1. Gene Aliases

PLA2G2A, PLA2B, PLA2L, Phospholipase A2, Group IIA (Platelets, Synovial Fluid), Non-Pancreatic Secretory Phospholipase A2, Phosphatidylcholine 2-Acylhydrolase 2A, Phospholipase A2, Membrane Associated, Group IIA Phospholipase A2, GIIC SPLA2, NPS-PLA2, EC 3.1.1.4, RASF-A, PLA2S, PLAS1, SPLA2, MOM1, PLA2

[https://www.genecards.org/cgi-bin/carddisp.pl?gene=PLA2G2A&keywords=Pla2g2a].

2. Association with Toxicity and/or Disease at a Transcriptional Level

3. Summary of Protein Family and Structure

4. Proteins Known to Interact with Gene Product

Interactions with experimental support

5. Links to Gene Databases

6. GO Terms, MSigDB Signatures, Pathways Containing Gene with Descriptions of Gene Sets

Pathways:

GO terms:

arachidonic acid secretion [The controlled release of arachidonic acid from a cell or a tissue. This term should be used to annotate release of arachidonic acid from the cell. For the hydrolytic release of arachidonic acid from a phospholipid, consider instead annotating to 'phospholipase A2 activity ; GO:0004623'. GO:0050482]

cell population proliferation [The multiplication or reproduction of cells, resulting in the expansion of a cell population. This term was moved out from being a child of 'cellular process' because it is a cell population-level process, and cellular processes are restricted to those processes that involve individual cells. Also note that this term is intended to be used for the proliferation of cells within a multicellular organism, not for the expansion of a population of single-celled organisms. GO:0008283]

defense response to Gram-positive bacterium [Reactions triggered in response to the presence of a Gram-positive bacterium that act to protect the cell or organism. GO:0050830]

inflammatory response [The immediate defensive reaction (by vertebrate tissue) to infection or injury caused by chemical or physical agents. The process is characterized by local vasodilation, extravasation of plasma into intercellular spaces and accumulation of white blood cells and macrophages. GO:0006954]

intestinal stem cell homeostasis [Any biological process involved in the maintenance of the steady-state number of intestinal stem cells within a population of cells. GO:0036335]

killing of cells of another organism [Any process in an organism that results in the killing of cells of another organism, including in some cases the death of the other organism. Killing here refers to the induction of death in one cell by another cell, not cell-autonomous death due to internal or other environmental conditions. GO:0031640]

lipid catabolic process [The chemical reactions and pathways resulting in the breakdown of lipids, compounds soluble in an organic solvent but not, or sparingly, in an aqueous solvent. GO:0016042]

negative regulation of T cell proliferation [Any process that stops, prevents or reduces the rate or extent of T cell proliferation. GO:0042130]

negative regulation of cell population proliferation [Any process that stops, prevents or reduces the rate or extent of cell proliferation. GO:0008285]

negative regulation of epithelial cell proliferation [Any process that stops, prevents or reduces the rate or extent of epithelial cell proliferation. GO:0050680]

phosphatidic acid metabolic process [The chemical reactions and pathways involving phosphatidic acid, any derivative of glycerol phosphate in which both the remaining hydroxyl groups of the glycerol moiety are esterified with fatty acids. GO:0046473]

phosphatidylcholine metabolic process [The chemical reactions and pathways involving phosphatidylcholines, any of a class of glycerophospholipids in which the phosphatidyl group is esterified to the hydroxyl group of choline. They are important constituents of cell membranes. GO:0046470]

phosphatidylethanolamine metabolic process [The chemical reactions and pathways involving phosphatidylethanolamine, any of a class of glycerophospholipids in which a phosphatidyl group is esterified to the hydroxyl group of ethanolamine. It is a major structural phospholipid in mammalian systems. It tends to be more abundant than phosphatidylcholine in the internal membranes of the cell and is an abundant component of prokaryotic membranes. GO:0046337]

phospholipid metabolic process [The chemical reactions and pathways involving phospholipids, any lipid containing phosphoric acid as a mono- or diester. GO:0006644]

positive regulation of ERK1 and ERK2 cascade [Any process that activates or increases the frequency, rate or extent of signal transduction mediated by the ERK1 and ERK2 cascade. GO:0070374]

prostaglandin biosynthetic process [The chemical reactions and pathways resulting in the formation of prostaglandins, any of a group of biologically active metabolites which contain a cyclopentane ring. GO:0001516]

regulation of cell population proliferation [Any process that modulates the frequency, rate or extent of cell proliferation. GO:0042127]

regulation of endothelial cell proliferation [Any process that modulates the frequency, rate, or extent of endothelial cell proliferation. GO:0001936]

regulation of epithelial cell proliferation [Any process that modulates the frequency, rate or extent of epithelial cell proliferation. GO:0050678]

regulation of neutrophil activation [Any process that modulates the frequency, rate or extent of neutrophil activation. GO:1902563]

somatic stem cell population maintenance [Any process by which an organism retains a population of somatic stem cells, undifferentiated cells in the embryo or adult which can undergo unlimited division and give rise to cell types of the body other than those of the germ-line. GO:0035019]

