Jethwa Susanna A, Leah Emma J, Zhang Qifeng, Bright Nicholas A, Oxley David, Bootman Martin D, Rudge Simon A, Wakelam Michael J O
Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, UK.
Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, UK.
J Cell Sci. 2016 Oct 15;129(20):3948-3957. doi: 10.1242/jcs.184424. Epub 2016 Aug 24.
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 Ca 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.
自分泌运动因子（ATX；也称为ENPP2）是一种负责生成脂质受体激动剂溶血磷脂酸（LPA）的溶血磷脂酶，是一种分泌酶。我们在此表明，一旦分泌出来，ATX就能结合到细胞分泌的外泌体表面。结合在外泌体上的ATX具有催化活性，并携带生成的LPA。一旦通过特异性整合素相互作用与细胞结合，ATX就会释放LPA以激活LPA的细胞表面G蛋白偶联受体；受体拮抗剂Ki1642对信号传导的抑制表明这些受体是LPAR1和LPAR3。这种结合刺激下游信号传导，包括AKT和丝裂原活化蛋白激酶的磷酸化、细胞内储存钙的释放以及细胞迁移。我们提出，负载LPA的ATX与外泌体的结合提供了一种将脂质激动剂有效递送至细胞表面受体以促进信号传导的方式。我们进一步提出，这是ATX-LPA信号传导在生理上发挥作用的一种方式。
