PPAP2B

Last updated
PLPP3
Identifiers
Aliases PLPP3 , Dri42, LPP3, PAP2B, VCIP, PPAP2B, phospholipid phosphatase 3
External IDs OMIM: 607125 MGI: 1915166 HomoloGene: 15410 GeneCards: PLPP3
Orthologs
SpeciesHumanMouse
Entrez

8613

67916

Ensembl

ENSG00000162407

ENSMUSG00000028517

UniProt

O14495

Q99JY8

RefSeq (mRNA)

NM_177414
NM_003713

NM_080555

RefSeq (protein)

NP_003704

NP_542122

Location (UCSC) Chr 1: 56.49 – 56.65 Mb Chr 4: 105.01 – 105.09 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Lipid phosphate phosphohydrolase 3 (LPP3), also known as phospholipid phosphatase 3 (PLPP3) and phosphatidic acid phosphatase type 2B (PAP-2b or PPAP2B), is an enzyme that in humans is encoded by the PPAP2B gene on chromosome 1. [5] [6] [7] It is ubiquitously expressed in many tissues and cell types. [8] LPP3 is a cell-surface glycoprotein that hydrolyzes extracellular lysophosphatidic acid (LPA) and short-chain phosphatidic acid. [9] Its function allows it to regulate vascular and embryonic development by inhibiting LPA signaling, which is associated with a wide range of human diseases, including cardiovascular disease and cancer, as well as developmental defects. [10] The PPAP2B gene also contains one of 27 loci associated with increased risk of coronary artery disease. [11]

Contents

Structure

Gene

The PPAP2B gene resides on chromosome 1 at the band 1p32.2 and includes 6 exons. [6]

Protein

LPP3 is a member of the PAP-related phosphoesterase family. [7] It is a type 2 activity PAP, which localizes to the plasma membrane, and is one of four known LPP isoforms. As an integral membrane protein, LPP3 contains six hydrophobic transmembrane domains and a hydrophilic catalytic site composed of three conserved domains. [12] [13] One catalytic domain is proposed to bind the substrate while the other two contribute to dephosphorylation of the substrate. The catalytic site typically faces the extracellular matrix when located on the cell membrane and faces the lumen when located in intracellular membranes. This protein can form homo- and hetero-oligomers. [13]

Function

This protein is a membrane glycoprotein localized at the cell plasma membrane. It has been shown to actively hydrolyze extracellular lysophosphatidic acid (LPA) and short-chain phosphatidic acid. [5] As an LPA inhibitor, PPAP2B is known to suppress LPA receptor mediated cellular signaling, which is associated with activation of vascular and blood cells and epithelial cell migration and proliferation. [14] [15] In response to dynamic athero relevant-flows, PPAP2B can promote anti-inflammatory phenotype via inhibition of LPA signaling and maintain vascular integrity of endothelial monolayer. This flow-sensitive PPAP2B expression is inhibited by microRNA-92a and activated by transcription factor KLF2. [16] In addition to LPA receptor-mediated signaling, PPAP2B is also associated with Wnt signaling, functioning in embryonic development for proper formation of important tissues including bone, heart and muscle. The phenotype of axis duplication in mice globally lacking PPAP2B resembles that observed in animals with altered Wnt signaling. [17] Furthermore, Wnt signaling mediated TCF/LEF-transcription via β-catenin is upregulated in PPAP2B null embryonic stem cells, implicating LPP3 as a negative regulator of the Wnt pathway. [18]

Clinical Significance

Due to the regulatory role of LPP3 in vascular and embryonic development, inactivation of this protein can contribute to cardiovascular disease and developmental complications. For example, inducible inactivation of LPP3 in both endothelial and hematopoietic cells leads to atherosclerosis due to accumulation of LPA in human plaques. [10] [19] Likewise, plasma LPA levels are significantly elevated in patients with acute coronary syndromes. [20] It was further observed that reduced levels of endothelial LPP3 is associated with disturbed flow and mechano-regulation in blood vessels. [16] During embryonic development in mice, inactivation of LPP3 results in early lethality in part due to failure of extra-embryonic vascular development. [21] Abnormal activation of LPA signaling has also been implicated in cancer, fibrotic disorders, and metabolic syndrome (involving insulin resistance). [22] [23]

Clinical Marker

In humans, PPAP2B emerged as 1 of 13 new loci associated with coronary artery disease by genome-wide association studies (GWAS). [24] [25] This prediction appears to be independent of traditional risk factors for cardiovascular disease such as high cholesterol levels, high blood pressure, obesity, smoking, and diabetes mellitus.

