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.

DOI: https://doi.org/10.1242/jcs.184424

Abstract

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.

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