scholarly journals Lipid Phosphate Phosphatases and Cancer

Biomolecules ◽  
2020 ◽  
Vol 10 (9) ◽  
pp. 1263 ◽  
Author(s):  
Xiaoyun Tang ◽  
David N. Brindley
Keyword(s):  
Endoplasmic Reticulum ◽  
Cancer Progression ◽  
Plasma Membranes ◽  
Wide Spectrum ◽  
Integral Membrane Proteins ◽  
Extracellular Signaling ◽  
Sphingosine 1 Phosphate ◽  
Lipid Phosphate ◽  
Golgi Network ◽  
Lipid Phosphate Phosphatases

Lipid phosphate phosphatases (LPPs) are a group of three enzymes (LPP1–3) that belong to a phospholipid phosphatase (PLPP) family. The LPPs dephosphorylate a wide spectrum of bioactive lipid phosphates, among which lysophosphatidate (LPA) and sphingosine 1-phosphate (S1P) are two important extracellular signaling molecules. The LPPs are integral membrane proteins, which are localized on plasma membranes and intracellular membranes, including the endoplasmic reticulum and Golgi network. LPPs regulate signaling transduction in cancer cells and demonstrate different effects in cancer progression through the breakdown of extracellular LPA and S1P and other intracellular substrates. This review is intended to summarize an up-to-date understanding about the functions of LPPs in cancers.

Co-ordinate regulation of growth factor receptors and lipid phosphate phosphatase-1 controls cell activation by exogenous lysophosphatidate

2001 ◽  
Vol 29 (6) ◽  
pp. 825-830 ◽  
Author(s):  
C. Pilquil ◽  
Z.-C. Ling ◽  
I. Singh ◽  
K. Buri ◽  
Q.-X. Zhang ◽  
...  
Keyword(s):  
Growth Factor ◽  
Cell Activation ◽  
Growth Factor Receptors ◽  
Exogenous Lipid ◽  
Edg Receptors ◽  
Sphingosine 1 Phosphate ◽  
Lipid Phosphate ◽  
Lipid Phosphate Phosphatases ◽  
Differentiation Gene

The serum-derived lipid growth factors, lysophosphatidate (LPA) and sphingosine 1-phosphate (S1P), activate cells selectively through different members of a family of endothelial differentiation gene (EDG) receptors. Activation of EDG receptors by LPA and S1P provides a variety of signalling cascades depending upon the G-protein coupling of the different EDG receptors. This leads to chemotactic and mitogenic responses, which are important in wound healing. For example, LPA stimulates fibroblast division and S1P stimulates the chemotaxis and division of endothelial cells leading to angiogenesis. Counteracting these effects of LPA and S1P, are the actions of lipid phosphate phosphatases (LPP, or phosphatidate phosphohydrolases, Type 2). The isoform LPP-1 is expressed in the plasma membrane with its active site outside the cell. This enzyme is responsible for ‘ecto-phosphatase’ activity leading to the degradation of exogenous lipid phosphate mediators, particularly LPA. Expression of LPP-1 decreases cell activation by exogenous LPA. The mechanism for this is controversial and several mechanisms have been proposed. Evidence will be presented that the LPPs cross-talk with EDG and other growth factor receptors, thus, regulating the responses of the cells to lipid phosphate mediators of signal transduction.

scholarly journals Lipid phosphate phosphatases form homo- and hetero-oligomers: catalytic competency, subcellular distribution and function

2008 ◽  
Vol 411 (2) ◽  
pp. 371-377 ◽  
Author(s):  
Jaclyn S. Long ◽  
Nigel J. Pyne ◽  
Susan Pyne
Keyword(s):  
Recombinant Expression ◽  
Catalytic Site ◽  
Wild Type ◽  
Catalytically Active ◽  
Exclusion Chromatography ◽  
Sphingosine 1 Phosphate ◽  
Lipid Phosphate ◽  
Extracellular Side ◽  
And Function ◽  
Lipid Phosphate Phosphatases

Lipid phosphate phosphatases (LPP1–LPP3) have been topographically modelled as monomers (molecular mass of 31–36 kDa) composed of six transmembrane domains and with the catalytic site facing the extracellular side of the plasma membrane or the luminal side of intracellular membranes. The catalytic motif has three conserved domains, termed C1, C2 and C3. The C1 domain may be involved in substrate recognition, whereas C2 and C3 domains appear to participate in the catalytic dephosphorylation of the substrate. We have obtained three lines of evidence to demonstrate that LPPs exist as functional oligomers. First, we have used recombinant expression and immunoprecipitation analysis to demonstrate that LPP1, LPP2 and LPP3 form both homo- and hetero-oligomers. Secondly, large LPP oligomeric complexes that are catalytically active were isolated using gel-exclusion chromatography. Thirdly, we demonstrate that catalytically deficient guinea-pig FLAG-tagged H223L LPP1 mutant can form an oligomer with wild-type LPP1 and that wild-type LPP1 activity is preserved in the oligomer. These findings suggest that, in an oligomeric arrangement, the catalytic site of the wild-type LPP can function independently of the catalytic site of the mutant LPP. Finally, we demonstrate that endogenous LPP2 and LPP3 form homo- and hetero-oligomers, which differ in their subcellular localization and which may confer differing spatial regulation of phosphatidic acid and sphingosine 1-phosphate signalling.

