PLA2G4A (phospholipase A2, group IVA (cytosolic, calcium-dependent))

2009-12-01   Amanda Linkous , Eugenia Yazlovitskaya 

Department of Radiation Oncology, Vanderbilt Ingram Cancer Center, Vanderbilt University, SS1411 Medical Center North, 1161 21 Avenue S., Nashville, TN 37232, USA




Atlas Image
PLA2G4A gene. PLA2G4A is comprised of 18 exons. The ATG start codon is located within exon 2 and the TAG stop codon is found in exon 18. The sizes of exons 1-18 are 135 bp, 101 bp, 81 bp, 148 bp, 113 bp, 37 bp, 141 bp, 136 bp, 222 bp, 114 bp, 137 bp, 92 bp, 71 bp, 242 bp, 184 bp, 195 bp, 157 bp, and 604 bp, respectively.


According to Entrez-Gene, human PLA2G4A maps to locus NC_000001.10. This gene contains 18 exons that encompass approximately 160 kb of genomic DNA. In mice, Pla2g4a maps to NC_000067.5 and contains 18 exons that span 131 kb of DNA within the mouse genome.


Human PLA2G4A mRNA (NG_024420) consists of 2940 bp, and murine Pla2g4a mRNA (NM_008869) contains 2846 bp.


No pseudogene has been identified for PLA2G4A.


Atlas Image
cPLA2-alpha structure. The binding of calcium (Ca2+) ions to the C2 domain promotes the translocation of cPLA2alpha from the cytosol to the perinuclear/membrane region of the cell. Following this change in subcellular localization, cPLA2alpha is phosphorylated on key serine residues by MAPKs (ERK1/ERK2 and p38), Ca2+/calmodulin-dependent protein kinase II (CaMKII), or MAPK-interacting kinase (Mnk1). Ser228 is located in the first catalytic domain and is critical for the enzymatic activity of cPLA2alpha.


cPLA2alpha is an 85 kDa protein consisting of 749 amino acids. cPLA2alpha belongs to the alpha-beta hydrolase family which is identified by a characteristic nucleophile elbow with a consensus sequence of Sm-X-Nu-Sm (Sm = small residue, X = any residue and Nu = nucleophile). The protein contains an N-terminal C2 domain (Ca2+-dependent, phospholipid binding) and two catalytic domains (alpha/beta hydrolase). The N-terminal region of the first catalytic domain contains the lipase consensus sequence, GXSGS. At the active site, cPLA2alpha contains a serine nucleophile (Ser228) through which the catalytic mechanism is initiated. The active site is partially covered by a solvent-accessible flexible lid which spans from Arg413 to Gln457. cPLA2alpha displays interfacial activation as it exists in both "closed lid" and "open lid" forms. Upon membrane binding, gross conformational changes in the enzyme result in the movement of the cPLA2alpha lid thus exposing a greater hydrophobic surface and the active site. This allows the fatty acyl chain of a substrate phospholipid molecule to enter the active site.


cPLA2alpha is ubiquitously expressed throughout normal tissues, but is often overexpressed in human cancers.


Prior to activation, cPLA2alpha is localized to the cytoplasm. Upon an influx of intracellular calcium (Ca2+), however, Ca2+ ions bind to the C2 domain and promote the translocation of cPLA2alpha to either the nuclear envelope, Golgi apparatus, endoplasmic reticulum, or plasma membrane. The membrane-associated localization is then stabilized through the binding of the protein to anionic phospholipids or by phosphorylation of Ser505, Ser515, or Ser727. As a result of these molecular events, the enzymatic activity of cPLA2alpha is increased.


Following activation by Ca2+ concentration and/or phosphorylation, cPLA2alpha hydrolyzes phospholipids at the sn-2-acyl ester bond to yield both free fatty acid as well as lysophospholipid second messengers.
Phosphatidylcholine (PC) is the most abundant phospholipid in mammalian cell membranes and is the primary target of cPLA2alpha. The cPLA2alpha-mediated cleavage of PC results in the release of arachidonic acid (AA) and lysophosphatidylcholine (LPC). AA is further metabolized to prostaglandins and leukotrienes by the cyclooxygenase and 5-lipoxygenase pathways, respectively. Thus, cPLA2alpha and AA are key contributors to the inflammatory process. Lipid second messengers such as LPC and lysophosphatidic acid (LPA) are involved in downstream signal transduction that affects cell survival, proliferation, motility, and invasiveness.


