PEA15 (phosphoprotein enriched in astrocytes 15)

2012-05-01   Chandra Bartholomeusz , Jangsoon Lee , Naoto T Ueno 

Section of Translational Breast Cancer Research, Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA




Atlas Image
Structure of the human PEA15 gene. Red box: PEA15 coding region; blue box: PEA15 non-coding region; white box: 3 end of H326 region; SNP position: indicated by vertical arrows; Alu element (AA491823) 5 of PEA15: represented by brackets (Wolford et al., 2000, license permission no.: 2907741403264).


According to Entrez Gene, PEA15 maps to NC_000001.10 and spans a region of 10042 bases. PEA15 consists of four exons. Exon 1 and the beginning of exon 2 contain untranslated sequences. The end of exon 2, exon 3, and the beginning of exon 4 contain the coding sequence.


Two transcripts, with lengths of 2,5 and 1,7 kb, have been identified. They are identical except for the length of their 3 UTRs.


No pseudogene of PEA15 known.


Atlas Image
DED: death effector domain, amino acid region 3-81, Pfam: PF01335 (Sanger); NES: leucine-rich nuclear export sequence, amino acid region 7-17; MT: microtubule-binding region, amino acid region 98-107, and 122-129; PLD-1 binding region: phospholipase D1 binding site, amino acid region 1-24; ERK binding site: amino acid position 74, 121, 123, and 129; RSK2 binding site: amino acid position 123; Serine 104: phosphorylation site by PKC; Serine 116: phosphorylation site by AKT or CaKMII.


PEA-15 is a 130-amino-acid protein with a predicted molecular mass of 15054 daltons and a calculated isoelectric point of 5.12.


Ovary, breast, brain, placenta, liver, eye, lung, heart, endothelial cells, pancreas, testis, uterus, adrenal gland, prostate gland, kidney, spleen, and astrocytes.


Cytoplasm. PEA-15 has a leucine-rich nuclear export sequence (NES), which is required for predominantly localizing in the cytoplasm (Formstecher et al., 2001).


PEA-15 is a ubiquitously expressed protein that exists in non-phosphorylated, mono-phosphorylated, and double-phosphorylated forms (Danziger et al., 1995). PEA-15 does not have an enzymatic domain but serves as a binding molecule in protein complexes. PEA-15 is an endogenous substrate that depends on two distinct serine sites: Ser104, which is phosphorylated by protein kinase C (PKC) (Kubes et al., 1998), and Ser116, which is phosphorylated by Ca2+/calmodulin kinase II (CaMKII) (Kubes et al., 1998) or by AKT (Trencia et al., 2003). At its NH2 terminus, PEA-15 has a PLD-interacting region, which enhances PLD 1 stability and activity (Zhang et al., 2000), and a death effector domain (DED), which enables interaction with DED-containing signaling proteins, including Fas-associated protein with death domain (FADD) and FADD-like IL-1β-converting enzyme (Peter et al., 1999). At its COOH terminus, PEA-15 has a microtubule-binding region, which regulates the stability of tubulins (Danziger et al., 1995).
ERK inhibition. PEA-15 can bind to ERK and sequester it in the cytoplasm. The resulting inhibition of ERKs translocalization into the nucleus blocks ERK-dependent transcriptional activity and cell proliferation (Formstecher et al., 2001).
Apoptosis and anti-apoptosis. PEA-15 interacts with different DED-containing proteins such as FADD and FLICE and inhibits Fas/TNFR1-induced apoptosis by preventing formation of the death-inducing signaling complex (DISC) (Condorelli et al., 1999; Song et al., 2006). On the other hand, under different cellular stresses, PEA-15 acts as a substrate of Omi/HtrA2, which is a proapoptotic mitochondrial serine protease; it results in reducing anti-apoptotic action of Omi/HtrA2 and triggering apoptotic programs (Trencia et al., 2004).
Metabolism. In skeletal muscle and adipose cells, PEA-15 binds to PLD1 and enhances PKC-α activity, thereby inducing resistance to insulin action in glucose uptake (Condorelli et al., 1998).
Invasion. A high expression level of PEA-15 is correlated with low invasive behavior of breast cancer (Glading et al., 2007). PEA-15s prevention of ERKs nuclear localization results in reduced invasion capability in breast cancer.
Tumorigenicity. In human breast cancers, low levels of PEA-15 expression correlated with high nuclear grade and with negative hormone receptor status. Overexpression of PEA-15 in breast cancer cells resulted in growth inhibition, reduction in DNA synthesis, and onset of caspase-8-dependent apoptosis (Bartholomeusz et al., 2010). In transgenic mice with overexpression of PEA-15, its expression level had a significant impact on skin tumor development upon chemically induced skin carcinogenesis (Formisano et al., 2005). In in vitro studies, PEA-15 enhanced Ras-MAPK/ERK signaling in the presence of constitutively active H-Ras and drove transformation of kidney epithelial cells (Sulzmaier et al., 2012; Ramos et al., 2000).