Additionally, a multi-locus genetic risk score study, based on a combination of 27 loci including the PPAP2B gene, identified individuals at increased risk for both incident and recurrent coronary artery disease events, as well as an enhanced clinical benefit from statin therapy. The study was based on a community cohort study (the Malmo Diet and Cancer study) and four additional randomized controlled trials of primary prevention cohorts (JUPITER and ASCOT) and secondary prevention cohorts (CARE and PROVE IT-TIMI 22). [11]

Taken together, these findings also suggest that PPAP2B and LPA may serve a role in predicting and screening coronary artery disease for early prevention. [14]

Interactions

Interactive Pathway Map

LPP3 participates in interactions within the triacylglyceride synthesis and sphingolipid metabolism pathways.

Related Research Articles

<span class="mw-page-title-main">Endothelium</span> Layer of cells that lining inner surface of blood vessels

The endothelium is a single layer of squamous endothelial cells that line the interior surface of blood vessels and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and the rest of the vessel wall. Endothelial cells form the barrier between vessels and tissue and control the flow of substances and fluid into and out of a tissue.

Phosphatidic acids are anionic phospholipids important to cell signaling and direct activation of lipid-gated ion channels. Hydrolysis of phosphatidic acid gives rise to one molecule each of glycerol and phosphoric acid and two molecules of fatty acids. They constitute about 0.25% of phospholipids in the bilayer.

<span class="mw-page-title-main">Lipid signaling</span> Biological signaling using lipid molecules

Lipid signaling, broadly defined, refers to any biological signaling event involving a lipid messenger that binds a protein target, such as a receptor, kinase or phosphatase, which in turn mediate the effects of these lipids on specific cellular responses. Lipid signaling is thought to be qualitatively different from other classical signaling paradigms because lipids can freely diffuse through membranes. One consequence of this is that lipid messengers cannot be stored in vesicles prior to release and so are often biosynthesized "on demand" at their intended site of action. As such, many lipid signaling molecules cannot circulate freely in solution but, rather, exist bound to special carrier proteins in serum.

Phospholipase D (EC 3.1.4.4, lipophosphodiesterase II, lecithinase D, choline phosphatase, PLD; systematic name phosphatidylcholine phosphatidohydrolase) is an enzyme of the phospholipase superfamily that catalyses the following reaction

<span class="mw-page-title-main">Lysophosphatidic acid</span> Chemical compound

Lysophosphatidic acid (LPA) is a phospholipid derivative that can act as a signaling molecule.

The lysophospholipid receptor (LPL-R) group are members of the G protein-coupled receptor family of integral membrane proteins that are important for lipid signaling. In humans, there are eleven LPL receptors, each encoded by a separate gene. These LPL receptor genes are also sometimes referred to as "Edg".

Endothelial lipase (LIPG) is a form of lipase secreted by vascular endothelial cells in tissues with high metabolic rates and vascularization, such as the liver, lung, kidney, and thyroid gland. The LIPG enzyme is a vital component to many biological processes. These processes include lipoprotein metabolism, cytokine expression, and lipid composition in cells. Unlike the lipases that hydrolyze Triglycerides, endothelial lipase primarily hydrolyzes phospholipids. Due to the hydrolysis specificity, endothelial lipase contributes to multiple vital systems within the body. On the contrary to the beneficial roles that LIPG plays within the body, endothelial lipase is thought to play a potential role in cancer and inflammation. Knowledge obtained in vitro and in vivo suggest the relations to these conditions, but human interaction knowledge lacks due to the recent discovery of endothelial lipase. Endothelial lipase was first characterized in 1999. The two independent research groups which are notable for this discovery cloned the endothelial lipase gene and identified the novel lipase secreted from endothelial cells. The anti-Atherosclerosis opportunity through alleviating plaque blockage and prospective ability to raise High-density lipoprotein (HDL) have gained endothelial lipase recognition.

