Lipid phosphate phosphatases: more than one way to put the brakes on LPA signaling?

Abstract

Journal of Lipid Research Volume 55, 2014 2195Lipid phosphate phosphatases (LPPs, encoded by the PPAP2 genes) are broad specifi city enzymes that can dephosphorylate lipid phosphate esters such as phosphatidic acid (PA), lysophosphatidic acid (LPA), and sphingosine-1-phosphate (S1P) that serve as critical intermediates in intracellular pathways of lipid metabolism and signaling ( Fig. 1 ) ( 1 ). Of these substrates, LPA and S1P are also bioactive mediators that can be released or generated extracellularly and/or act on cell surface receptors to initiate a broad range of cellular responses ( 2 ). LPPs can localize to the cell surface with their active site facing the extracellular space allowing them to function as ecto enzymes ( 3 , 4 ). Accordingly, it has been attractive to speculate that one function of these enzymes is to terminate the receptormediated signaling actions of LPA and S1P by dephosphorylating them to generate the corresponding alcohols, which are not receptor-active. In support of this concept, overexpression of LPP1 or LPP3 increases the LPP activity of several intact cells, and this activity is decreased by silencing or genetic inactivation of the corresponding PPAP2A and PPAP2B genes ( 5 -7 ). These manipulations are broadly associated with reciprocal effects on LPA responsiveness of stereotypic cellular responses to this stimulus, particularly cell growth and migration. Mice that are genetically hypomorphic for the PPAP2A gene encoding LPP1 exhibit increased circulating LPA levels ( 8 ) whereas inducible postnatal and/or tissue-restricted inactivation of the PPAP2B gene encoding LPP3 alters S1P gradients that control lymphocyte egress from the lymphatic system to the peripheral circulation ( 9 ) and renders vascular smooth muscle cells more responsive to LPA ( 6 ).In Drosophila , LPP homologs encoded by the Wunen genes regulate the migration of germ cells in the developing embryo ( 10 ). Ectopic expression of these genes in somatic tissues that are normally permissive for germ cell migration results in repulsion of the migrating germ cells. This nonautonomous function of the Wunen genes is consistent with the idea that a diffusible Wunen substrate regulates germ cell migration ( 11 ). However, Wunens are also expressed in the germ cells themselves from maternally inherited mRNA and inactivation of Wunen in the female germline also decreases germ cell migration identifying a cell autonomous function for these genes ( 12 ).LPPs also localize to intracellular membranes. Manipulations of LPP expression have also been shown to alter levels of cell-associated LPP substrates and products including PA and its dephosphorylation product diacylglycerol (DG) that are well established to regulate intracellular signaling pathways. These include pathways mediated by the Raf and mTOR protein kinases and conventional protein kinases C ( 13 , 14 ). Evidence that LPP3 has an intracellular role as a regulator of vesicular transport between the endoplasmic reticulum and Golgi apparatus has also been reported ( 1...

High-fat diet reprograms the epigenome of rat spermatozoa and transgenerationally affects metabolism of the offspring

“…We were unable to detect differential mRNA expression of insulin-PI3K signaling-related genes previously shown to be regulated by expression of the broad let-7 family [21] , whereas more pronounced changes were observed at the protein level, suggesting that let-7c could regulate these predicted targets by inhibiting translation. Of potential let-7c targets in rats, is the Ppap2a gene that encodes a lipid phosphatic phosphatase enzyme involved in the dephosphorylation of lipid phosphate esters such as phophatidic acid (PA) and lysophosphatidic acid (LPA), two important intermediates of intracellular lipid metabolism and signaling pathways [39] . Let-7c expression was increased in WAT of F1 and F2 offspring from HFD-fed fathers and grandfathers, while expression of its potential target Ppap2a was reduced.…”

Lysophosphatidic acid via LPA-receptor 5/protein kinase D-dependent pathways induces a motile and pro-inflammatory microglial phenotype

“…Microglial dysfunction and neuroinflammation are implicated in the initiation and progression of many neurological diseases [ 60 – 62 ]. LPA levels increase under inflammatory conditions and in response to brain injury [ 63 – 65 ] and can be manipulated via ATX inhibition or lipid phosphate phosphatase-mediated degradation [ 66 , 67 ]. Prenatal exposure to elevated LPA levels and dysregulated LPA signaling may have chronic effects and can be prevented through inhibition of different LPARs [ 16 , 68 , 69 ].…”

Thematic Review Series: Phospholipases: Central Role in Lipid Signaling and Disease Autotaxin, a lysophospholipase D with pleomorphic effects in oncogenesis and cancer progression

“…In addition to synergizing with RAS signaling to promote tumor migration and metastatic dissemination in RAS-transformed cells ( 153 ), lysoPLD activity, likely mediated by ATX, has been proposed as one of the contributing factors in developing acquired resistance to the receptor tyrosine kinase inhibitor, sunitinib, in renal cell carcinoma ( 154 ) and carboplatin-induced implicated in driving the progression of atherosclerosis ( 83 ), neuropathic pain (84)(85)(86), and T cell homing ( 87 ), respectively. In contrast to ATX, there is no evidence indicating that lipid phosphate phosphatases, the main enzymes mediating LPA degradation (88)(89)(90)(91), have an equivalent mechanism for local action through binding to integrins or other extracellular receptors. Like other factors involved in development, fi ne spatiotemporal regulation of ATX expression and activity is essential not only for proper vasculogenesis but also for other key biological functions.…”