The mouse and human sequences are conserved. In both species, the 3 UTR of the 2,5-kb PEA15 cDNA contains the proto-oncogene MAT1 (Tsukamoto et al., 2000).



No known mutations have been reported.

Implicated in

Entity name
Breast cancer
See above "Invasion" and "Tumorigenicity" sections.
Entity name
Ovarian cancer
In ovarian cancer, women with high PEA-15-expressing tumors survive longer than those with low PEA-15-expressing tumors, indicating that PEA-15 is a good prognostic marker (Bartholomeusz et al., 2008).
Entity name
Astrocytic tumors
In astrocytic tumors, decreased PEA-15 expression level was correlated with poor overall survival in patients with high-grade astrocytoma (Watanabe et al., 2010).
Entity name
High levels of PEA-15 expression correlated with increased survival of patients with neuroblastoma (Gawecka et al., 2012).
Entity name
Skin tumors
PEA-15 increases the susceptibility to chemically induced skin cancer in transgenic mice (Formisano et al., 2005).


Pubmed IDLast YearTitleAuthors
202155472010PEA-15 inhibits tumorigenesis in an MDA-MB-468 triple-negative breast cancer xenograft model through increased cytoplasmic localization of activated extracellular signal-regulated kinase.Bartholomeusz C et al
104426311999PED/PEA-15: an anti-apoptotic molecule that regulates FAS/TNFR1-induced apoptosis.Condorelli G et al
78611301995Cellular expression, developmental regulation, and phylogenic conservation of PEA-15, the astrocytic major phosphoprotein and protein kinase C substrate.Danziger N et al
86629701996The major astrocytic phosphoprotein PEA-15 is encoded by two mRNAs conserved on their full length in mouse and human.Estellés A et al
160441592005Raised expression of the antiapoptotic protein ped/pea-15 increases susceptibility to chemically induced skin tumor development.Formisano P et al
117027832001PEA-15 mediates cytoplasmic sequestration of ERK MAP kinase.Formstecher E et al
222130502012PEA15 impairs cell migration and correlates with clinical features predicting good prognosis in neuroblastoma.Gawecka JE et al
173080922007PEA-15 inhibits tumor cell invasion by binding to extracellular signal-regulated kinase 1/2.Glading A et al
97217571998Endothelin induces a calcium-dependent phosphorylation of PEA-15 in intact astrocytes: identification of Ser104 and Ser116 phosphorylated, respectively, by protein kinase C and calcium/calmodulin kinase II in vitro.Kubes M et al
99500281999The death receptors.Peter ME et al
109823862000Death effector domain protein PEA-15 potentiates Ras activation of extracellular signal receptor-activated kinase by an adhesion-independent mechanism.Ramos JW et al
165544802006Human astrocytes are resistant to Fas ligand and tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis.Song JH et al
160616472005PED mediates AKT-dependent chemoresistance in human breast cancer cells.Stassi G et al
221053572012PEA-15 potentiates H-Ras-mediated epithelial cell transformation through phospholipase D.Sulzmaier FJ et al
153283492004Omi/HtrA2 promotes cell death by binding and degrading the anti-apoptotic protein ped/pea-15.Trencia A et al
128080932003Protein kinase B/Akt binds and phosphorylates PED/PEA-15, stabilizing its antiapoptotic action.Trencia A et al
107377142000Expression of MAT1/PEA-15 mRNA isoforms during physiological and neoplastic changes in the mouse mammary gland.Tsukamoto T et al
204550022010Expression of phosphoprotein enriched in astrocytes 15 kDa (PEA-15) in astrocytic tumors: a novel approach of correlating malignancy grade and prognosis.Watanabe Y et al
106079082000Molecular characterization of the human PEA15 gene on 1q21-q22 and association with type 2 diabetes mellitus in Pima Indians.Wolford JK et al
109269292000Regulation of expression of phospholipase D1 and D2 by PEA-15, a novel protein that interacts with them.Zhang Y et al

Other Information

Locus ID:

NCBI: 8682
MIM: 603434
HGNC: 8822
Ensembl: ENSG00000162734


dbSNP: 8682
ClinVar: 8682
TCGA: ENSG00000162734


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
Immune SystemREACTOMER-HSA-168256
Innate Immune SystemREACTOMER-HSA-168249
DAP12 interactionsREACTOMER-HSA-2172127
DAP12 signalingREACTOMER-HSA-2424491
RAF/MAP kinase cascadeREACTOMER-HSA-5673001
Fc epsilon receptor (FCERI) signalingREACTOMER-HSA-2454202
FCERI mediated MAPK activationREACTOMER-HSA-2871796
Cytokine Signaling in Immune systemREACTOMER-HSA-1280215
Signaling by InterleukinsREACTOMER-HSA-449147
Interleukin-2 signalingREACTOMER-HSA-451927
Interleukin receptor SHC signalingREACTOMER-HSA-912526
Interleukin-3, 5 and GM-CSF signalingREACTOMER-HSA-512988
Signal TransductionREACTOMER-HSA-162582
Signaling by EGFRREACTOMER-HSA-177929
GRB2 events in EGFR signalingREACTOMER-HSA-179812
SHC1 events in EGFR signalingREACTOMER-HSA-180336
Signaling by Insulin receptorREACTOMER-HSA-74752
Insulin receptor signalling cascadeREACTOMER-HSA-74751
IRS-mediated signallingREACTOMER-HSA-112399
SOS-mediated signallingREACTOMER-HSA-112412
Signalling by NGFREACTOMER-HSA-166520
NGF signalling via TRKA from the plasma membraneREACTOMER-HSA-187037
Signalling to ERKsREACTOMER-HSA-187687
Signalling to RASREACTOMER-HSA-167044
Signalling to p38 via RIT and RINREACTOMER-HSA-187706
Prolonged ERK activation eventsREACTOMER-HSA-169893
Frs2-mediated activationREACTOMER-HSA-170968
ARMS-mediated activationREACTOMER-HSA-170984
Signaling by PDGFREACTOMER-HSA-186797
Downstream signal transductionREACTOMER-HSA-186763
Signaling by VEGFREACTOMER-HSA-194138
VEGFR2 mediated cell proliferationREACTOMER-HSA-5218921
Signaling by SCF-KITREACTOMER-HSA-1433557
MAPK family signaling cascadesREACTOMER-HSA-5683057
MAPK1/MAPK3 signalingREACTOMER-HSA-5684996
RAF-independent MAPK1/3 activationREACTOMER-HSA-112409
Signaling by GPCRREACTOMER-HSA-372790
Gastrin-CREB signalling pathway via PKC and MAPKREACTOMER-HSA-881907
Signaling by Type 1 Insulin-like Growth Factor 1 Receptor (IGF1R)REACTOMER-HSA-2404192
IGF1R signaling cascadeREACTOMER-HSA-2428924
IRS-related events triggered by IGF1RREACTOMER-HSA-2428928
Signaling by LeptinREACTOMER-HSA-2586552
Developmental BiologyREACTOMER-HSA-1266738
Axon guidanceREACTOMER-HSA-422475
NCAM signaling for neurite out-growthREACTOMER-HSA-375165
RET signalingREACTOMER-HSA-8853659

Protein levels (Protein atlas)

Not detected


Pubmed IDYearTitleCitations
128080932003Protein kinase B/Akt binds and phosphorylates PED/PEA-15, stabilizing its antiapoptotic action.51
119763442002Tumor necrosis factor-related apoptosis-inducing ligand-induced death-inducing signaling complex and its modulation by c-FLIP and PED/PEA-15 in glioma cells.45
159165342005Phosphorylation of PEA-15 switches its binding specificity from ERK/MAPK to FADD.40
195316392009Frontiers: PED/PEA-15, a multifunctional protein controlling cell survival and glucose metabolism.34
176588922007The anti-apoptotic protein PEA-15 is a tight binding inhibitor of ERK1 and ERK2, which blocks docking interactions at the D-recruitment site.30
235756852013Structure of ERK2 bound to PEA-15 reveals a mechanism for rapid release of activated MAPK.29
127964922003RSK2 activity is regulated by its interaction with PEA-15.26
180774172007ERK MAP kinase is targeted to RSK2 by the phosphoprotein PEA-15.26
160616472005PED mediates AKT-dependent chemoresistance in human breast cancer cells.25
177005182008The PEA-15/PED protein protects glioblastoma cells from glucose deprivation-induced apoptosis via the ERK/MAP kinase pathway.24


Chandra Bartholomeusz ; Jangsoon Lee ; Naoto T Ueno

PEA15 (phosphoprotein enriched in astrocytes 15)

Atlas Genet Cytogenet Oncol Haematol. 2012-05-01

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