<span class="mw-page-title-main">LPAR1</span> Protein

Lysophosphatidic acid receptor 1 also known as LPA1 is a protein that in humans is encoded by the LPAR1 gene. LPA1 is a G protein-coupled receptor that binds the lipid signaling molecule lysophosphatidic acid (LPA).

<span class="mw-page-title-main">S1PR3</span> Protein and coding gene in humans

Sphingosine-1-phosphate receptor 3 also known as S1PR3 is a human gene which encodes a G protein-coupled receptor which binds the lipid signaling molecule sphingosine 1-phosphate (S1P). Hence this receptor is also known as S1P3.

<span class="mw-page-title-main">LPAR4</span> Protein-coding gene in the species Homo sapiens

Lysophosphatidic acid receptor 4 also known as LPA4 is a protein that in humans is encoded by the LPAR4 gene. LPA4 is a G protein-coupled receptor that binds the lipid signaling molecule lysophosphatidic acid (LPA).

<span class="mw-page-title-main">LPAR2</span> Protein-coding gene in the species Homo sapiens

Lysophosphatidic acid receptor 2 also known as LPA2 is a protein that in humans is encoded by the LPAR2 gene. LPA2 is a G protein-coupled receptor that binds the lipid signaling molecule lysophosphatidic acid (LPA).

<span class="mw-page-title-main">Phosphatidate phosphatase</span>

The enzyme phosphatidate phosphatase (PAP, EC 3.1.3.4) is a key regulatory enzyme in lipid metabolism, catalyzing the conversion of phosphatidate to diacylglycerol:

<span class="mw-page-title-main">LPAR3</span> Protein-coding gene in the species Homo sapiens

Lysophosphatidic acid receptor 3 also known as LPA3 is a protein that in humans is encoded by the LPAR3 gene. LPA3 is a G protein-coupled receptor that binds the lipid signaling molecule lysophosphatidic acid (LPA).

<span class="mw-page-title-main">PPAP2A</span> Protein-coding gene in the species Homo sapiens

Lipid phosphate phosphohydrolase 1 also known as phosphatidic acid phosphatase 2a is an enzyme that in humans is encoded by the PPAP2A gene.

<span class="mw-page-title-main">Phosphatidic acid phosphatase 2c</span> Protein-coding gene in the species Homo sapiens

Lipid phosphate phosphohydrolase 2 is an enzyme that in humans is encoded by the PPAP2C gene.

<span class="mw-page-title-main">AGPAT1</span> Protein-coding gene in the species Homo sapiens

1-acyl-sn-glycerol-3-phosphate acyltransferase alpha is an enzyme that in humans is encoded by the AGPAT1 gene.

<span class="mw-page-title-main">AGK (gene)</span> Protein-coding gene in the species Homo sapiens

The human gene AGK encodes the enzyme mitochondrial acylglycerol kinase.

<span class="mw-page-title-main">Epoxide hydrolase 2</span> Protein-coding gene in the species Homo sapiens

Soluble epoxide hydrolase (sEH) is a bifunctional enzyme that in humans is encoded by the EPHX2 gene. sEH is a member of the epoxide hydrolase family. This enzyme, found in both the cytosol and peroxisomes, binds to specific epoxides and converts them to the corresponding diols. A different region of this protein also has lipid-phosphate phosphatase activity. Mutations in the EPHX2 gene have been associated with familial hypercholesterolemia.

<span class="mw-page-title-main">Gintonin</span> Protein found in [[ginseng]]

Gintonin is a glycolipoprotein fraction isolated from ginseng. The non-saponin ingredient was designated as gintonin, where gin was derived from ginseng, ton from the tonic effects of ginseng, and in from protein. The main component of gintonin is a complex of lysophosphatidic acids (LPA) and ginseng proteins such as ginseng major latex-like protein151 (GLP151) and ginseng ribonuclease-like storage protein.

