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

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. Exosomebound 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 downstreamsignalling, including phosphorylation of AKT andmitogenactivated protein kinases, the release of intracellular stored Ca2+ and cell migration. We propose that exosomal binding of LPA-loaded ATX provides ameans 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.