Homologs of human PLA2G4A have been identified in the following organisms : Pan troglodytes, Canis lupus familiaris, Bos taurus, Mus musculus, Rattus norvegicus, Gallus gallus, Danio rerio. In addition, at least four paralogs of cPLA2 have been identified in mammals. They include cPLA2alpha, cPLA2beta, cPLA2gamma, and cPLA2delta. All paralogs contain the N-terminal C2 domain except cPLA2gamma. Human cPLA2gamma also harbors a myristoylation site at the N-terminus and is farnesylated at the C-terminus. The main residues that are essential to cPLA2 catalytic activity (Arg200, Ser228, Asp549, Arg566) are conserved among all four paralogs of the enzyme.



In a study performed on 118 British family trios of schizophrenia patients, six single nucleotide polymorphisms (SNPs) were identified in the PTGS2/PLA2G4A locus. SNP4 was detected in the 5-flanking region of the gene and was associated with elevated susceptibility to schizophrenia.
In a separate study of inherited prostanoid biosynthesis deficiency, a patient was found to possess three mutations of the PLA2G4A gene (S111P, R485H, and K651R). As a result of these mutations, the patient suffered from recurrent ulcerations of the small intestine and repeated episodes of gastrointestinal bleeding. Thus, such findings suggest that cPLA2alpha is important for maintaining the integrity of the small intestine.


Overexpression of cPLA2alpha has been identified in a variety of cancers including Non-small cell lung cancer (NSCLC), cholangiosarcomas, esophageal cancers, and cancers of the colon and small intestine. In many cases of NSCLC, cPLA2alpha expression is often associated with the presence of oncogenic Ras mutations.

Implicated in

Entity name
Solid cancers
Non-small cell lung cancer, cholangiosarcoma, colorectal cancer, esophageal cancer, cancer of the small intestine, and ovarian cancer.
cPLA2alpha has been shown to contribute to tumor progression through increased COX-2 production and the promotion of angiogenesis by arachidonic acid and LPC. Activation of cPLA2alpha is also associated with increased resistance to radiation therapy among tumor vasculature. This resistance is often the result of cPLA2alpha-mediated LPC generation and subsequent downstream activation of the PI3K/Akt and MAPK pro-survival signal transduction pathways.
Entity name
Non-small cell lung cancer (NSCLC)
Multiple studies have shown that cPLA2alpha is frequently overexpressed in established NSCLC cell lines and tumor tissue samples from NSCLC patients. Overexpression of cPLA2alpha resulted in increased levels of COX-2 as well as PGE2. Both COX-2 and PGE2 are associated with enhanced lung tumorigenesis.
Entity name
Cholangiosarcoma is a tumor of the bile duct connective tissues that accounts for 10-15% of primary liver cancers. In this highly malignant tumor, a 5-fold increase in cPLA2alpha mRNA has been reported. In addition, cPLA2alpha has been shown to activate a nuclear receptor, peroxisome proliferator-activated receptor-delta (PPARdelta). Activation of PPARdelta accelerates the growth of human cholangiosarcoma.
Entity name
Colorectal cancer
Compared to normal colon tissue, cPLA2alpha protein levels and enzymatic activity are often elevated as much as 50-60% in surgically excised human tumor tissue and established colon cancer cell lines. Increased cPLA2alpha expression was positively correlated with enhanced COX-2 expression. COX-2 plays a vital role in the progression of colorectal cancer through its promotion of cellular proliferation, angiogenesis, invasion, and metastasis.
Entity name
Esophageal cancer
Esophageal cancer is the sixth-leading cause of cancer-related death in the world. With an 18% increase in cPLA2alpha protein levels in tumor cells, recent reports have demonstrated that activation of the cPLA2alpha/COX-2 pathway stimulates esophageal squamous-cell carcinoma cellular proliferation.
Entity name
Tumors of the small intestine
In vivo studies using cPLA2alpha-deficient/APCMin mice revealed that the size of small intestinal polyps was reduced by 11-fold compared to their cPLA2alpha+/+/APCMin counterparts. The results also demonstrated an 83% reduction in the total number of intestinal tumors in cPLA2alpha-deficient/APCMin mice.
Entity name
Ovarian cancer
cPLA2alpha is responsible for the production of lysophosphatidylcholine (LPC). However, LPC is frequently hydrolyzed to lysophosphatidic acid (LPA) which is a known stimulant of tumor cell proliferation, migration, invasion, and metastasis. A growing number of reports have shown that plasma LPA levels are elevated in ovarian cancer patients. In a study of 133 patients, women with ovarian cancer exhibited significantly higher LPA levels within their plasma (16.99 µM) compared to patients with benign ovarian tumors (7.73 µM) or patients with no ovarian malignancy (2.92 µM). Thus, cPLA2alpha may serve as an important target for ovarian cancer therapy.
Entity name
Other diseases
cPLA2alpha has also been implicated in a variety of other diseases including cardiovascular disease, diabetes, asthma, and arthritis. In addition to these and other inflammatory disorders, cPLA2alpha expression is positively correlated with psychiatric disease states such as schizophrenia, Alzheimers disease, and mood disorders.