<span class="mw-page-title-main">Lysophosphatidic acid phosphatase type 6</span> Protein-coding gene in the species Homo sapiens

Lysophosphatidic acid phosphatase type 6 is an acid phosphatase enzyme that is encoded in humans by the ACP6 gene.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000162407 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000028517 - Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ↑ Kai M, Wada I, Imai Si, Sakane F, Kanoh H (September 1997). "Cloning and characterization of two human isozymes of Mg2+-independent phosphatidic acid phosphatase". The Journal of Biological Chemistry. 272 (39): 24572–8. doi: 10.1074/jbc.272.39.24572 . PMID   9305923.
  6. 1 2 "Entrez Gene: PPAP2B phosphatidic acid phosphatase type 2B".
  7. 1 2 "PLPP3 - Phospholipid phosphatase 3 - Homo sapiens (Human) - PLPP3 gene & protein". www.uniprot.org. Retrieved 2016-08-17.
  8. ↑ "BioGPS - your Gene Portal System". biogps.org. Retrieved 2016-08-17.
  9. ↑ Ishikawa T, Kai M, Wada I, Kanoh H (April 2000). "Cell surface activities of the human type 2b phosphatidic acid phosphatase". Journal of Biochemistry. 127 (4): 645–51. doi:10.1093/oxfordjournals.jbchem.a022652. PMID   10739957.
  10. 1 2 Yung YC, Stoddard NC, Chun J (July 2014). "LPA receptor signaling: pharmacology, physiology, and pathophysiology". Journal of Lipid Research. 55 (7): 1192–214. doi:10.1194/jlr.R046458. PMC   4076099 . PMID   24643338.
  11. 1 2 Mega JL, Stitziel NO, Smith JG, Chasman DI, Caulfield MJ, Devlin JJ, Nordio F, Hyde CL, Cannon CP, Sacks FM, Poulter NR, Sever PS, Ridker PM, Braunwald E, Melander O, Kathiresan S, Sabatine MS (June 2015). "Genetic risk, coronary heart disease events, and the clinical benefit of statin therapy: an analysis of primary and secondary prevention trials". Lancet. 385 (9984): 2264–71. doi:10.1016/S0140-6736(14)61730-X. PMC   4608367 . PMID   25748612.
  12. ↑ Roberts R, Sciorra VA, Morris AJ (August 1998). "Human type 2 phosphatidic acid phosphohydrolases. Substrate specificity of the type 2a, 2b, and 2c enzymes and cell surface activity of the 2a isoform". The Journal of Biological Chemistry. 273 (34): 22059–67. doi: 10.1074/jbc.273.34.22059 . PMID   9705349.
  13. 1 2 Long JS, Pyne NJ, Pyne S (April 2008). "Lipid phosphate phosphatases form homo- and hetero-oligomers: catalytic competency, subcellular distribution and function" (PDF). The Biochemical Journal. 411 (2): 371–7. doi:10.1042/BJ20071607. PMID   18215144.
  14. 1 2 Ren H, Panchatcharam M, Mueller P, Escalante-Alcalde D, Morris AJ, Smyth SS (January 2013). "Lipid phosphate phosphatase (LPP3) and vascular development". Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids. 1831 (1): 126–32. doi:10.1016/j.bbalip.2012.07.012. PMC   3683602 . PMID   22835522.
  15. ↑ English D, Kovala AT, Welch Z, Harvey KA, Siddiqui RA, Brindley DN, Garcia JG (December 1999). "Induction of endothelial cell chemotaxis by sphingosine 1-phosphate and stabilization of endothelial monolayer barrier function by lysophosphatidic acid, potential mediators of hematopoietic angiogenesis". Journal of Hematotherapy & Stem Cell Research. 8 (6): 627–34. doi:10.1089/152581699319795. PMID   10645770.