MSigDB Signatures:

WP_CARDIAC_HYPERTROPHIC_RESPONSE: Cardiac hypertrophic response [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/WP_CARDIAC_HYPERTROPHIC_RESPONSE.html]

KEGG_VASCULAR_SMOOTH_MUSCLE_CONTRACTION: Vascular smooth muscle contraction [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/KEGG_VASCULAR_SMOOTH_MUSCLE_CONTRACTION.html]

WP_MICRORNAS_IN_CARDIOMYOCYTE_HYPERTROPHY: MicroRNAs in cardiomyocyte hypertrophy [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/WP_MICRORNAS_IN_CARDIOMYOCYTE_HYPERTROPHY.html]

REACTOME_METABOLISM_OF_LIPIDS: Metabolism of lipids [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/REACTOME_METABOLISM_OF_LIPIDS.html]

KEGG_VEGF_SIGNALING_PATHWAY: VEGF signaling pathway [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/KEGG_VEGF_SIGNALING_PATHWAY.html]

REACTOME_INNATE_IMMUNE_SYSTEM: Innate Immune System [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/REACTOME_INNATE_IMMUNE_SYSTEM.html]

REACTOME_PHOSPHOLIPID_METABOLISM: Phospholipid metabolism [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/REACTOME_PHOSPHOLIPID_METABOLISM.html]

KEGG_ETHER_LIPID_METABOLISM: Ether lipid metabolism [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/KEGG_ETHER_LIPID_METABOLISM.html]

WP_SPINAL_CORD_INJURY: Spinal cord injury [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/WP_SPINAL_CORD_INJURY.html]

KEGG_ALPHA_LINOLENIC_ACID_METABOLISM: alpha-Linolenic acid metabolism [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/KEGG_ALPHA_LINOLENIC_ACID_METABOLISM.html]

KEGG_ARACHIDONIC_ACID_METABOLISM: Arachidonic acid metabolism [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/KEGG_ARACHIDONIC_ACID_METABOLISM.html]

KEGG_MAPK_SIGNALING_PATHWAY: MAPK signaling pathway [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/KEGG_MAPK_SIGNALING_PATHWAY.html]

WP_RAS_SIGNALING: Ras signaling [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/WP_RAS_SIGNALING.html]

KEGG_GLYCEROPHOSPHOLIPID_METABOLISM: Glycerophospholipid metabolism [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/KEGG_GLYCEROPHOSPHOLIPID_METABOLISM.html]

REACTOME_GLYCEROPHOSPHOLIPID_BIOSYNTHESIS: Glycerophospholipid biosynthesis [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/REACTOME_GLYCEROPHOSPHOLIPID_BIOSYNTHESIS.html]

WP_GLYCEROPHOSPHOLIPID_BIOSYNTHETIC_PATHWAY: Glycerophospholipid biosynthetic pathway [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/WP_GLYCEROPHOSPHOLIPID_BIOSYNTHETIC_PATHWAY.html]

KEGG_LINOLEIC_ACID_METABOLISM: Linoleic acid metabolism [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/KEGG_LINOLEIC_ACID_METABOLISM.html]

REACTOME_ACYL_CHAIN_REMODELLING_OF_PC: Acyl chain remodelling of PC [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/REACTOME_ACYL_CHAIN_REMODELLING_OF_PC.html]

7. Gene Descriptions

NCBI Gene Summary: The protein encoded by this gene is a member of the phospholipase A2 family (PLA2). PLA2s constitute a diverse family of enzymes with respect to sequence, function, localization, and divalent cation requirements. This gene product belongs to group II, which contains secreted form of PLA2, an extracellular enzyme that has a low molecular mass and requires calcium ions for catalysis. It catalyzes the hydrolysis of the sn-2 fatty acid acyl ester bond of phosphoglycerides, releasing free fatty acids and lysophospholipids, and thought to participate in the regulation of the phospholipid metabolism in biomembranes. Several alternatively spliced transcript variants with different 5' UTRs have been found for this gene.

GeneCards Summary: PLA2G2A (Phospholipase A2 Group IIA) is a Protein Coding gene. Diseases associated with PLA2G2A include Colorectal Cancer and Familial Adenomatous Polyposis. Among its related pathways are Glycerophospholipid biosynthesis and MIF Mediated Glucocorticoid Regulation. Gene Ontology (GO) annotations related to this gene include calcium ion binding and phospholipase A2 activity. An important paralog of this gene is PLA2G2E.