Lipid phosphate phosphatases and lipid phosphate signalling

2005 ◽  
Vol 33 (6) ◽  
pp. 1370-1374 ◽  
Author(s):  
S. Pyne ◽  
J.S. Long ◽  
N.T. Ktistakis ◽  
N.J. Pyne
Keyword(s):  
Physiological Role ◽  
Mitogen Activated Protein Kinase ◽  
Hek 293 ◽  
Lipid Phosphatases ◽  
Mitogen Activated Protein ◽  
Phospholipase D1 ◽  
Sphingosine 1 Phosphate ◽  
Lipid Phosphate ◽  
Lipid Phosphate Phosphatases

Mammalian LPPs (lipid phosphate phosphatases) are integral membrane proteins that belong to a superfamily of lipid phosphatases/phosphotransferases. They have broad substrate specificity in vitro, dephosphorylating PA (phosphatidic acid), S1P (sphingosine 1-phosphate), LPA (lysophosphatidic acid) etc. Their physiological role may include the attenuation of S1P- and LPA-stimulated signalling by virtue of an ecto-activity (i.e. dephosphorylation of extracellular S1P and LPA), thereby limiting the activation of LPA- and S1P-specific G-protein-coupled receptors at the cell surface. However, our recent work suggests that an intracellular action of LPP2 and LPP3 may account for the reduced agonist-stimulated p42/p44 mitogen-activated protein kinase activation of HEK-293 (human embryonic kidney 293) cells. This may involve a reduction in the basal levels of PA and S1P respectively and the presence of an early apoptotic phenotype under conditions of stress (serum deprivation). Additionally, we describe a model whereby LPP2, but not LPP3, may be functionally linked to the phospholipase D1-derived PA-dependent recruitment of sphingosine kinase 1 to the perinuclear compartment. We also consider the potential regulatory mechanisms for LPPs, which may involve oligomerization. Lastly, we highlight many aspects of the LPP biology that remain to be fully defined.

scholarly journals Lipid phosphate phosphohydrolase-1 degrades exogenous glycerolipid and sphingolipid phosphate esters

1999 ◽  
Vol 340 (3) ◽  
pp. 677-686 ◽  
Author(s):  
Renata JASINSKA ◽  
Qiu-Xia ZHANG ◽  
Carlos PILQUIL ◽  
Indrapal SINGH ◽  
James XU ◽  
...  
Keyword(s):  
Plasma Membranes ◽  
Cell Signalling ◽  
Mitogen Activated Protein Kinase ◽  
C Terminus ◽  
Liver Cdna Library ◽  
Mitogen Activated Protein ◽  
Sphingosine 1 Phosphate ◽  
Lipid Phosphate ◽  
Lipid Phosphate Phosphohydrolase ◽  
Ceramide 1

Lipid phosphate phosphohydrolase (LPP)-1 cDNA was cloned from a rat liver cDNA library. It codes for a 32-kDa protein that shares 87 and 82% amino acid sequence identities with putative products of murine and human LPP-1 cDNAs, respectively. Membrane fractions of rat2 fibroblasts that stably expressed mouse or rat LPP-1 exhibited 3.1-3.6-fold higher specific activities for phosphatidate dephosphorylation compared with vector controls. Increases in the dephosphorylation of lysophosphatidate, ceramide 1-phosphate, sphingosine 1-phosphate and diacylglycerol pyrophosphate were similar to those for phosphatidate. Rat2 fibroblasts expressing mouse LPP-1 cDNA showed 1.6-2.3-fold increases in the hydrolysis of exogenous lysophosphatidate, phosphatidate and ceramide 1-phosphate compared with vector control cells. Recombinant LPP-1 was located partially in plasma membranes with its C-terminus on the cytosolic surface. Lysophosphatidate dephosphorylation was inhibited by extracellular Ca2+ and this inhibition was diminished by extracellular Mg2+. Changing intracellular Ca2+ concentrations did not alter exogenous lysophosphatidate dephosphorylation significantly. Permeabilized fibroblasts showed relatively little latency for the dephosphorylation of exogenous lysophosphatidate. LPP-1 expression decreased the activation of mitogen-activated protein kinase and DNA synthesis by exogenous lysophosphatidate. The product of LPP-1 cDNA is concluded to act partly to degrade exogenous lysophosphatidate and thereby regulate its effects on cell signalling.

