Lipid phosphate phosphatases and their roles in mammalian physiology and pathology

Abstract

Lipid phosphate phosphatases (LPPs) are a group of enzymes that belong to a phosphatase/phosphotransferase family. Mammalian LPPs consist of three isoforms: LPP1, LPP2, and LPP3. They share highly conserved catalytic domains and catalyze the dephosphorylation of a variety of lipid phosphates, including phosphatidate, lysophosphatidate (LPA), sphingosine 1-phosphate (S1P), ceramide 1-phosphate, and diacylglycerol pyrophosphate. LPPs are integral membrane proteins, which are localized on plasma membranes with the active site on the outer leaflet. This enables the LPPs to degrade extracellular LPA and S1P, thereby attenuating their effects on the activation of surface receptors. LPP3 also exhibits noncatalytic effects at the cell surface. LPP expression on internal membranes, such as endoplasmic reticulum and Golgi, facilitates the metabolism of internal lipid phosphates, presumably on the luminal surface of these organelles. This action probably explains the signaling effects of the LPPs, which occur downstream of receptor activation. The three isoforms of LPPs show distinct and nonredundant effects in several physiological and pathological processes including embryo development, vascular function, and tumor progression. This review is intended to present an up-to-date understanding of the physiological and pathological consequences of changing the activities of the different LPPs, especially in relation to cell signaling by LPA and S1P.

Keywords: G-protein coupled receptors; autotaxin; breast cancer; cell migration; epidermal growth factor (EGF) receptor; lysophosphatidate; thyroid cancer.

Fig. 1.

Structure of the LPPs. The figure illustrates the structure and orientation of the LPPs in the plasma membrane. The structure of the three conserved catalytic domains (red circles) is shown with the amino acids involved in substrate binding and catalysis highlighted in red. The N-glycosylation site is shown as a green square.

Fig. 2.

Roles of the LPPs in regulating the dephosphorylation of extracellular lipid phosphates at the cell’s surface (ecto-activities) and internal substrates through the intracellular activities. LPPs dephosphorylate extracellular LPA and S1P. LPPs also have intracellular effects, which depend on their catalytic activities. These effects occur downstream of receptor stimulation and they regulate the activations of phospholipase D, ERK, and Ca²⁺-transients, The lipid targets of these intracellular activities are unknown.

Fig. 3.

Relative expressions of the LPPs in breast, lung, and ovarian cancers. LPP1 and LPP3 expression is decreased in cancers, whereas LPP2 activity is increased. The results for breast (149), lung (150), and ovarian cancers (151) are taken from published gene arrays through the free Oncomine^TM Research Edition platform (152, 153). LPP expressions in other cancers from other gene arrays can also be obtained from this resource.