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.
The authors declare no competing or financial interests.
S.A.J., E.J.L., S.A.R., N.A.B., Q.Z., M.D.B. and D.O. performed experiments, M.J.O.W. and S.A.R. directed the research. M.J.O.W. wrote the paper.
This work was supported by funding from the Biotechnology and Biological Sciences Research Council (BBSRC, UK) [grant number BBS\E\B\0000CO415]. Deposited in PMC for release after 6 months.
- Received December 3, 2015.
- Accepted August 14, 2016.
- © 2016. Published by The Company of Biologists Ltd