Long Jaclyn S, Yokoyama Kazuaki, Tigyi Gabor, Pyne Nigel J, Pyne Susan
Department of Physiology and Pharmacology, Strathclyde Institute for Biomedical Sciences, University of Strathclyde, 27 Taylor Street, Glasgow G4 0NR, UK.
Biochem J. 2006 Mar 1;394(Pt 2):495-500. doi: 10.1042/BJ20051674.
LPPs (lipid phosphate phosphatases) are members of a family of enzymes that catalyse the dephosphorylation of lipid phosphates. The only known form of regulation of this family of enzymes is via de novo expression of LPP isoforms in response to growth factors. In this respect, we evaluated the effect of moderate increases in the expression of recombinant LPP1 on signal transduction by both G-protein-coupled receptors and receptor tyrosine kinases. We present evidence for a novel role of LPP1 in reducing PDGF (platelet-derived growth factor)- and lysophosphatidic acid-induced migration of embryonic fibroblasts. We demonstrate that the overexpression of LPP1 inhibits cell migration by reducing the PDGF-induced activation of p42/p44 MAPK (mitogen-activated protein kinase). This appears to occur via a mechanism that involves the LPP1-induced down-regulation of typical PKC (protein kinase C) isoform(s), which are normally required for PDGF-induced activation of p42/p44 MAPK and migration. In this regard, DAG (diacylglycerol) levels are high and sustained in cells overexpressing LPP1, suggesting a dynamic interconversion of phosphatidic acid into DAG by LPP1. This may account for the effects of LPP1 on cell migration, as sustained DAG is known to down-regulate PKC isoforms in cells. Therefore the physiological changes in the expression levels of LPP1 might represent a heterologous desensitization mechanism for attenuating PKC-mediated signalling and regulation of cell migration.
脂质磷酸酶（LPPs）是一类催化脂质磷酸去磷酸化反应的酶家族成员。已知该酶家族唯一的调节形式是通过LPP亚型的从头表达来响应生长因子。在这方面，我们评估了重组LPP1表达适度增加对G蛋白偶联受体和受体酪氨酸激酶信号转导的影响。我们提供了证据表明LPP1在减少血小板衍生生长因子（PDGF）和溶血磷脂酸诱导的胚胎成纤维细胞迁移中具有新作用。我们证明LPP1的过表达通过减少PDGF诱导的p42/p44丝裂原活化蛋白激酶（MAPK）激活来抑制细胞迁移。这似乎是通过一种机制发生的，该机制涉及LPP1诱导的典型蛋白激酶C（PKC）亚型的下调，而这些亚型通常是PDGF诱导p42/p44 MAPK激活和迁移所必需的。在这方面，过表达LPP1的细胞中甘油二酯（DAG）水平高且持续，这表明LPP1可使磷脂酸动态转化为DAG。这可能解释了LPP1对细胞迁移的影响，因为已知持续的DAG会下调细胞中的PKC亚型。因此，LPP1表达水平的生理变化可能代表一种异源脱敏机制，用于减弱PKC介导的信号传导和细胞迁移调节。
