interactions, ATX releases the LPA to activate cell surface G-protein-coupled receptors of LPA; inhibition of signalling by the receptor antagonist Ki1642 suggests that these receptors are LPAR1 and LPAR3. The binding stimulates downstream signalling, including phosphorylation of AKT and mitogen-activated protein kinases, the release of intracellular stored Ca2+ and cell migration. We propose that exosomal binding of LPA-loaded ATX provides a means of efficiently delivering the lipid agonist to cell surface receptors to promote signalling. We further propose that this is a means by which ATX–LPA signalling operates physiologically.

Item Type: Journal Item
Copyright Holders: 2016 The Company of Biologists
ISSN: 0021-9533
Project Funding Details:
Funded Project NameProject IDFunding Body
Not SetBBS\E\b\0000CO415BBSRC (Biotechnology and Biological Sciences Research Council)
Keywords: autotaxin; exosome; integrin; LPA
Academic Unit/School: Faculty of Science, Technology, Engineering and Mathematics (STEM) > Life, Health and Chemical Sciences
Faculty of Science, Technology, Engineering and Mathematics (STEM)
Research Group: Health and Wellbeing PRA (Priority Research Area)
Item ID: 47738
Depositing User: Martin Bootman
Date Deposited: 04 Nov 2016 16:44
Last Modified: 02 May 2018 14:24
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