title: 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. 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.
authors.affiliation: Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, UK.
authors.forename: Susanna A
authors.initials: SA
authors.lastname: Jethwa
authors.affiliation: Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, UK.
authors.forename: Emma J
authors.initials: EJ
authors.lastname: Leah
authors.affiliation: Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, UK.
authors.forename: Qifeng
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, UK.
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Bright
authors.affiliation: Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, UK.
authors.forename: David
authors.initials: D
authors.lastname: Oxley
authors.affiliation: Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, UK.
authors.forename: Martin D
authors.initials: MD
authors.lastname: Bootman
authors.affiliation: Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, UK Simon.rudge@babraham.ac.uk Michael.wakelam@babraham.ac.uk.
authors.forename: Simon A
authors.initials: SA
authors.lastname: Rudge
authors.affiliation: Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, UK Simon.rudge@babraham.ac.uk Michael.wakelam@babraham.ac.uk.
authors.forename: Michael J O
authors.identifier: 0000-0003-4059-9276
authors.initials: MJ
authors.lastname: Wakelam
mesh_terms: D000818:Animals; D002499:Centrifugation, Density Gradient; D005591:Chemical Fractionation; D017077:Culture Media, Conditioned / Q000494:pharmacology; D004247:DNA / Q000096:biosynthesis; D055354:Exosomes / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D057809:HEK293 Cells; D006801:Humans; D007797:Laminin / Q000378:metabolism; D008246:Lysophospholipids / Q000378:metabolism; D013058:Mass Spectrometry; D051379:Mice; D057146:Multivesicular Bodies / Q000378:metabolism / Q000648:ultrastructure; D041681:NIH 3T3 Cells; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism*; D021381:Protein Transport / Q000187:drug effects; D049368:Receptors, Lysophosphatidic Acid / Q000378:metabolism*; D022142:Secretory Vesicles / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D015398:Signal Transduction / Q000187:drug effects; D000099189:Lysophospholipase D
chemical_list: D017077:Culture Media, Conditioned; D004247:DNA; D007797:Laminin; D008246:Lysophospholipids; D010727:Phosphoric Diester Hydrolases; D049368:Receptors, Lysophosphatidic Acid; D000099189:Lysophospholipase D
keywords: Autotaxin; Exosome; Integrin; LPA