scholarly journals Regulation of cell survival by lipid phosphate phosphatases involves the modulation of intracellular phosphatidic acid and sphingosine 1-phosphate pools

2005 ◽  
Vol 391 (1) ◽  
pp. 25-32 ◽  
Author(s):  
Jaclyn Long ◽  
Peter Darroch ◽  
Kah Fei Wan ◽  
Kok Choi Kong ◽  
Nicholas Ktistakis ◽  
...  
Keyword(s):  
Phosphatidic Acid ◽  
Caspase 3 ◽  
Chinese Hamster Ovary Cells ◽  
Chinese Hamster ◽  
Hek 293 ◽  
Hek 293 Cells ◽  
293 Cells ◽  
Sphingosine 1 Phosphate ◽  
Lipid Phosphate ◽  
Lipid Phosphate Phosphatases

We have shown previously that LPPs (lipid phosphate phosphatases) reduce the stimulation of the p42/p44 MAPK (p42/p44 mitogen-activated protein kinase) pathway by the GPCR (G-protein-coupled receptor) agonists S1P (sphingosine 1-phosphate) and LPA (lysophosphatidic acid) in serum-deprived HEK-293 cells [Alderton, Darroch, Sambi, McKie, Ahmed, N. J. Pyne and S. Pyne (2001) J. Biol. Chem. 276, 13452–13460]. In the present study, we now show that this can be blocked by pretreating HEK-293 cells with the caspase 3/7 inhibitor, Ac-DEVD-CHO [N-acetyl-Asp-Glu-Val-Asp-CHO (aldehyde)]. Therefore LPP2 and LPP3 appear to regulate the apoptotic status of serum-deprived HEK-293 cells. This was supported further by: (i) caspase 3/7-catalysed cleavage of PARP [poly(ADP-ribose) polymerase] was increased in serum-deprived LPP2-overexpressing compared with vector-transfected HEK-293 cells; and (ii) serum-deprived LPP2- and LPP3-overexpressing cells exhibited limited intranucleosomal DNA laddering, which was absent in vector-transfected cells. Moreover, LPP2 reduced basal intracellular phosphatidic acid levels, whereas LPP3 decreased intracellular S1P in serum-deprived HEK-293 cells. LPP2 and LPP3 are constitutively co-localized with SK1 (sphingosine kinase 1) in cytoplasmic vesicles in HEK-293 cells. Moreover, LPP2 but not LPP3 prevents SK1 from being recruited to a perinuclear compartment upon induction of PLD1 (phospholipase D1) in CHO (Chinese-hamster ovary) cells. Taken together, these data are consistent with an important role for LPP2 and LPP3 in regulating an intracellular pool of PA and S1P respectively, that may govern the apoptotic status of the cell upon serum deprivation.

Acid ceramidase, a double-edged sword in cancer aggression: A minireview

2020 ◽  
Vol 20 ◽  
Author(s):  
Helen Shiphrah Vethakanraj ◽  
Niveditha Chandrasekaran ◽  
Ashok Kumar Sekar
Keyword(s):  
Cell Fate ◽  
Cancer Progression ◽  
Potential Role ◽  
Tumour Progression ◽  
Acid Ceramidase ◽  
The Core ◽  
The Past ◽  
Sphingosine 1 Phosphate ◽  
Key Enzyme

: Acid ceramidase (AC), the key enzyme of the ceramide metabolic pathway hydrolyzes pro-apoptotic ceramide to sphingosine, which by the action of sphingosine-1-kinase is metabolized to mitogenic sphingosine-1-phosphate. The intracellular level of AC determines ceramide/sphingosine-1-phosphate rheostat which in turn decides the cell fate. The upregulated AC expression during cancerous condition acts as a “double-edged sword” by converting pro-apoptotic ceramide to anti-apoptotic sphingosine-1-phosphate, wherein on one end, the level of ceramide is decreased and on the other end, the level of sphingosine-1-phosphate is increased, thus altogether aggravating the cancer progression. In addition, cancer cells with upregulated AC expression exhibited increased cell proliferation, metastasis, chemoresistance, radioresistance and numerous strategies were developed in the past to effectively target the enzyme. Gene silencing and pharmacological inhibition of AC sensitized the resistant cells to chemo/radiotherapy thereby promoting cell death. The core objective of this review is to explore AC mediated tumour progression and the potential role of AC inhibitors in various cancer cell lines/models.

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