UniProtKB/Swiss-Prot Summary: Secretory calcium-dependent phospholipase A2 that primarily targets extracellular phospholipids with implications in host antimicrobial defense, inflammatory response and tissue regeneration [PMID: 10455175, PMID: 10681567, PMID: 2925633]. Hydrolyzes the ester bond of the fatty acyl group attached at sn-2 position of phospholipids (phospholipase A2 activity) with preference for phosphatidylethanolamines and phosphatidylglycerols over phosphatidylcholines [PMID: 10455175, PMID: 10681567]. Contributes to lipid remodeling of cellular membranes and generation of lipid mediators involved in pathogen clearance. Displays bactericidal activity against Gram-positive bacteria by directly hydrolyzing phospholipids of the bacterial membrane [PMID: 11694541, PMID: 10358193]. Upon sterile inflammation, targets membrane phospholipids of extracellular mitochondria released from activated platelets, generating free unsaturated fatty acids such as arachidonate that is used by neighboring leukocytes to synthesize inflammatory eicosanoids such as leukotrienes. Simultaneously, by compromising mitochondrial membrane integrity, promotes the release in circulation of potent damage-associated molecular pattern molecules that activate the innate immune response [PMID: 25082876]. Plays a stem cell regulator role in the intestinal crypt. Within intracellular compartment mediates Paneth cell differentiation and its stem cell supporting functions by inhibiting Wnt signaling pathway in intestinal stem cell (ICS). Secreted in the intestinal lumen upon inflammation, acts in an autocrine way and promotes prostaglandin E2 synthesis that stimulates Wnt signaling pathway in ICS cells and tissue regeneration. May play a role in the biosynthesis of N-acyl ethanolamines that regulate energy metabolism and inflammation. Hydrolyzes N-acyl phosphatidylethanolamines to N-acyl lysophosphatidylethanolamines, which are further cleaved by a lysophospholipase D to release N-acyl ethanolamines [PMID: 14998370]. Independent of its catalytic activity, acts as a ligand for integrins [PMID: 18635536, PMID: 25398877]. Binds to and activates integrins ITGAV:ITGB3, ITGA4:ITGB1 and ITGA5:ITGB1 [PMID: 18635536, PMID: 25398877]. Binds to a site (site 2) which is distinct from the classical ligand-binding site (site 1) and induces integrin conformational changes and enhanced ligand binding to site 1 [PMID: 25398877]. Induces cell proliferation in an integrin-dependent manner [PMID: 18635536].

8. Cellular Location of Gene Product

Predicted location: Secreted, Intracellular (different isoforms) [https://www.proteinatlas.org/ENSG00000188257/subcellular]

9. Mechanistic Information

Summary

In heart diseases and toxic events affecting the heart, the upregulation of PLA2G2A, results in increased activity of secretory type II phospholipase A2 (sPLA2-IIA). This enzyme hydrolyzes the sn-2 fatty acid acyl ester bond of phospholipids, releasing free fatty acids and lysophospholipids [CS: 9]. This activity is vital in modulating the phospholipid metabolism in biomembranes and plays a role in inflammatory responses [CS: 8]. The upregulation of PLA2G2A in response to cellular stress and damage in the heart, such as in conditions induced by amiodarone treatment, suggests a defensive response involving altered phospholipid metabolism and cellular repair mechanisms [CS: 7].

The increased sPLA2-IIA activity due to PLA2G2A upregulation has several downstream effects in heart diseases. It amplifies inflammation by producing fatty acids that are precursors to pro-inflammatory eicosanoids [CS: 8]. Conditions like chronic intermittent hypoxia (CIH) lead to an increase in reactive oxygen species (ROS), which activate different forms of PLA2 [CS: 7]. The increased expression of sPLA2-IIa, encoded by PLA2G2A, in response to pro-inflammatory cytokines like IFN-gamma, TNF-alpha, and IL-1beta indicates its involvement in the inflammatory response [CS: 8]. Additionally, the enzyme's action on cellular membranes changes their composition, impacting cell signaling and function in the heart [CS: 6]. This response, while potentially aiding in clearing damaged cells and tissues, can contribute to further inflammation and damage [CS: 7].

10. Upstream Regulators

11. Tissues/Cell Type Where Genes are Overexpressed

Tissue type enchanced: adipose tissue, intestine, placenta, urinary bladder (group enriched) [https://www.proteinatlas.org/ENSG00000188257/tissue]

Cell type enchanced: distal enterocytes, exocrine glandular cells, fibroblasts, mesothelial cells, proximal enterocytes, undifferentiated cells (cell type enhanced) [https://www.proteinatlas.org/ENSG00000188257/single+cell+type]

12. Role of Gene in Other Tissues

13. Chemicals Known to Elicit Transcriptional Response of Biomarker in Tissue of Interest

Compounds that increase expression of the gene:

Compounds that decrease expression of the gene:

14. DisGeNet Biomarker Associations to Disease in Organ of Interest