  16. 1 2 Wu C, Huang RT, Kuo CH, Kumar S, Kim CW, Lin YC, Chen YJ, Birukova A, Birukov KG, Dulin NO, Civelek M, Lusis AJ, Loyer X, Tedgui A, Dai G, Jo H, Fang Y (July 2015). "Mechanosensitive PPAP2B Regulates Endothelial Responses to Atherorelevant Hemodynamic Forces". Circulation Research. 117 (4): e41–53. doi:10.1161/CIRCRESAHA.117.306457. PMC   4522239 . PMID   26034042.
  17. ↑ Escalante-Alcalde D, Hernandez L, Le Stunff H, Maeda R, Lee HS, Sciorra VA, Daar I, Spiegel S, Morris AJ, Stewart CL (October 2003). "The lipid phosphatase LPP3 regulates extra-embryonic vasculogenesis and axis patterning". Development. 130 (19): 4623–37. doi: 10.1242/dev.00635 . PMID   12925589.
  18. ↑ Arnold SJ, Stappert J, Bauer A, Kispert A, Herrmann BG, Kemler R (March 2000). "Brachyury is a target gene of the Wnt/beta-catenin signaling pathway". Mechanisms of Development. 91 (1–2): 249–58. doi: 10.1016/s0925-4773(99)00309-3 . PMID   10704849. S2CID   8394480.
  19. ↑ Siess W, Zangl KJ, Essler M, Bauer M, Brandl R, Corrinth C, Bittman R, Tigyi G, Aepfelbacher M (June 1999). "Lysophosphatidic acid mediates the rapid activation of platelets and endothelial cells by mildly oxidized low density lipoprotein and accumulates in human atherosclerotic lesions". Proceedings of the National Academy of Sciences of the United States of America. 96 (12): 6931–6. Bibcode:1999PNAS...96.6931S. doi: 10.1073/pnas.96.12.6931 . PMC   22019 . PMID   10359816.
  20. ↑ Kurano M, Suzuki A, Inoue A, Tokuhara Y, Kano K, Matsumoto H, Igarashi K, Ohkawa R, Nakamura K, Dohi T, Miyauchi K, Daida H, Tsukamoto K, Ikeda H, Aoki J, Yatomi Y (February 2015). "Possible involvement of minor lysophospholipids in the increase in plasma lysophosphatidic acid in acute coronary syndrome". Arteriosclerosis, Thrombosis, and Vascular Biology. 35 (2): 463–70. doi: 10.1161/ATVBAHA.114.304748 . PMID   25425621.
  21. ↑ Escalante-Alcalde D, Hernandez L, Le Stunff H, Maeda R, Lee HS, Sciorra VA, Daar I, Spiegel S, Morris AJ, Stewart CL (October 2003). "The lipid phosphatase LPP3 regulates extra-embryonic vasculogenesis and axis patterning". Development. 130 (19): 4623–37. doi: 10.1242/dev.00635 . PMID   12925589.
  22. ↑ Evans JF, Hutchinson JH (July 2010). "Seeing the future of bioactive lipid drug targets". Nature Chemical Biology. 6 (7): 476–9. doi:10.1038/nchembio.394. PMID   20559310.
  23. ↑ Schober A, Siess W (October 2012). "Lysophosphatidic acid in atherosclerotic diseases". British Journal of Pharmacology. 167 (3): 465–82. doi:10.1111/j.1476-5381.2012.02021.x. PMC   3449253 . PMID   22568609.
  24. ↑ Schunkert H, König IR, Kathiresan S, Reilly MP, Assimes TL, Holm H, et al. (April 2011). "Large-scale association analysis identifies 13 new susceptibility loci for coronary artery disease". Nature Genetics. 43 (4): 333–8. doi:10.1038/ng.784. PMC   3119261 . PMID   21378990.
  25. ↑ Erbilgin A, Civelek M, Romanoski CE, Pan C, Hagopian R, Berliner JA, Lusis AJ (July 2013). "Identification of CAD candidate genes in GWAS loci and their expression in vascular cells". Journal of Lipid Research. 54 (7): 1894–905. doi:10.1194/jlr.M037085. PMC   3679391 . PMID   23667179.

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