Pubmed IDLast YearTitleAuthors
184519932008Inherited human cPLA(2alpha) deficiency is associated with impaired eicosanoid biosynthesis, small intestinal ulceration, and platelet dysfunction.Adler DH et al
102153421999The 85-kD cytosolic phospholipase A2 knockout mouse: a new tool for physiology and cell biology.Bonventre JV et al
110806752000Structure and mechanism of human cytosolic phospholipase A(2).Dessen A et al
153050152004Regulatory mechanism and physiological role of cytosolic phospholipase A2.Hirabayashi T et al
192401732009Cytosolic phospholipase A2: targeting cancer through the tumor vasculature.Linkous A et al
184521592008Epinephrine stimulates esophageal squamous-cell carcinoma cell proliferation via beta-adrenoceptor-dependent transactivation of extracellular signal-regulated kinase/cyclooxygenase-2 pathway.Liu X et al
170529512006Roles of cPLA2alpha and arachidonic acid in cancer.Nakanishi M et al
190518242008Lysophosphatidic acid: an ovarian cancer marker.Sedláková I et al
150410362004A study of a genetic association between the PTGS2/PLA2G4A locus and schizophrenia.Wei J et al
192088322009Depletion of cytosolic phospholipase A2 in bone marrow-derived macrophages protects against lung cancer progression and metastasis.Weiser-Evans MC et al
169663362006A novel positive feedback loop between peroxisome proliferator-activated receptor-delta and prostaglandin E2 signaling pathways for human cholangiocarcinoma cell growth.Xu L et al
185666012008Cytosolic phospholipase A2 regulates viability of irradiated vascular endothelium.Yazlovitskaya EM et al

Other Information

Locus ID:

NCBI: 5321
MIM: 600522
HGNC: 9035
Ensembl: ENSG00000116711


dbSNP: 5321
ClinVar: 5321
TCGA: ENSG00000116711


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
Glycerophospholipid metabolismKEGGko00564
Ether lipid metabolismKEGGko00565
Arachidonic acid metabolismKEGGko00590
Linoleic acid metabolismKEGGko00591
alpha-Linolenic acid metabolismKEGGko00592
MAPK signaling pathwayKEGGko04010
VEGF signaling pathwayKEGGko04370
Fc epsilon RI signaling pathwayKEGGko04664
Long-term depressionKEGGko04730
GnRH signaling pathwayKEGGko04912
Glycerophospholipid metabolismKEGGhsa00564
Ether lipid metabolismKEGGhsa00565
Arachidonic acid metabolismKEGGhsa00590
Linoleic acid metabolismKEGGhsa00591
alpha-Linolenic acid metabolismKEGGhsa00592
MAPK signaling pathwayKEGGhsa04010
VEGF signaling pathwayKEGGhsa04370
Fc epsilon RI signaling pathwayKEGGhsa04664
Long-term depressionKEGGhsa04730
GnRH signaling pathwayKEGGhsa04912
Vascular smooth muscle contractionKEGGhsa04270
Vascular smooth muscle contractionKEGGko04270
Fc gamma R-mediated phagocytosisKEGGko04666
Fc gamma R-mediated phagocytosisKEGGhsa04666
Metabolic pathwaysKEGGhsa01100
Glutamatergic synapseKEGGko04724
Glutamatergic synapseKEGGhsa04724
Serotonergic synapseKEGGhsa04726
Ovarian steroidogenesisKEGGhsa04913
Ovarian steroidogenesisKEGGko04913
Ras signaling pathwayKEGGhsa04014
Inflammatory mediator regulation of TRP channelsKEGGhsa04750
Inflammatory mediator regulation of TRP channelsKEGGko04750
Platelet activationKEGGhsa04611
Oxytocin signaling pathwayKEGGhsa04921
Oxytocin signaling pathwayKEGGko04921
Choline metabolism in cancerKEGGhsa05231
Choline metabolism in cancerKEGGko05231
Platelet homeostasisREACTOMER-HSA-418346
Platelet sensitization by LDLREACTOMER-HSA-432142
Platelet activation, signaling and aggregationREACTOMER-HSA-76002
Signal amplificationREACTOMER-HSA-392518
ADP signalling through P2Y purinoceptor 1REACTOMER-HSA-418592
Signal TransductionREACTOMER-HSA-162582
Signaling by GPCRREACTOMER-HSA-372790
Opioid SignallingREACTOMER-HSA-111885
G-protein mediated eventsREACTOMER-HSA-112040
PLC beta mediated eventsREACTOMER-HSA-112043
Ca-dependent eventsREACTOMER-HSA-111996
phospho-PLA2 pathwayREACTOMER-HSA-111995
Vesicle-mediated transportREACTOMER-HSA-5653656
Membrane TraffickingREACTOMER-HSA-199991
Metabolism of lipids and lipoproteinsREACTOMER-HSA-556833
Phospholipid metabolismREACTOMER-HSA-1483257
Glycerophospholipid biosynthesisREACTOMER-HSA-1483206
Synthesis of PAREACTOMER-HSA-1483166
Acyl chain remodelling of PEREACTOMER-HSA-1482839
Acyl chain remodelling of PCREACTOMER-HSA-1482788
Hydrolysis of LPCREACTOMER-HSA-1483115
Acyl chain remodelling of PSREACTOMER-HSA-1482801
Acyl chain remodelling of PIREACTOMER-HSA-1482922
Acyl chain remodelling of PGREACTOMER-HSA-1482925
Acyl chain remodeling of CLREACTOMER-HSA-1482798
Arachidonic acid metabolismREACTOMER-HSA-2142753
Phospholipase D signaling pathwayKEGGko04072
Phospholipase D signaling pathwayKEGGhsa04072
Intra-Golgi and retrograde Golgi-to-ER trafficREACTOMER-HSA-6811442
Golgi-to-ER retrograde transportREACTOMER-HSA-8856688
COPI-independent Golgi-to-ER retrograde trafficREACTOMER-HSA-6811436

Protein levels (Protein atlas)

Not detected


Entity IDNameTypeEvidenceAssociationPKPDPMIDs
PA451140propionic acid derivativesChemicalClinicalAnnotationassociatedPD26398624


Pubmed IDYearTitleCitations
185839792008Systematic meta-analyses and field synopsis of genetic association studies in schizophrenia: the SzGene database.395
203517142011Poor replication of candidate genes for major depressive disorder using genome-wide association data.92
199131212009Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip.85
203796142010Personalized smoking cessation: interactions between nicotine dose, dependence and quit-success genotype score.62
150070702004Arachidonic acid release from mammalian cells transfected with human groups IIA and X secreted phospholipase A(2) occurs predominantly during the secretory process and with the involvement of cytosolic phospholipase A(2)-alpha.55
200346142010Phospholipase A2 and cyclooxygenase 2 genes influence the risk of interferon-alpha-induced depression by regulating polyunsaturated fatty acids levels.53
200346142010Phospholipase A2 and cyclooxygenase 2 genes influence the risk of interferon-alpha-induced depression by regulating polyunsaturated fatty acids levels.53
229114312012MAP-kinase regulated cytosolic phospholipase A2 activity is essential for production of infectious hepatitis C virus particles.47
197531002009Group IV phospholipase A(2)alpha controls the formation of inter-cisternal continuities involved in intra-Golgi transport.44
154753632005Cytosolic phospholipase A2-alpha is necessary for platelet-activating factor biosynthesis, efficient neutrophil-mediated bacterial killing, and the innate immune response to pulmonary infection: cPLA2-alpha does not regulate neutrophil NADPH oxidase activity.40


Amanda Linkous ; Eugenia Yazlovitskaya

PLA2G4A (phospholipase A2, group IVA (cytosolic, calcium-dependent))

Atlas Genet Cytogenet Oncol Haematol. 2009-12-01

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